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Sadowski M, Thompson M, Mefford J, Haldar T, Oni-Orisan A, Border R, Pazokitoroudi A, Cai N, Ayroles JF, Sankararaman S, Dahl AW, Zaitlen N. Characterizing the genetic architecture of drug response using gene-context interaction methods. CELL GENOMICS 2024; 4:100722. [PMID: 39637863 DOI: 10.1016/j.xgen.2024.100722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 06/24/2024] [Accepted: 11/15/2024] [Indexed: 12/07/2024]
Abstract
Identifying factors that affect treatment response is a central objective of clinical research, yet the role of common genetic variation remains largely unknown. Here, we develop a framework to study the genetic architecture of response to commonly prescribed drugs in large biobanks. We quantify treatment response heritability for statins, metformin, warfarin, and methotrexate in the UK Biobank. We find that genetic variation modifies the primary effect of statins on LDL cholesterol (9% heritable) as well as their side effects on hemoglobin A1c and blood glucose (10% and 11% heritable, respectively). We identify dozens of genes that modify drug response, which we replicate in a retrospective pharmacogenomic study. Finally, we find that polygenic score (PGS) accuracy varies up to 2-fold depending on treatment status, showing that standard PGSs are likely to underperform in clinical contexts.
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Affiliation(s)
- Michal Sadowski
- Bioinformatics Interdepartmental Program, University of California Los Angeles, Los Angeles, CA 90095, USA.
| | - Mike Thompson
- Bioinformatics Interdepartmental Program, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Joel Mefford
- Department of Neurology, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Tanushree Haldar
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94143, USA; Department of Clinical Pharmacy, University of California San Francisco, San Francisco, CA 94143, USA
| | - Akinyemi Oni-Orisan
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94143, USA; Department of Clinical Pharmacy, University of California San Francisco, San Francisco, CA 94143, USA
| | - Richard Border
- Department of Neurology, University of California Los Angeles, Los Angeles, CA 90095, USA; Department of Computer Science, University of California Los Angeles, Los Angeles, CA 90095, USA; Department of Computational Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Ali Pazokitoroudi
- Department of Computer Science, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Na Cai
- Helmholtz Pioneer Campus, Helmholtz Munich, 85764 Neuherberg, Germany; Computational Health Centre, Helmholtz Munich, 85764 Neuherberg, Germany; School of Medicine and Health, Technical University of Munich, 80333 Munich, Germany
| | - Julien F Ayroles
- Department of Ecology and Evolution, Princeton University, Princeton, NJ 08544, USA; Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA
| | - Sriram Sankararaman
- Bioinformatics Interdepartmental Program, University of California Los Angeles, Los Angeles, CA 90095, USA; Department of Computer Science, University of California Los Angeles, Los Angeles, CA 90095, USA; Department of Computational Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Andy W Dahl
- Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL 60637, USA
| | - Noah Zaitlen
- Bioinformatics Interdepartmental Program, University of California Los Angeles, Los Angeles, CA 90095, USA; Department of Neurology, University of California Los Angeles, Los Angeles, CA 90095, USA; Department of Computational Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
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Pierzchlińska A, Sławek J, Kwaśniak-Butowska M, Malinowski D, Komaniecka N, Mak M, Czerkawska A, Kukowka A, Białecka M. Genetic Polymorphisms in the HMGCR Gene and Associations with Cognitive Decline in Parkinson's Disease Patients. Int J Mol Sci 2024; 25:8964. [PMID: 39201649 PMCID: PMC11354436 DOI: 10.3390/ijms25168964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 08/07/2024] [Accepted: 08/14/2024] [Indexed: 09/02/2024] Open
Abstract
Parkinson's disease (PD) is a common neurodegenerative disease characterized by motor and non-motor symptoms including cognitive impairment and dementia. The etiopathogenesis of PD, as well as its protective and susceptibility factors, are still elusive. 3-Hydroxy-3-methyglutaryl coenzyme A reductase (HMGCR) is an enzyme regulating cholesterol synthesis. Single-nucleotide polymorphisms (SNPs) in the gene coding HMGCR have recently been correlated with the risk of Alzheimer's disease. Alternative splicing of exon 13 of the HMGCR transcript and its strongly associated HMGCR haplotype 7 (H7: rs17244841, rs3846662, rs17238540) may downregulate protein activity and cholesterol synthesis, with lower low-density lipoprotein cholesterol (LDL) levels associated with PD that may affect cognitive abilities. We genotyped three SNPs in the H7 HMGCR gene in 306 PD patients divided into three groups-without cognitive decline, with mild cognitive impairment (MCI), and with PD dementia-and in 242 healthy participants. A correlation between the rs17238540 genotype and PD susceptibility as well as a minor association between rs3846662 and cognitive status in PD patients was observed; however, the two-sided analysis of these groups did not reveal any significance. We observed a statistically significant elevated high-density lipoprotein cholesterol (HDL) plasma level in the minor allele carriers of rs17238540 and rs17244841 among PD patients. This study should be replicated in a larger population.
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Affiliation(s)
- Anna Pierzchlińska
- Department of Pharmacokinetics and Therapeutic Drug Monitoring, Pomeranian Medical University, 70-111 Szczecin, Poland; (A.P.); (A.C.); (A.K.); (M.B.)
- Department of Animal Physiology, Institute of Zoology, University of Cologne, 50923 Cologne, Germany
| | - Jarosław Sławek
- Department of Neurological-Psychiatric Nursing, Faculty of Health Sciences, Medical University of Gdańsk, 80-211 Gdańsk, Poland; (J.S.); (M.K.-B.)
- Department of Neurology, St Adalbert Hospital, 61-144 Gdańsk, Poland
| | - Magdalena Kwaśniak-Butowska
- Department of Neurological-Psychiatric Nursing, Faculty of Health Sciences, Medical University of Gdańsk, 80-211 Gdańsk, Poland; (J.S.); (M.K.-B.)
- Department of Neurology, St Adalbert Hospital, 61-144 Gdańsk, Poland
| | - Damian Malinowski
- Department of Pharmacokinetics and Therapeutic Drug Monitoring, Pomeranian Medical University, 70-111 Szczecin, Poland; (A.P.); (A.C.); (A.K.); (M.B.)
| | - Nina Komaniecka
- Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, 70-111 Szczecin, Poland;
| | - Monika Mak
- Department of Health Psychology, Pomeranian Medical University, 70-111 Szczecin, Poland;
| | - Anna Czerkawska
- Department of Pharmacokinetics and Therapeutic Drug Monitoring, Pomeranian Medical University, 70-111 Szczecin, Poland; (A.P.); (A.C.); (A.K.); (M.B.)
| | - Arnold Kukowka
- Department of Pharmacokinetics and Therapeutic Drug Monitoring, Pomeranian Medical University, 70-111 Szczecin, Poland; (A.P.); (A.C.); (A.K.); (M.B.)
| | - Monika Białecka
- Department of Pharmacokinetics and Therapeutic Drug Monitoring, Pomeranian Medical University, 70-111 Szczecin, Poland; (A.P.); (A.C.); (A.K.); (M.B.)
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Theusch E, Ting FY, Qin Y, Stevens K, Naidoo D, King SM, Yang NV, Orr J, Han BY, Cyster JG, Chen YDI, Rotter JI, Krauss RM, Medina MW. Participant-derived cell line transcriptomic analyses and mouse studies reveal a role for ZNF335 in plasma cholesterol statin response. Genome Med 2024; 16:93. [PMID: 39061094 PMCID: PMC11282643 DOI: 10.1186/s13073-024-01366-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 07/18/2024] [Indexed: 07/28/2024] Open
Abstract
BACKGROUND Statins lower circulating low-density lipoprotein cholesterol (LDLC) levels and reduce cardiovascular disease risk. Though highly efficacious in general, there is considerable inter-individual variation in statin efficacy that remains largely unexplained. METHODS To identify novel genes that may modulate statin-induced LDLC lowering, we used RNA-sequencing data from 426 control- and 2 µM simvastatin-treated lymphoblastoid cell lines (LCLs) derived from European and African American ancestry participants of the Cholesterol and Pharmacogenetics (CAP) 40 mg/day 6-week simvastatin clinical trial (ClinicalTrials.gov Identifier: NCT00451828). We correlated statin-induced changes in LCL gene expression with plasma LDLC statin response in the corresponding CAP participants. For the most correlated gene identified (ZNF335), we followed up in vivo by comparing plasma cholesterol levels, lipoprotein profiles, and lipid statin response between wild-type mice and carriers of a hypomorphic (partial loss of function) missense mutation in Zfp335 (the mouse homolog of ZNF335). RESULTS The statin-induced expression changes of 147 human LCL genes were significantly correlated to the plasma LDLC statin responses of the corresponding CAP participants in vivo (FDR = 5%). The two genes with the strongest correlations were zinc finger protein 335 (ZNF335 aka NIF-1, rho = 0.237, FDR-adj p = 0.0085) and CCR4-NOT transcription complex subunit 3 (CNOT3, rho = 0.233, FDR-adj p = 0.0085). Chow-fed mice carrying a hypomorphic missense (R1092W; aka bloto) mutation in Zfp335 had significantly lower non-HDL cholesterol levels than wild-type C57BL/6J mice in a sex combined model (p = 0.04). Furthermore, male (but not female) mice carrying the Zfp335R1092W allele had significantly lower total and HDL cholesterol levels than wild-type mice. In a separate experiment, wild-type mice fed a control diet for 4 weeks and a matched simvastatin diet for an additional 4 weeks had significant statin-induced reductions in non-HDLC (-43 ± 18% and -23 ± 19% for males and females, respectively). Wild-type male (but not female) mice experienced significant reductions in plasma LDL particle concentrations, while male mice carrying Zfp335R1092W allele(s) exhibited a significantly blunted LDL statin response. CONCLUSIONS Our in vitro and in vivo studies identified ZNF335 as a novel modulator of plasma cholesterol levels and statin response, suggesting that variation in ZNF335 activity could contribute to inter-individual differences in statin clinical efficacy.
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Affiliation(s)
- Elizabeth Theusch
- Department of Pediatrics, University of California San Francisco, Oakland, CA, USA.
| | - Flora Y Ting
- Department of Pediatrics, University of California San Francisco, Oakland, CA, USA
| | - Yuanyuan Qin
- Department of Pediatrics, University of California San Francisco, Oakland, CA, USA
| | - Kristen Stevens
- Department of Pediatrics, University of California San Francisco, Oakland, CA, USA
| | - Devesh Naidoo
- Department of Pediatrics, University of California San Francisco, Oakland, CA, USA
| | - Sarah M King
- Department of Pediatrics, University of California San Francisco, Oakland, CA, USA
| | - Neil V Yang
- Department of Pediatrics, University of California San Francisco, Oakland, CA, USA
| | - Joseph Orr
- Department of Pediatrics, University of California San Francisco, Oakland, CA, USA
| | - Brenda Y Han
- Howard Hughes Medical Institute, Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA, USA
| | - Jason G Cyster
- Howard Hughes Medical Institute, Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA, USA
| | - Yii-Der I Chen
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Jerome I Rotter
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Ronald M Krauss
- Department of Pediatrics, University of California San Francisco, Oakland, CA, USA
- Department of Medicine, University of California San Francisco, Oakland, CA, USA
| | - Marisa W Medina
- Department of Pediatrics, University of California San Francisco, Oakland, CA, USA.
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Lusiki Z, Blom D, Soko ND, Malema S, Jones E, Rayner B, Blackburn J, Sinxadi P, Dandara MT, Dandara C. Major Genetic Drivers of Statin Treatment Response in African Populations and Pharmacogenetics of Dyslipidemia Through a One Health Lens. OMICS : A JOURNAL OF INTEGRATIVE BIOLOGY 2024; 28:261-279. [PMID: 37956269 DOI: 10.1089/omi.2023.0122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
A One Health lens is increasingly significant to address the intertwined challenges in planetary health concerned with the health of humans, nonhuman animals, plants, and ecosystems. A One Health approach can benefit the public health systems in Africa that are overburdened by noncommunicable, infectious, and environmental diseases. Notably, the COVID-19 pandemic revealed the previously overlooked two-fold importance of pharmacogenetics (PGx), for individually tailored treatment of noncommunicable diseases and environmental pathogens. For example, dyslipidemia, a common cardiometabolic risk factor, has been identified as an independent COVID-19 severity risk factor. Observational data suggest that patients with COVID-19 infection receiving lipid-lowering therapy may have better outcomes. However, among African patients, the response to these drugs varies from patient to patient, pointing to the possible contribution of genetic variation in important pharmacogenes. The PGx of lipid-lowering therapies may underlie differences in treatment responses observed among dyslipidemia patients as well as patients comorbid with COVID-19 and dyslipidemia. Genetic variations in APOE, ABCB1, CETP, CYP2C9, CYP3A4, CYP3A5, HMGCR, LDLR, NPC1L1, and SLCO1B1 genes affect the pharmacogenomics of statins, and they have individually been linked to differential responses to dyslipidemia and COVID-19 treatment. African populations are underrepresented in PGx research. This leads to poor accounting of additional diverse genetic variants that could be important in understanding interindividual and between-population variations in therapeutic responses to dyslipidemia and COVID-19. This expert review examines and synthesizes the salient and priority PGx variations, as seen through a One Health lens in Africa, to improve and inform personalized medicine in both dyslipidemia and COVID-19.
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Affiliation(s)
- Zizo Lusiki
- Division of Human Genetics, Department of Pathology, Institute of Infectious Diseases and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa
- Platform for Pharmacogenomics Research and Translation (PREMED) Unit, South African Medical Research Council (SAMRC), Cape Town, South Africa
| | - Dirk Blom
- Platform for Pharmacogenomics Research and Translation (PREMED) Unit, South African Medical Research Council (SAMRC), Cape Town, South Africa
- Division of Lipidology and Cape Heart Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Nyarai D Soko
- Division of Human Genetics, Department of Pathology, Institute of Infectious Diseases and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa
- Platform for Pharmacogenomics Research and Translation (PREMED) Unit, South African Medical Research Council (SAMRC), Cape Town, South Africa
| | - Smangele Malema
- Platform for Pharmacogenomics Research and Translation (PREMED) Unit, South African Medical Research Council (SAMRC), Cape Town, South Africa
| | - Erika Jones
- Platform for Pharmacogenomics Research and Translation (PREMED) Unit, South African Medical Research Council (SAMRC), Cape Town, South Africa
- Division of Nephrology and Hypertension, Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Brian Rayner
- Platform for Pharmacogenomics Research and Translation (PREMED) Unit, South African Medical Research Council (SAMRC), Cape Town, South Africa
- Division of Nephrology and Hypertension, Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Jonathan Blackburn
- Division of Chemical and Systems Biology, Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa
| | - Phumla Sinxadi
- Platform for Pharmacogenomics Research and Translation (PREMED) Unit, South African Medical Research Council (SAMRC), Cape Town, South Africa
- Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Michelle T Dandara
- Platform for Pharmacogenomics Research and Translation (PREMED) Unit, South African Medical Research Council (SAMRC), Cape Town, South Africa
| | - Collet Dandara
- Division of Human Genetics, Department of Pathology, Institute of Infectious Diseases and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa
- Platform for Pharmacogenomics Research and Translation (PREMED) Unit, South African Medical Research Council (SAMRC), Cape Town, South Africa
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Jmel H, Sarno S, Giuliani C, Boukhalfa W, Abdelhak S, Luiselli D, Kefi R. Genetic diversity of variants involved in drug response among Tunisian and Italian populations toward personalized medicine. Sci Rep 2024; 14:5842. [PMID: 38462643 PMCID: PMC10925599 DOI: 10.1038/s41598-024-55239-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 02/21/2024] [Indexed: 03/12/2024] Open
Abstract
Adverse drug reactions (ADR) represent a significant contributor to morbidity and mortality, imposing a substantial financial burden. Genetic ancestry plays a crucial role in drug response. The aim of this study is to characterize the genetic variability of selected pharmacogenes involved with ADR in Tunisians and Italians, with a comparative analysis against global populations. A cohort of 135 healthy Tunisians and 737 Italians were genotyped using a SNP array. Variants located in 25 Very Important Pharmacogenes implicated in ADR were extracted from the genotyping data. Distribution analysis of common variants in Tunisian and Italian populations in comparison to 24 publicly available worldwide populations was performed using PLINK and R software. Results from Principle Component and ADMIXTURE analyses showed a high genetic similarity among Mediterranean populations, distinguishing them from Sub-Saharan African and Asian populations. The Fst comparative analysis identified 27 variants exhibiting significant differentiation between the studied populations. Among these variants, four SNPs rs622342, rs3846662, rs7294, rs5215 located in SLC22A1, HMGCR, VKORC1 and KCNJ11 genes respectively, are reported to be associated with ethnic variability in drug responses. In conclusion, correlating the frequencies of genotype risk variants with their associated ADRs would enhance drug outcomes and the implementation of personalized medicine in the studied populations.
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Affiliation(s)
- Haifa Jmel
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis, Tunisia
- University of Tunis El Manar, Tunis, Tunisia
- Genetic Typing DNA Service Pasteur Institute, Institut Pasteur de Tunis, Tunis, Tunisia
| | - Stefania Sarno
- Laboratory of Molecular Anthropology & Centre for Genome Biology, Department of Biological, Geological and Environmental Sciences (BiGeA), University of Bologna, Bologna, Italy
| | - Cristina Giuliani
- Laboratory of Molecular Anthropology & Centre for Genome Biology, Department of Biological, Geological and Environmental Sciences (BiGeA), University of Bologna, Bologna, Italy
| | - Wided Boukhalfa
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis, Tunisia
- University of Tunis El Manar, Tunis, Tunisia
| | - Sonia Abdelhak
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis, Tunisia
- University of Tunis El Manar, Tunis, Tunisia
| | - Donata Luiselli
- Laboratory of Ancient DNA (aDNALab), Department of Cultural Heritage (DBC), University of Bologna, Ravenna, Italy
| | - Rym Kefi
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis, Tunisia.
- University of Tunis El Manar, Tunis, Tunisia.
- Genetic Typing DNA Service Pasteur Institute, Institut Pasteur de Tunis, Tunis, Tunisia.
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Mauriello A, Ascrizzi A, Molinari R, Falco L, Caturano A, D’Andrea A, Russo V. Pharmacogenomics of Cardiovascular Drugs for Atherothrombotic, Thromboembolic and Atherosclerotic Risk. Genes (Basel) 2023; 14:2057. [PMID: 38003001 PMCID: PMC10671139 DOI: 10.3390/genes14112057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 10/25/2023] [Accepted: 11/07/2023] [Indexed: 11/26/2023] Open
Abstract
PURPOSE OF REVIEW Advances in pharmacogenomics have paved the way for personalized medicine. Cardiovascular diseases still represent the leading cause of mortality in the world. The aim of this review is to summarize the background, rationale, and evidence of pharmacogenomics in cardiovascular medicine, in particular, the use of antiplatelet drugs, anticoagulants, and drugs used for the treatment of dyslipidemia. RECENT FINDINGS Randomized clinical trials have supported the role of a genotype-guided approach for antiplatelet therapy in patients with coronary heart disease undergoing percutaneous coronary interventions. Numerous studies demonstrate how the risk of ineffectiveness of new oral anticoagulants and vitamin K anticoagulants is linked to various genetic polymorphisms. Furthermore, there is growing evidence to support the association of some genetic variants and poor adherence to statin therapy, for example, due to the appearance of muscular symptoms. There is evidence for resistance to some drugs for the treatment of dyslipidemia, such as anti-PCSK9. SUMMARY Pharmacogenomics has the potential to improve patient care by providing the right drug to the right patient and could guide the identification of new drug therapies for cardiovascular disease. This is very important in cardiovascular diseases, which have high morbidity and mortality. The improvement in therapy could be reflected in the reduction of healthcare costs and patient mortality.
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Affiliation(s)
- Alfredo Mauriello
- Cardiology Unit, Department of Medical Translational Science, University of Campania “Luigi Campania”—Monaldi Hospital, 80126 Naples, Italy; (A.M.); (A.A.); (R.M.); (L.F.); (A.D.)
| | - Antonia Ascrizzi
- Cardiology Unit, Department of Medical Translational Science, University of Campania “Luigi Campania”—Monaldi Hospital, 80126 Naples, Italy; (A.M.); (A.A.); (R.M.); (L.F.); (A.D.)
| | - Riccardo Molinari
- Cardiology Unit, Department of Medical Translational Science, University of Campania “Luigi Campania”—Monaldi Hospital, 80126 Naples, Italy; (A.M.); (A.A.); (R.M.); (L.F.); (A.D.)
| | - Luigi Falco
- Cardiology Unit, Department of Medical Translational Science, University of Campania “Luigi Campania”—Monaldi Hospital, 80126 Naples, Italy; (A.M.); (A.A.); (R.M.); (L.F.); (A.D.)
| | - Alfredo Caturano
- Department of Experimental Medicine, University of Campania Luigi Vanvitelli, 80100 Naples, Italy;
| | - Antonello D’Andrea
- Cardiology Unit, Department of Medical Translational Science, University of Campania “Luigi Campania”—Monaldi Hospital, 80126 Naples, Italy; (A.M.); (A.A.); (R.M.); (L.F.); (A.D.)
- Unit of Cardiology, “Umberto I” Hospital, Nocera Inferiore, 84014 Salerno, Italy
| | - Vincenzo Russo
- Cardiology Unit, Department of Medical Translational Science, University of Campania “Luigi Campania”—Monaldi Hospital, 80126 Naples, Italy; (A.M.); (A.A.); (R.M.); (L.F.); (A.D.)
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Yang NV, Rogers S, Guerra R, Pagliarini DJ, Theusch E, Krauss RM. TOMM40 and TOMM22 of the Translocase Outer Mitochondrial Membrane Complex rescue statin-impaired mitochondrial dynamics, morphology, and mitophagy in skeletal myotubes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.06.24.546411. [PMID: 37425714 PMCID: PMC10327005 DOI: 10.1101/2023.06.24.546411] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/11/2023]
Abstract
Background Statins are the drugs most commonly used for lowering plasma low-density lipoprotein (LDL) cholesterol levels and reducing cardiovascular disease risk. Although generally well tolerated, statins can induce myopathy, a major cause of non-adherence to treatment. Impaired mitochondrial function has been implicated as a cause of statin-induced myopathy, but the underlying mechanism remains unclear. We have shown that simvastatin downregulates transcription of TOMM40 and TOMM22 , genes that encode major subunits of the translocase of outer mitochondrial membrane (TOM) complex which is responsible for importing nuclear-encoded proteins and maintaining mitochondrial function. We therefore investigated the role of TOMM40 and TOMM22 in mediating statin effects on mitochondrial function, dynamics, and mitophagy. Methods Cellular and biochemical assays and transmission electron microscopy were used to investigate effects of simvastatin and TOMM40 and TOMM22 expression on measures of mitochondrial function and dynamics in C2C12 and primary human skeletal cell myotubes. Results Knockdown of TOMM40 and TOMM22 in skeletal cell myotubes impaired mitochondrial oxidative function, increased production of mitochondrial superoxide, reduced mitochondrial cholesterol and CoQ levels, disrupted mitochondrial dynamics and morphology, and increased mitophagy, with similar effects resulting from simvastatin treatment. Overexpression of TOMM40 and TOMM22 in simvastatin-treated muscle cells rescued statin effects on mitochondrial dynamics, but not on mitochondrial function or cholesterol and CoQ levels. Moreover, overexpression of these genes resulted in an increase in number and density of cellular mitochondria. Conclusion These results confirm that TOMM40 and TOMM22 are central in regulating mitochondrial homeostasis and demonstrate that downregulation of these genes by statin treatment mediates disruption of mitochondrial dynamics, morphology, and mitophagy, effects that may contribute to statin-induced myopathy. GRAPHICAL ABSTRACT
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Li J, Tang X, Xu J, Liu R, Jiang L, Xu L, Tian J, Feng X, Wu Y, Zhang Y, Wang D, Sun K, Xu B, Zhao W, Hui R, Gao R, Song L, Yuan J, Zhao X. HMGCR gene polymorphism is associated with residual cholesterol risk in premature triple-vessel disease patients treated with moderate-intensity statins. BMC Cardiovasc Disord 2023; 23:317. [PMID: 37355634 PMCID: PMC10290797 DOI: 10.1186/s12872-023-03285-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 05/08/2023] [Indexed: 06/26/2023] Open
Abstract
BACKGROUND To investigate the association of HMGCR and NPC1L1 gene polymorphisms with residual cholesterol risk (RCR) in patients with premature triple-vessel disease (PTVD). METHODS Three SNPs within HMGCR including rs12916, rs2303151, and rs4629571, and four SNPs within NPC1L1 including rs11763759, rs4720470, rs2072183, and rs2073547 were genotyped. RCR was defined as achieved low-density lipoprotein cholesterol (LDL-C) concentrations after statins higher than 1.8 mmol/L (70 mg/dL). RESULTS Finally, a total of 609 PTVD patients treated with moderate-intensity statins were included who were divided into two groups: non-RCR group (n = 88) and RCR group (n = 521) according to LDL-C concentrations. Multivariate logistic regression showed the homozygotes for the minor allele of rs12916 within HMGCR gene (CC) were associated with a 2.08 times higher risk of RCR in recessive model [odds ratio (OR): 2.08, 95% confidence interval (CI): 1.16-3.75]. In codominant model, the individuals homozygous for the minor allele of rs12916 (CC) were associated with a 2.26 times higher risk of RCR (OR: 2.26, 95% CI: 1.16-4.43) while the heterozygous individuals (CT) were not, compared with the individuals homozygous for the major allele of rs12916 (TT). There was no significant association between the SNPs within NPC1L1 gene and RCR in various models. CONCLUSIONS We first reported that the variant homozygous CC of rs12916 within HMGCR gene may incur a significantly higher risk of RCR in PTVD patients treated with statins, providing new insights into early individualized guidance of precise lipid-lowering treatment.
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Affiliation(s)
- Jiawen Li
- National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 167 Beilishi Road, Xicheng District, Beijing, 100037, China
| | - Xiaofang Tang
- National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 167 Beilishi Road, Xicheng District, Beijing, 100037, China
| | - Jingjing Xu
- National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 167 Beilishi Road, Xicheng District, Beijing, 100037, China
| | - Ru Liu
- National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 167 Beilishi Road, Xicheng District, Beijing, 100037, China
| | - Lin Jiang
- National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 167 Beilishi Road, Xicheng District, Beijing, 100037, China
| | - Lianjun Xu
- National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 167 Beilishi Road, Xicheng District, Beijing, 100037, China
| | - Jian Tian
- National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 167 Beilishi Road, Xicheng District, Beijing, 100037, China
| | - Xinxing Feng
- National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 167 Beilishi Road, Xicheng District, Beijing, 100037, China
| | - Yajie Wu
- National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 167 Beilishi Road, Xicheng District, Beijing, 100037, China
| | - Yin Zhang
- National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 167 Beilishi Road, Xicheng District, Beijing, 100037, China
| | - Dong Wang
- National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 167 Beilishi Road, Xicheng District, Beijing, 100037, China
| | - Kai Sun
- National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 167 Beilishi Road, Xicheng District, Beijing, 100037, China
| | - Bo Xu
- National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 167 Beilishi Road, Xicheng District, Beijing, 100037, China
| | - Wei Zhao
- National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 167 Beilishi Road, Xicheng District, Beijing, 100037, China
| | - Rutai Hui
- National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 167 Beilishi Road, Xicheng District, Beijing, 100037, China
| | - Runlin Gao
- National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 167 Beilishi Road, Xicheng District, Beijing, 100037, China
| | - Lei Song
- National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 167 Beilishi Road, Xicheng District, Beijing, 100037, China.
| | - Jinqing Yuan
- National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 167 Beilishi Road, Xicheng District, Beijing, 100037, China.
| | - Xueyan Zhao
- National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 167 Beilishi Road, Xicheng District, Beijing, 100037, China.
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9
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Theusch E, Ting FY, Qin Y, Stevens K, Naidoo D, King SM, Yang N, Orr J, Han BY, Cyster JG, Chen YDI, Rotter JI, Krauss RM, Medina MW. Participant-derived cell line transcriptomic analyses and mouse studies reveal a role for ZNF335 in plasma cholesterol statin response. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.06.14.544860. [PMID: 37397985 PMCID: PMC10312755 DOI: 10.1101/2023.06.14.544860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
Background Statins lower circulating low-density lipoprotein cholesterol (LDLC) levels and reduce cardiovascular disease risk. Though highly efficacious in general, there is considerable inter-individual variation in statin efficacy that remains largely unexplained. Methods To identify novel genes that may modulate statin-induced LDLC lowering, we used RNA-sequencing data from 426 control- and 2 μM simvastatin-treated lymphoblastoid cell lines (LCLs) derived from European and African American ancestry participants of the Cholesterol and Pharmacogenetics (CAP) 40 mg/day 6-week simvastatin clinical trial (ClinicalTrials.gov Identifier: NCT00451828). We correlated statin-induced changes in LCL gene expression with plasma LDLC statin response in the corresponding CAP participants. For the most correlated gene identified (ZNF335), we followed up in vivo by comparing plasma cholesterol levels, lipoprotein profiles, and lipid statin response between wild-type mice and carriers of a hypomorphic (partial loss of function) missense mutation in Zfp335 (the mouse homolog of ZNF335). Results The statin-induced expression changes of 147 human LCL genes were significantly correlated to the plasma LDLC statin responses of the corresponding CAP participants in vivo (FDR=5%). The two genes with the strongest correlations were zinc finger protein 335 (ZNF335 aka NIF-1, rho=0.237, FDR-adj p=0.0085) and CCR4-NOT transcription complex subunit 3 (CNOT3, rho=0.233, FDR-adj p=0.0085). Chow-fed mice carrying a hypomorphic missense (R1092W; aka bloto) mutation in Zfp335 had significantly lower non-HDL cholesterol levels than wild type C57BL/6J mice in a sex combined model (p=0.04). Furthermore, male (but not female) mice carrying the Zfp335R1092W allele had significantly lower total and HDL cholesterol levels than wild-type mice. In a separate experiment, wild-type mice fed a control diet for 4 weeks and a matched simvastatin diet for an additional 4 weeks had significant statin-induced reductions in non-HDLC (-43±18% and -23±19% for males and females, respectively). Wild-type male (but not female) mice experienced significant reductions in plasma LDL particle concentrations, while male mice carrying Zfp335R1092W allele(s) exhibited a significantly blunted LDL statin response. Conclusions Our in vitro and in vivo studies identified ZNF335 as a novel modulator of plasma cholesterol levels and statin response, suggesting that variation in ZNF335 activity could contribute to inter-individual differences in statin clinical efficacy.
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Affiliation(s)
- Elizabeth Theusch
- Department of Pediatrics, University of California San Francisco, Oakland, CA USA
| | - Flora Y. Ting
- Department of Pediatrics, University of California San Francisco, Oakland, CA USA
| | - Yuanyuan Qin
- Department of Pediatrics, University of California San Francisco, Oakland, CA USA
| | - Kristen Stevens
- Department of Pediatrics, University of California San Francisco, Oakland, CA USA
| | - Devesh Naidoo
- Department of Pediatrics, University of California San Francisco, Oakland, CA USA
| | - Sarah M. King
- Department of Pediatrics, University of California San Francisco, Oakland, CA USA
| | - Neil Yang
- Department of Pediatrics, University of California San Francisco, Oakland, CA USA
| | - Joseph Orr
- Department of Pediatrics, University of California San Francisco, Oakland, CA USA
| | - Brenda Y. Han
- Howard Hughes Medical Institute, Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA USA
| | - Jason G. Cyster
- Howard Hughes Medical Institute, Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA USA
| | - Yii-Der I. Chen
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA USA
| | - Jerome I. Rotter
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA USA
| | - Ronald M. Krauss
- Department of Pediatrics, University of California San Francisco, Oakland, CA USA
- Department of Medicine, University of California San Francisco, Oakland, CA USA
| | - Marisa W. Medina
- Department of Pediatrics, University of California San Francisco, Oakland, CA USA
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10
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Shatnawi A, Kamran Z, Al-Share Q. Pharmacogenomics of lipid-lowering agents: the impact on efficacy and safety. Per Med 2022; 20:65-86. [DOI: 10.2217/pme-2022-0041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Hyperlipidemia is a significant risk factor for cardiovascular disease morbidity and mortality. The lipid-lowering drugs are considered the cornerstone of primary and secondary prevention of atherosclerotic cardiovascular disease. Unfortunately, the lack of efficacy and associated adverse effects, ranging from mild-to-moderate to potentially life-threatening, lead to therapy discontinuation. Numerous reports support the role of gene polymorphisms in drugs' pharmacokinetic parameters and their associated adverse reactions. Therefore, this study aims to understand the pharmacogenomics of lipid-lowering drugs and the impact of genetic variants of key genes on the drugs' efficacy and toxicity. Indeed, genetically guided lipid-lowering therapy enhances overall safety, improves drug adherence and achieves long-term therapy.
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Affiliation(s)
- Aymen Shatnawi
- Department of Drug Discovery & Biomedical Sciences, College of Pharmacy, Medical University of South Carolina, 70 President St., Room 402, Charleston, SC 29425, USA
| | - Zourayz Kamran
- Department of Pharmaceutical & Administrative Sciences, University of Charleston School of Pharmacy, 2300 MacCorkle Ave SE, Charleston, WV 25304, USA
| | - Qusai Al-Share
- Department of Clinical Pharmacy, Assistant Professor of Pharmacology & Therapeutics, Faculty of Pharmacy, Jordan University of Science & Technology, P.O. Box 3030, Irbid, 22110, Jordan
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11
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Xiao P, Goodarzi P, Pezeshki A, Hagen DE. RNA-seq reveals insights into molecular mechanisms of metabolic restoration via tryptophan supplementation in low birth weight piglet model. J Anim Sci 2022; 100:skac156. [PMID: 35552417 PMCID: PMC9155244 DOI: 10.1093/jas/skac156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 04/26/2022] [Indexed: 11/23/2022] Open
Abstract
Low birth weight (LBW) is associated with metabolic disorders in early life. While dietary l-tryptophan (Trp) can ameliorate postprandial plasma triglycerides (TG) disposal in LBW piglets, the genetic and biological basis underlying Trp-caused alterations in lipid metabolism is poorly understood. In this study, we collected 24 liver samples from 1-mo-old LBW and normal birth weight (NBW) piglets supplemented with different concentrations of dietary Trp (NBW with 0% Trp, N0; LBW with 0% Trp, L0; LBW with 0.4% Trp, L4; LBW with 0.8% Trp, L8; N = 6 in each group.) and conducted systematic, transcriptome-wide analysis using RNA sequencing (RNA-seq). We identified 39 differentially expressed genes (DEG) between N0 and L0, and genes within "increased dose effect" clusters based on dose-series expression profile analysis, enriched in fatty acid response of gene ontology (GO) biological process (BP). We then identified RNA-binding proteins including SRSF1, DAZAP1, PUM2, PCBP3, IGF2BP2, and IGF2BP3 significantly (P < 0.05) enriched in alternative splicing events (ASE) in comparison with L0 as control. There were significant positive and negative relationships between candidate genes from co-expression networks (including PID1, ANKRD44, RUSC1, and CYP2J34) and postprandial plasma TG concentration. Further, we determined whether these candidate hub genes were also significantly associated with metabolic and cardiovascular traits in humans via human phenome-wide association study (Phe-WAS), and analysis of mammalian orthologs suggests a functional conservation between human and pig. Our work demonstrates that transcriptomic changes during dietary Trp supplementation in LBW piglets. We detected candidate genes and related BP that may play roles on lipid metabolism restoration. These findings will help to better understand the amino acid support in LBW metabolic complications.
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Affiliation(s)
- Ping Xiao
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK 74078, USA
| | - Parniyan Goodarzi
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK 74078, USA
| | - Adel Pezeshki
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK 74078, USA
| | - Darren E Hagen
- Department of Animal and Food Sciences, Oklahoma State University, Stillwater, OK 74078, USA
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12
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Pierzchlińska A, Droździk M, Białecka M. A Possible Role for HMG-CoA Reductase Inhibitors and Its Association with HMGCR Genetic Variation in Parkinson's Disease. Int J Mol Sci 2021; 22:12198. [PMID: 34830081 PMCID: PMC8620375 DOI: 10.3390/ijms222212198] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 11/03/2021] [Accepted: 11/08/2021] [Indexed: 12/22/2022] Open
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disease characterised by both motor- and non-motor symptoms, including cognitive impairment. The aetiopathogenesis of PD, as well as its protective and susceptibility factors, are still elusive. Neuroprotective effects of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors-statins-via both cholesterol-dependent and independent mechanisms have been shown in animal and cell culture models. However, the available data provide conflicting results on the role of statin treatment in PD patients. Moreover, cholesterol is a vital component for brain functions and may be considered as protective against PD. We present possible statin effects on PD under the hypothesis that they may depend on the HMG-CoA reductase gene (HMGCR) variability, such as haplotype 7, which was shown to affect cholesterol synthesis and statin treatment outcome, diminishing possible neuroprotection associated with HMG-CoA reductase inhibitors administration. Statins are among the most prescribed groups of drugs. Thus, it seems important to review the available data in the context of their possible neuroprotective effects in PD, and the HMG-CoA reductase gene's genetic variability.
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Affiliation(s)
- Anna Pierzchlińska
- Department of Pharmacokinetics and Therapeutic Drug Monitoring, Pomeranian Medical University, 70-111 Szczecin, Poland; (A.P.); (M.B.)
| | - Marek Droździk
- Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, 70-111 Szczecin, Poland
| | - Monika Białecka
- Department of Pharmacokinetics and Therapeutic Drug Monitoring, Pomeranian Medical University, 70-111 Szczecin, Poland; (A.P.); (M.B.)
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13
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Alternative Splicing in Cardiovascular Disease-A Survey of Recent Findings. Genes (Basel) 2021; 12:genes12091457. [PMID: 34573439 PMCID: PMC8469243 DOI: 10.3390/genes12091457] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 09/11/2021] [Accepted: 09/16/2021] [Indexed: 12/22/2022] Open
Abstract
Alternative splicing, a driver of posttranscriptional variance, differs from canonical splicing by arranging the introns and exons of an immature pre-mRNA transcript in a multitude of different ways. Although alternative splicing was discovered almost half a century ago, estimates of the proportion of genes that undergo alternative splicing have risen drastically over the last two decades. Deep sequencing methods and novel bioinformatic algorithms have led to new insights into the prevalence of spliced variants, tissue-specific splicing patterns and the significance of alternative splicing in development and disease. Thus far, the role of alternative splicing has been uncovered in areas ranging from heart development, the response to myocardial infarction to cardiac structural disease. Circular RNAs, a product of alternative back-splicing, were initially discovered in 1976, but landmark publications have only recently identified their regulatory role, tissue-specific expression, and transcriptomic abundance, spurring a renewed interest in the topic. The aim of this review is to provide a brief insight into some of the available findings on the role of alternative splicing in cardiovascular disease, with a focus on atherosclerosis, myocardial infarction, heart failure, dilated cardiomyopathy and circular RNAs in myocardial infarction.
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14
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Gebremichael LG, Suppiah V, Wiese MD, Mackenzie L, Phillips C, Williams DB, Roberts MS. Efficacy and safety of statins in ethnic differences: a lesson for application in Indigenous Australian patient care. Pharmacogenomics 2021; 22:553-571. [PMID: 34120458 DOI: 10.2217/pgs-2020-0152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 03/29/2021] [Indexed: 11/21/2022] Open
Abstract
Although statins are effective in treating high cholesterol, adverse effects do occur with their use. Efficacy and tolerability vary among statins in different ethnic groups. Indigenous Australians have a high risk for cardiovascular and kidney diseases. Prescribing statins to Indigenous Australians with multi-morbidity requires different strategies to increase efficacy and reduce their toxicity. Previous studies have reported that Indigenous Australians are more susceptible to severe statin-induced myopathies. However, there is a lack of evidence in the underlying genetic factors in this population. This review aims to identify: inter-ethnic differences in the efficacy and safety of statins; major contributing factors accounting for any identified differences; and provide an overview of statin-induced adverse effects in Indigenous Australians.
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Affiliation(s)
- Lemlem G Gebremichael
- UniSA Clinical & Health Science, University of South Australia, Adelaide, SA 5000, Australia
| | - Vijayaprakash Suppiah
- UniSA Clinical & Health Science, University of South Australia, Adelaide, SA 5000, Australia
- Australian Centre for Precision Health, University of South Australia, Adelaide, SA 5000, Australia
| | - Michael D Wiese
- UniSA Clinical & Health Science, University of South Australia, Adelaide, SA 5000, Australia
| | - Lorraine Mackenzie
- UniSA Clinical & Health Science, University of South Australia, Adelaide, SA 5000, Australia
| | - Craig Phillips
- UniSA Clinical & Health Science, University of South Australia, Adelaide, SA 5000, Australia
| | - Desmond B Williams
- UniSA Clinical & Health Science, University of South Australia, Adelaide, SA 5000, Australia
| | - Michael S Roberts
- UniSA Clinical & Health Science, University of South Australia, Adelaide, SA 5000, Australia
- Therapeutics Research Centre, Diamantina Institute, The University of Queensland, Translational Research Institute, Woolloongabba, QLD 4102, Australia
- Basil Hetzel Institute for Translational Medical Research, The Queen Elizabeth Hospital, 28 Woodville Rd, Woodville, SA 5011, Australia
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15
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Fenech EJ, Ben-Dor S, Schuldiner M. Double the Fun, Double the Trouble: Paralogs and Homologs Functioning in the Endoplasmic Reticulum. Annu Rev Biochem 2021; 89:637-666. [PMID: 32569522 DOI: 10.1146/annurev-biochem-011520-104831] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The evolution of eukaryotic genomes has been propelled by a series of gene duplication events, leading to an expansion in new functions and pathways. While duplicate genes may retain some functional redundancy, it is clear that to survive selection they cannot simply serve as a backup but rather must acquire distinct functions required for cellular processes to work accurately and efficiently. Understanding these differences and characterizing gene-specific functions is complex. Here we explore different gene pairs and families within the context of the endoplasmic reticulum (ER), the main cellular hub of lipid biosynthesis and the entry site for the secretory pathway. Focusing on each of the ER functions, we highlight specificities of related proteins and the capabilities conferred to cells through their conservation. More generally, these examples suggest why related genes have been maintained by evolutionary forces and provide a conceptual framework to experimentally determine why they have survived selection.
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Affiliation(s)
- Emma J Fenech
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel;
| | - Shifra Ben-Dor
- Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Maya Schuldiner
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel;
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16
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Green AJ, Anchang B, Akhtari FS, Reif DM, Motsinger-Reif A. Extending the lymphoblastoid cell line model for drug combination pharmacogenomics. Pharmacogenomics 2021; 22:543-551. [PMID: 34044623 DOI: 10.2217/pgs-2020-0160] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Combination drug therapies have become an integral part of precision oncology, and while evidence of clinical effectiveness continues to grow, the underlying mechanisms supporting synergy are poorly understood. Immortalized human lymphoblastoid cell lines (LCLs) have been proven as a particularly useful, scalable and low-cost model in pharmacogenetics research, and are suitable for elucidating the molecular mechanisms of synergistic combination therapies. In this review, we cover the advantages of LCLs in synergy pharmacogenomics and consider recent studies providing initial evidence of the utility of LCLs in synergy research. We also discuss several opportunities for LCL-based systems to address gaps in the research through the expansion of testing regimens, assessment of new drug classes and higher-order combinations, and utilization of integrated omics technologies.
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Affiliation(s)
- Adrian J Green
- Department of Biological Sciences & the Bioinformatics Research Center, NC State University, Raleigh, NC, USA
| | - Benedict Anchang
- Biostatistics & Computational Biology Branch, National Institute of Environmental Health Sciences, Durham, NC, USA
| | - Farida S Akhtari
- Biostatistics & Computational Biology Branch, National Institute of Environmental Health Sciences, Durham, NC, USA
| | - David M Reif
- Department of Biological Sciences & the Bioinformatics Research Center, NC State University, Raleigh, NC, USA
| | - Alison Motsinger-Reif
- Biostatistics & Computational Biology Branch, National Institute of Environmental Health Sciences, Durham, NC, USA
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17
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Kuang YL, Theusch E, M Krauss R, W Medina M. Identifying genetic modulators of statin response using subject-derived lymphoblastoid cell lines. Pharmacogenomics 2021; 22:413-421. [PMID: 33858191 DOI: 10.2217/pgs-2020-0197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Although statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) have proven effective in reducing plasma low-density lipoprotein levels and risk of cardiovascular disease, their lipid lowering efficacy is highly variable among individuals. Furthermore, statin treatment carries a small but significant risk of adverse effects, most notably myopathy and new onset diabetes. Hence, identification of biomarkers for predicting patients who would most likely benefit from statin treatment without incurring increased risk of adverse effects can have a significant public health impact. In this review, we discuss the rationale for the use of subject-derived lymphoblastoid cell lines in studies of statin pharmacogenomics and describe a variety of approaches we have employed to identify novel genetic markers associated with interindividual variation in statin response.
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Affiliation(s)
- Yu-Lin Kuang
- Department of Pediatrics, University of California San Francisco, Oakland, CA, USA
| | - Elizabeth Theusch
- Department of Pediatrics, University of California San Francisco, Oakland, CA, USA
| | - Ronald M Krauss
- Departments of Pediatrics and Medicine, University of California San Francisco, Oakland, CA, USA
| | - Marisa W Medina
- Department of Pediatrics, University of California San Francisco, Oakland, CA, USA
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18
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Theusch E, Chen YDI, Rotter JI, Krauss RM, Medina MW. Genetic variants modulate gene expression statin response in human lymphoblastoid cell lines. BMC Genomics 2020; 21:555. [PMID: 32787775 PMCID: PMC7430882 DOI: 10.1186/s12864-020-06966-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Accepted: 08/03/2020] [Indexed: 01/10/2023] Open
Abstract
Background Statins are widely prescribed to lower plasma low-density lipoprotein cholesterol levels. Though statins reduce cardiovascular disease risk overall, statin efficacy varies, and some people experience adverse side effects while on statin treatment. Statins also have pleiotropic effects not directly related to their cholesterol-lowering properties, but the mechanisms are not well understood. To identify potential genetic modulators of clinical statin response, we looked for genetic variants associated with statin-induced changes in gene expression (differential eQTLs or deQTLs) in lymphoblastoid cell lines (LCLs) derived from participants of the Cholesterol and Pharmacogenetics (CAP) 40 mg/day 6-week simvastatin clinical trial. We exposed CAP LCLs to 2 μM simvastatin or control buffer for 24 h and performed polyA-selected, strand-specific RNA-seq. Statin-induced changes in gene expression from 259 European ancestry or 153 African American ancestry LCLs were adjusted for potential confounders prior to association with genotyped and imputed genetic variants within 1 Mb of each gene’s transcription start site. Results From the deQTL meta-analysis of the two ancestral populations, we identified significant cis-deQTLs for 15 genes (TBC1D4, MDGA1, CHI3L2, OAS1, GATM, ASNSD1, GLUL, TDRD12, PPIP5K2, OAS3, SERPINB1, ANKDD1A, DTD1, CYFIP2, and GSDME), eight of which were significant in at least one of the ancestry subsets alone. We also conducted eQTL analyses of the endogenous (control-treated), statin-treated, and average of endogenous and statin-treated LCL gene expression levels. We identified eQTLs for approximately 6000 genes in each of the three (endogenous, statin-treated, and average) eQTL meta-analyses, with smaller numbers identified in the ancestral subsets alone. Conclusions Several of the genes in which we identified deQTLs have functions in human health and disease, such as defense from viruses, glucose regulation, and response to chemotherapy drugs. This suggests that DNA variation may play a role in statin effects on various health outcomes. These findings could prove useful to future studies aiming to assess benefit versus risk of statin treatment using individual genetic profiles.
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Affiliation(s)
- Elizabeth Theusch
- Department of Pediatrics, University of California San Francisco, Oakland, CA, USA
| | - Yii-Der I Chen
- Department of Pediatrics, The Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Jerome I Rotter
- Departments of Pediatrics and Medicine, The Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Ronald M Krauss
- Departments of Pediatrics and Medicine, University of California San Francisco, Oakland, CA, USA
| | - Marisa W Medina
- Department of Pediatrics, University of California San Francisco, Oakland, CA, USA.
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20
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Tragante V, Hemerich D, Alshabeeb M, Brænne I, Lempiäinen H, Patel RS, den Ruijter HM, Barnes MR, Moore JH, Schunkert H, Erdmann J, Asselbergs FW. Druggability of Coronary Artery Disease Risk Loci. CIRCULATION-GENOMIC AND PRECISION MEDICINE 2019; 11:e001977. [PMID: 30354342 DOI: 10.1161/circgen.117.001977] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND Genome-wide association studies have identified multiple loci associated with coronary artery disease and myocardial infarction, but only a few of these loci are current targets for on-market medications. To identify drugs suitable for repurposing and their targets, we created 2 unique pipelines integrating public data on 49 coronary artery disease/myocardial infarction-genome-wide association studies loci, drug-gene interactions, side effects, and chemical interactions. METHODS We first used publicly available genome-wide association studies results on all phenotypes to predict relevant side effects, identified drug-gene interactions, and prioritized candidates for repurposing among existing drugs. Second, we prioritized gene product targets by calculating a druggability score to estimate how accessible pockets of coronary artery disease/myocardial infarction-associated gene products are, then used again the genome-wide association studies results to predict side effects, excluded loci with widespread cross-tissue expression to avoid housekeeping and genes involved in vital processes and accordingly ranked the remaining gene products. RESULTS These pipelines ultimately led to 3 suggestions for drug repurposing: pentolinium, adenosine triphosphate, and riociguat (to target CHRNB4, ACSS2, and GUCY1A3, respectively); and 3 proteins for drug development: LMOD1 (leiomodin 1), HIP1 (huntingtin-interacting protein 1), and PPP2R3A (protein phosphatase 2, regulatory subunit b-double prime, α). Most current therapies for coronary artery disease/myocardial infarction treatment were also rediscovered. CONCLUSIONS Integration of genomic and pharmacological data may prove beneficial for drug repurposing and development, as evidence from our pipelines suggests.
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Affiliation(s)
- Vinicius Tragante
- Division of Heart and Lungs, Department of Cardiology (V.T., D.H., F.W.A.)
| | - Daiane Hemerich
- Division of Heart and Lungs, Department of Cardiology (V.T., D.H., F.W.A.).,University Medical Center Utrecht, Utrecht University, The Netherlands. CAPES Foundation, Ministry of Education of Brazil, Brasília (D.H.)
| | - Mohammad Alshabeeb
- Developmental Medicine Department, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Kingdom of Saudi Arabia (M.A.)
| | - Ingrid Brænne
- Institute for Cardiogenetics, University of Lübeck, Germany (I.B., J.E.)
| | | | - Riyaz S Patel
- Institute of Cardiovascular Science, University College London, United Kingdom (R.P., F.W.A.). Bart's Heart Centre, St Bartholomew's Hospital, London, United Kingdom (R.P.).,William Harvey Research Institute, Centre for Translational Bioinformatics, Barts and The London School of Medicine and Dentistry, Charterhouse Square, United Kingdom (M.R.B.)
| | | | - Michael R Barnes
- William Harvey Research Institute, Centre for Translational Bioinformatics, Barts and The London School of Medicine and Dentistry, Charterhouse Square, United Kingdom (M.R.B.)
| | - Jason H Moore
- Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia (J.H.M.)
| | - Heribert Schunkert
- Deutsches Herzzentrum München, Technische Universität München, Germany (H.S.).,DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Germany (H.S.)
| | - Jeanette Erdmann
- Institute for Cardiogenetics, University of Lübeck, Germany (I.B., J.E.).,DZHK (German Research Center for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Munich, Germany (J.E.).,University Heart Center Lübeck, Germany (J.E.)
| | - Folkert W Asselbergs
- Division of Heart and Lungs, Department of Cardiology (V.T., D.H., F.W.A.).,Institute of Cardiovascular Science, University College London, United Kingdom (R.P., F.W.A.). Bart's Heart Centre, St Bartholomew's Hospital, London, United Kingdom (R.P.).,Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht (F.W.A.).,Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, United Kingdom (F.W.A.)
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21
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Abstract
The reduction of plasma apolipoprotein B (apoB) containing lipoproteins has long been pursued as the main modifiable risk factor for the development of cardiovascular disease (CVD). This has led to an intense search for strategies aiming at reducing plasma apoB-lipoproteins, culminating in reduction of overall CV risk. Despite 3 decades of progress, CVD remains the leading cause of morbidity and mortality worldwide and, as such, new therapeutic targets are still warranted. Clinical and preclinical research has moved forward from the original concept, under which some lipids must be accumulated and other removed to achieve the ideal condition in disease prevention, into the concept that mechanisms that orchestrate lipid movement between lipoproteins, cells and organelles is equally involved in CVD. As such, this review scrutinizes potentially atherogenic changes in lipid trafficking and assesses the molecular mechanisms behind it. New developments in risk assessment and new targets for the mitigation of residual CVD risk are also addressed.
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Affiliation(s)
- Andrei C Sposito
- Atherosclerosis and Vascular Biology Laboratory (Aterolab), State University of Campinas (Unicamp), São Paulo, Brazil.
| | | | - Joaquim Barreto
- Atherosclerosis and Vascular Biology Laboratory (Aterolab), State University of Campinas (Unicamp), São Paulo, Brazil
| | - Ilaria Zanotti
- Department of Food and Drug, University of Parma, Parma, Italy
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22
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Wright SM, Jensen SL, Cockriel KL, Davis B, Tschanz JT, Munger RG, Corcoran CD, Kauwe JSK. Association study of rs3846662 with Alzheimer's disease in a population-based cohort: the Cache County Study. Neurobiol Aging 2019; 84:242.e1-242.e6. [PMID: 30975575 DOI: 10.1016/j.neurobiolaging.2019.03.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Revised: 03/05/2019] [Accepted: 03/08/2019] [Indexed: 11/28/2022]
Abstract
3-Hydroxy-3-methylglutaryl coenzyme A reductase is associated with monitoring cholesterol levels. The presence of the single-nucleotide polymorphism rs3846662 introduces alternative splicing at exon 13; the exclusion of this exon leads to a reduction in total cholesterol levels. Lower cholesterol levels are linked to a reduction in Alzheimer's disease (AD) risk. The major allele of rs3846662, which encourages the splicing of exon 13, has recently been shown to act as a preventative allele for AD, especially in women. The purpose of our research was to replicate and confirm this finding. Using logistic regressions and survival curves, we found a significant association between AD and rs3846662, with a stronger association in individuals who carry the APOE e4 allele, supporting previously published work. The effect of rs3846662 on women is insignificant in our cohort. We confirmed that rs3846662 is associated with reduced risk for AD without gender differences; however, we failed to detect association between rs3846662 and delayed mild cognitive impairment conversion to AD for either of the APOE e4 allelic groups.
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Affiliation(s)
- Sage M Wright
- Department of Biology, Brigham Young University, Provo, UT, USA
| | | | | | - Brian Davis
- Department of Biology, Brigham Young University, Provo, UT, USA
| | - JoAnn T Tschanz
- Department of Psychology, Utah State University, Logan, UT, USA
| | - Ronald G Munger
- Department of Nutrition, Dietetics, and Food Science, Utah State University, Logan, UT, USA
| | | | - John S K Kauwe
- Department of Biology, Brigham Young University, Provo, UT, USA.
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23
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Ma S, Sun W, Gao L, Liu S. Therapeutic targets of hypercholesterolemia: HMGCR and LDLR. Diabetes Metab Syndr Obes 2019; 12:1543-1553. [PMID: 31686875 PMCID: PMC6709517 DOI: 10.2147/dmso.s219013] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 07/25/2019] [Indexed: 12/14/2022] Open
Abstract
Cholesterol homeostasis is critical and necessary for the body's functions. Hypercholesterolemia can lead to significant clinical problems, such as cardiovascular disease (CVD). 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and low-density lipoprotein cholesterol receptor (LDLR) are major points of control in cholesterol homeostasis. We summarize the regulatory mechanisms of HMGCR and LDLR, which may provide insight for new drug design and development.
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Affiliation(s)
- Shizhan Ma
- Department of Endocrinology and Metabolism, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan250021, People’s Republic of China
- Department of Endocrinology and Metabolism, Shandong Provincial Hospital Affiliated to Shandong University, Jinan250021, People’s Republic of China
| | - Wenxiu Sun
- Department of Pharmacy, Taishan Vocational College of Nursing, Taian271000, People’s Republic of China
| | - Ling Gao
- Department of Endocrinology and Metabolism, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan250021, People’s Republic of China
- Scientific Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan250021, People’s Republic of China
- Scientific Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan250021, People’s Republic of China
- Correspondence: Ling GaoScientific Center, Shandong Provincial Hospital Affiliated to Shandong University, 324 Jing 5 Road, Jinan, Shandong Province250021, People’s Republic of ChinaTel +86 531 6877 6910Email
| | - Shudong Liu
- Department of Endocrinology, Shandong Rongjun General Hospital, Jinan250013, People’s Republic of China
- Shudong LiuDepartment of Endocrinology, Shandong Rongjun General Hospital, 23 Jiefang Road, Jinan, Shandong Province250013, People’s Republic of ChinaTel +86 531 8238 2351Email
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24
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ZNF542P is a pseudogene associated with LDL response to simvastatin treatment. Sci Rep 2018; 8:12443. [PMID: 30127457 PMCID: PMC6102286 DOI: 10.1038/s41598-018-30859-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 08/03/2018] [Indexed: 02/07/2023] Open
Abstract
Statins are the most commonly prescribed cardiovascular disease drug, but their inter-individual efficacy varies considerably. Genetic factors uncovered to date have only explained a small proportion of variation in low-density lipoprotein cholesterol (LDLC) lowering. To identify novel markers and determinants of statin response, we used whole transcriptome sequence data collected from simvastatin and control incubated lymphoblastoid cell lines (LCLs) established from participants of the Cholesterol and Pharmacogenetics (CAP) simvastatin clinical trial. We looked for genes whose statin-induced expression changes were most different between LCLs derived from individuals with high versus low plasma LDLC statin response during the CAP trial. We created a classification model of 82 “signature” gene expression changes that distinguished high versus low LDLC statin response. One of the most differentially changing genes was zinc finger protein 542 pseudogene (ZNF542P), the signature gene with changes most correlated with statin-induced change in cellular cholesterol ester, an in vitro marker of statin response. ZNF542P knock-down in a human hepatoma cell line increased intracellular cholesterol ester levels upon simvastatin treatment. Together, these findings imply a role for ZNF542P in LDLC response to simvastatin and, importantly, highlight the potential significance of noncoding RNAs as a contributing factor to variation in drug response.
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25
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Turner AW, Wong D, Dreisbach CN, Miller CL. GWAS Reveal Targets in Vessel Wall Pathways to Treat Coronary Artery Disease. Front Cardiovasc Med 2018; 5:72. [PMID: 29988570 PMCID: PMC6026658 DOI: 10.3389/fcvm.2018.00072] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Accepted: 05/29/2018] [Indexed: 12/22/2022] Open
Abstract
Coronary artery disease (CAD) is the leading cause of mortality worldwide and poses a considerable public health burden. Recent genome-wide association studies (GWAS) have revealed >100 genetic loci associated with CAD susceptibility in humans. While a number of these loci harbor gene targets of currently approved therapies, such as statins and PCSK9 inhibitors, the majority of the annotated genes at these loci encode for proteins involved in vessel wall function with no known drugs available. Importantly many of the associated genes linked to vascular (smooth muscle, endothelial, and macrophage) cell processes are now organized into distinct functional pathways, e.g., vasodilation, growth factor responses, extracellular matrix and plaque remodeling, and inflammation. In this mini-review, we highlight the most recently identified loci that have predicted roles in the vessel wall and provide genetic context for pre-existing therapies as well as new drug targets informed from GWAS. With the development of new modalities to target these pathways, (e.g., antisense oligonucleotides, CRISPR/Cas9, and RNA interference) as well as the computational frameworks to prioritize or reposition therapeutics, there is great opportunity to close the gap from initial genetic discovery to clinical translation for many patients affected by this common disease.
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Affiliation(s)
- Adam W Turner
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, United States
| | - Doris Wong
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, United States.,Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, United States
| | - Caitlin N Dreisbach
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, United States.,Data Science Institute, University of Virginia, Charlottesville, VA, United States
| | - Clint L Miller
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, United States.,Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, United States.,Data Science Institute, University of Virginia, Charlottesville, VA, United States.,Department of Public Health Sciences, University of Virginia, Charlottesville, VA, United States
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26
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Abstract
Considerable interindividual variability in response to cardiovascular pharmacotherapy exists with drug responses varying from being efficacious to inadequate to induce severe adverse events. Fueled by advancements and multidisciplinary collaboration across disciplines such as genetics, bioinformatics, and basic research, the vision of personalized medicine, rather than a one-size-fits-all approach, may be within reach. Pharmacogenetics offers the potential to optimize the benefit-risk profile of drugs by tailoring diagnostic and treatment strategies according to the individual patient. To date, a multitude of studies has tried to delineate the effects of gene-drug interactions for drugs commonly used to treat cardiovascular-related disease. The focus of this review is on how genetic variability may modify drug responsiveness and patient outcomes following therapy with commonly used cardiovascular drugs including clopidogrel, warfarin, statins, and β-blockers. Also included are examples of how genetic studies can be used to guide drug discovery and examples of how genetic information may be deployed in clinical decision making.
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Affiliation(s)
- Peter E Weeke
- Department of Cardiology, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Denmark.
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27
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Cano-Corres R, Candás-Estébanez B, Padró-Miquel A, Fanlo-Maresma M, Pintó X, Alía-Ramos P. Influence of 6 genetic variants on the efficacy of statins in patients with dyslipidemia. J Clin Lab Anal 2018; 32:e22566. [PMID: 29732606 DOI: 10.1002/jcla.22566] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Accepted: 04/12/2018] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Patients with dyslipidemia are often treated with statins to reduce lipids and hence cardiovascular risk, but treatment response is variable, partly due to genetic factors. METHODS We studied the influence of 6 gene variants (APOE c.526C > T (APOE2), APOE c.388T > C (APOE4), SLCO1B1 c.521T > C, CYP3A4 c.-392G > A, HMGCR c.1564-106A > G, and LPA c.3947 + 467T > C) on statin efficacy assessing 2 indicators: the percent reduction in total cholesterol (TC) and non-HDL cholesterol (non-HDL), as well as the achievement of therapeutic goals. The study was performed in a group of patients (n = 100) without previous pharmacological treatment. Multiple regression models were used to calculate the percentage of explanation in response variability added by every variant to a basal model constructed with significant nongenetic control variables. RESULTS The most influential variant was HMGCR c.1564-106A > G (rs3846662), and carriers showed a significantly lower reduction in TC and non-HDL. This variant is related to an alternative splicing involving exon 13, which is also regulated by lipid concentrations in patients without the variant. Concerning therapeutic goals, HMGCR c.1564-106A > G hindered the achievement of TC targets on patients. CONCLUSIONS The HMGCR c.1564-106A > G variant was associated with less statin efficacy to decrease cholesterol.
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Affiliation(s)
- Ruth Cano-Corres
- Clinical Laboratory, Biochemistry Department, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain
| | - Beatriz Candás-Estébanez
- Clinical Laboratory, Biochemistry and Molecular Genetics, Hospital Universitari de Bellvitge-IDIBELL, Barcelona, Spain
| | - Ariadna Padró-Miquel
- Clinical Laboratory, Biochemistry and Molecular Genetics, Hospital Universitari de Bellvitge-IDIBELL, Barcelona, Spain
| | - Marta Fanlo-Maresma
- Unidad de Lípidos y Riesgo Vascular, Servicio de Medicina Interna, Hospital Universitario de Bellvitge, CiberObn, Idibell, Barcelona, Spain
| | - Xavier Pintó
- Unidad de Lípidos y Riesgo Vascular, Servicio de Medicina Interna, Hospital Universitario de Bellvitge, CiberObn, Idibell, Barcelona, Spain
| | - Pedro Alía-Ramos
- Clinical Laboratory, Biochemistry and Molecular Genetics, Hospital Universitari de Bellvitge-IDIBELL, Barcelona, Spain
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28
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Jmel H, Romdhane L, Ben Halima Y, Hechmi M, Naouali C, Dallali H, Hamdi Y, Shan J, Abid A, Jamoussi H, Trabelsi S, Chouchane L, Luiselli D, Abdelhak S, Kefi R. Pharmacogenetic landscape of Metabolic Syndrome components drug response in Tunisia and comparison with worldwide populations. PLoS One 2018; 13:e0194842. [PMID: 29652911 PMCID: PMC5898725 DOI: 10.1371/journal.pone.0194842] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 03/09/2018] [Indexed: 12/12/2022] Open
Abstract
Genetic variation is an important determinant affecting either drug response or susceptibility to adverse drug reactions. Several studies have highlighted the importance of ethnicity in influencing drug response variability that should be considered during drug development. Our objective is to characterize the genetic variability of some pharmacogenes involved in the response to drugs used for the treatment of Metabolic Syndrome (MetS) in Tunisia and to compare our results to the worldwide populations. A set of 135 Tunisians was genotyped using the Affymetrix Chip 6.0 genotyping array. Variants located in 24 Very Important Pharmacogenes (VIP) involved in MetS drug response were extracted from the genotyping data. Analysis of variant distribution in Tunisian population compared to 20 worldwide populations publicly available was performed using R software packages. Common variants between Tunisians and the 20 investigated populations were extracted from genotyping data. Multidimensional screening showed that Tunisian population is clustered with North African and European populations. The greatest divergence was observed with the African and Asian population. In addition, we performed Inter-ethnic comparison based on the genotype frequencies of five VIP biomarkers. The genotype frequencies of the biomarkers rs3846662, rs1045642, rs7294 and rs12255372 located respectively in HMGCR, ABCB1, VKORC1 and TCF7L2 are similar between Tunisian, Tuscan (TSI) and European (CEU). The genotype frequency of the variant rs776746 located in CYP3A5 gene is similar between Tunisian and African populations and different from CEU and TSI. The present study shows that the genetic make up of the Tunisian population is relatively complex in regard to pharmacogenes and reflects previous historical events. It is important to consider this ethnic difference in drug prescription in order to optimize drug response to avoid serious adverse drug reactions. Taking into account similarities with other neighboring populations, our study has an impact not only on the Tunisian population but also on North African population which are underrepresented in pharmacogenomic studies.
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Affiliation(s)
- Haifa Jmel
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis, Tunisia
- University of Carthage, Tunis, Tunisia
| | - Lilia Romdhane
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis, Tunisia
- University of Carthage, Tunis, Tunisia
| | - Yosra Ben Halima
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis, Tunisia
- University of Tunis El Manar, Tunis, Tunisia
| | - Meriem Hechmi
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis, Tunisia
- University of Carthage, Tunis, Tunisia
| | - Chokri Naouali
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis, Tunisia
- University of Tunis El Manar, Tunis, Tunisia
| | - Hamza Dallali
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis, Tunisia
- University of Carthage, Tunis, Tunisia
| | - Yosr Hamdi
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis, Tunisia
| | - Jingxuan Shan
- Laboratory of Genetic Medicine and Immunology, Weill Cornell Medical College in Qatar, Qatar Foundation, Doha, Qatar
| | - Abdelmajid Abid
- Department of external consultation, National Institute of Nutrition and Food Technology, Tunis, Tunisia
| | - Henda Jamoussi
- Department of external consultation, National Institute of Nutrition and Food Technology, Tunis, Tunisia
| | - Sameh Trabelsi
- Clinical Pharmacology Service, National Pharmacovigilance Center, Tunis, Tunisia
| | - Lotfi Chouchane
- Laboratory of Genetic Medicine and Immunology, Weill Cornell Medical College in Qatar, Qatar Foundation, Doha, Qatar
| | - Donata Luiselli
- Laboratory of Molecular Anthropology, Department of Biological, Geological and Environmental Sciences (BiGeA), University of Bologna, Bologna, Italy
| | - Sonia Abdelhak
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis, Tunisia
- University of Tunis El Manar, Tunis, Tunisia
| | - Rym Kefi
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis, Tunisia
- University of Tunis El Manar, Tunis, Tunisia
- * E-mail: ,
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29
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Seoane IV, Martínez C, García-Vicuña R, Ortiz AM, Juarranz Y, Talayero VC, González-Álvaro I, Gomariz RP, Lamana A. Vasoactive intestinal peptide gene polymorphisms, associated with its serum levels, predict treatment requirements in early rheumatoid arthritis. Sci Rep 2018; 8:2035. [PMID: 29391448 PMCID: PMC5794878 DOI: 10.1038/s41598-018-20400-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Accepted: 01/12/2018] [Indexed: 12/14/2022] Open
Abstract
We previously reported that early arthritis (EA) patients with low vasoactive intestinal peptide (VIP) serum levels demonstrate a worse clinical disease course. In this study, we analysed whether variants in the VIP gene correlated with its serum levels and clinical EA parameters. The VIP gene was sequenced in patients with extremely high/low VIP levels, measured by enzyme immunoassay. Sixteen single nucleotide polymorphisms (SNPs) were differentially distributed between both groups, which were subsequently genotyped in two patients’ sets. We observed that patients with rs688136 CC genotype showed higher VIP levels in both discovery (n = 91; p = 0.033) and validation populations (n = 131; p = 0.007). This effect was attenuated by the presence of minor alleles rs35643203 and rs12201140, which showed a clear trend towards low VIP level association (p = 0.118 and p = 0.049, respectively). Functional studies with miR-205-5p, which has a target site in the 3′ UTR close to rs688136, revealed a miRNA-mediated regulatory mechanism explaining the higher VIP gene expression in homozygous patients. Moreover, patients with an rs688136 CC genotype and no minor alleles of the other polymorphisms required less treatment (p = 0.009). We concluded that the identification of polymorphisms associated with VIP serum levels would complement the clinical assessment of the disease severity in rheumatoid arthritis patients.
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Affiliation(s)
- Iria V Seoane
- Departamento de Biología Celular, Facultad de Biología, Universidad Complutense de Madrid, Madrid, 28040, Spain
| | - Carmen Martínez
- Departamento de Biología Celular, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, 28040, Spain
| | - Rosario García-Vicuña
- Servicio de Reumatología, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria la Princesa, 28006, Madrid, Spain
| | - Ana M Ortiz
- Servicio de Reumatología, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria la Princesa, 28006, Madrid, Spain
| | - Yasmina Juarranz
- Departamento de Biología Celular, Facultad de Biología, Universidad Complutense de Madrid, Madrid, 28040, Spain
| | - Vanessa C Talayero
- Servicio de Reumatología, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria la Princesa, 28006, Madrid, Spain
| | - Isidoro González-Álvaro
- Servicio de Reumatología, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria la Princesa, 28006, Madrid, Spain
| | - Rosa P Gomariz
- Departamento de Biología Celular, Facultad de Biología, Universidad Complutense de Madrid, Madrid, 28040, Spain.
| | - Amalia Lamana
- Servicio de Reumatología, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria la Princesa, 28006, Madrid, Spain
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30
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Cao L, Wang HF, Tan L, Sun FR, Tan MS, Tan CC, Jiang T, Yu JT, Tan L. Effect of HMGCR genetic variation on neuroimaging biomarkers in healthy, mild cognitive impairment and Alzheimer's disease cohorts. Oncotarget 2017; 7:13319-27. [PMID: 26950278 PMCID: PMC4924644 DOI: 10.18632/oncotarget.7797] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Accepted: 02/11/2016] [Indexed: 12/18/2022] Open
Abstract
Alzheimer's disease (AD) has become a considerable public health issue. The mechanisms underlying AD onset and progression remain largely unclear. 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is a strong functional AD candidate gene because it encodes part of the statin-binding domain of the enzyme, which serves as the rate-limiting step in cholesterol synthesis in all mammalian cells. Here, we evaluated the potential role of HMGCR (rs3846662) in AD-related pathology by assessing neuroimaging biomarkers. We enrolled in 812 subjects from the Alzheimer's disease Neuroimaging Initiative dataset. In general, it is possible that HMGCR (rs3846662) could be involved in preventing the atrophy of right entorhinal (P=0.03385) and left hippocampus (P=0.01839) in the follow-up research of two years. What's more, it lowered the drop rate of glucose metabolism in right temporal. We then further validated them in the AD, mild cognitive impairment (MCI), normal control (NC) sub-groups. All the results in the MCI groups confirmed the association. The results of our study indicated that HMGCR (rs3846662) plays a vital role in AD pathology mainly by influencing brain structure and glucose metabolism during AD progression.
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Affiliation(s)
- Lei Cao
- Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Qingdao, China
| | - Hui-Fu Wang
- Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Qingdao, China
| | - Lin Tan
- College of Medicine and Pharmaceutics, Ocean University of China, Qingdao, China
| | - Fu-Rong Sun
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China
| | - Meng-Shan Tan
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China
| | - Chen-Chen Tan
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China
| | - Teng Jiang
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Jin-Tai Yu
- Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Qingdao, China
| | - Lan Tan
- Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Qingdao, China.,College of Medicine and Pharmaceutics, Ocean University of China, Qingdao, China.,Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China
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31
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Chang XL, Tan L, Tan MS, Wang HF, Tan CC, Zhang W, Zheng ZJ, Kong LL, Wang ZX, Jiang T, Yu JT, Tan L. Association of HMGCR polymorphism with late-onset Alzheimer's disease in Han Chinese. Oncotarget 2017; 7:22746-51. [PMID: 27009838 PMCID: PMC5008397 DOI: 10.18632/oncotarget.8176] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Accepted: 02/21/2016] [Indexed: 02/04/2023] Open
Abstract
The 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) acts as a potential genetic modifier for Alzheimer's disease (AD). Previous reports identified that HMGCR rs3846662 polymorphism is associated with biosynthesis of cholesterol in AD pathology. In order to assess the involvement of the HMGCR polymorphism in the risk of late-onset AD (LOAD) in northern Han Chinese, we performed a case–control study of 2334 unrelated subjects (984 cases and 1350 age- and gender-matched controls) to evaluate the genotype and allele distributions of the HMGCR rs3846662 with LOAD. The genotype distribution (GG, AG, AA) of rs3846662 was significantly different between LOAD patients and controls (P = 0.003), but the allele distribution did not reach a significant difference (P = 0.614). After adjusting for age, gender and the APOE ε4 status, the minor A allele of rs3846662 was validated as a protective factor for LOAD in dominant model (OR = 0.796, P = 0.02, 95% CI = 0.657–0.965). Interestingly, we observed rs3846662 polymorphism was only significantly associated with LOAD in APOE ε4 non-carriers (OR = 0.735, P = 0.005, 95% CI = [0.593, 0.912]). In conclusion, our study demonstrates A allele of HMGCR rs3846662 acts as a protective factor for LOAD in northern Han Chinese.
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Affiliation(s)
- Xiao-Long Chang
- Department of Neurology, Qingdao Municipal Hospital, Dalian Medical University, Qingdao, PR China
| | - Lin Tan
- College of Medicine and Pharmaceutics, Ocean University of China, Qingdao, PR China
| | - Meng-Shan Tan
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, PR China
| | - Hui-Fu Wang
- Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Qingdao, PR China
| | - Chen-Chen Tan
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, PR China
| | - Wei Zhang
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, PR China
| | - Zhan-Jie Zheng
- Department of Geriatric, Qingdao Mental Health Center, Qingdao, PR China
| | - Ling-Li Kong
- Department of Geriatric, Qingdao Mental Health Center, Qingdao, PR China
| | - Zi-Xuan Wang
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, PR China
| | - Teng Jiang
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, PR China
| | - Jin-Tai Yu
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, PR China
| | - Lan Tan
- Department of Neurology, Qingdao Municipal Hospital, Dalian Medical University, Qingdao, PR China.,College of Medicine and Pharmaceutics, Ocean University of China, Qingdao, PR China.,Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, PR China
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32
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Jack J, Small GW, Brown CC, Havener TM, McLeod HL, Motsinger-Reif AA, Richards KL. Gene expression and linkage analysis implicate CBLB as a mediator of rituximab resistance. THE PHARMACOGENOMICS JOURNAL 2017; 18:467-473. [PMID: 29205205 DOI: 10.1038/tpj.2017.41] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 05/02/2017] [Accepted: 06/07/2017] [Indexed: 01/29/2023]
Abstract
Elucidating resistance mechanisms for therapeutic monoclonal antibodies (MAbs) is challenging, because they are difficult to study in non-human models. We therefore developed a strategy to genetically map in vitro drug sensitivity, identifying genes that alter responsiveness to rituximab, a therapeutic anti-CD20 MAb that provides significant benefit to patients with B-cell malignancies. We discovered novel loci with genome-wide mapping analyses and functionally validated one of these genes, CBLB, which causes rituximab resistance when knocked down in lymphoma cells. This study demonstrates the utility of genome-wide mapping to discover novel biological mechanisms of potential clinical advantage.
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Affiliation(s)
- J Jack
- Department of Statistics, North Carolina State University, Raleigh, NC, USA.,Bioinformatics Research Center, North Carolina State University, Raleigh, NC, USA
| | - G W Small
- Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - C C Brown
- Q2 Solutions - EA Genomics, A Quintiles Quest Joint Venture, Morrisville, NC, USA
| | - T M Havener
- Center for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, NC, USA
| | - H L McLeod
- DeBartolo Family Personalized Medicine Institute, Moffitt Cancer Center, Tampa, Florida, USA
| | - A A Motsinger-Reif
- Department of Statistics, North Carolina State University, Raleigh, NC, USA.,Bioinformatics Research Center, North Carolina State University, Raleigh, NC, USA
| | - K L Richards
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.,Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY, USA
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33
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Human genetic variation in VAC14 regulates Salmonella invasion and typhoid fever through modulation of cholesterol. Proc Natl Acad Sci U S A 2017; 114:E7746-E7755. [PMID: 28827342 DOI: 10.1073/pnas.1706070114] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Risk, severity, and outcome of infection depend on the interplay of pathogen virulence and host susceptibility. Systematic identification of genetic susceptibility to infection is being undertaken through genome-wide association studies, but how to expeditiously move from genetic differences to functional mechanisms is unclear. Here, we use genetic association of molecular, cellular, and human disease traits and experimental validation to demonstrate that genetic variation affects expression of VAC14, a phosphoinositide-regulating protein, to influence susceptibility to Salmonella enterica serovar Typhi (S Typhi) infection. Decreased VAC14 expression increased plasma membrane cholesterol, facilitating Salmonella docking and invasion. This increased susceptibility at the cellular level manifests as increased susceptibility to typhoid fever in a Vietnamese population. Furthermore, treating zebrafish with a cholesterol-lowering agent, ezetimibe, reduced susceptibility to S Typhi. Thus, coupling multiple genetic association studies with mechanistic dissection revealed how VAC14 regulates Salmonella invasion and typhoid fever susceptibility and may open doors to new prophylactic/therapeutic approaches.
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34
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Theusch E, Kim K, Stevens K, Smith JD, Chen YDI, Rotter JI, Nickerson DA, Medina MW. Statin-induced expression change of INSIG1 in lymphoblastoid cell lines correlates with plasma triglyceride statin response in a sex-specific manner. THE PHARMACOGENOMICS JOURNAL 2017; 17:222-229. [PMID: 26927283 PMCID: PMC5008997 DOI: 10.1038/tpj.2016.12] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Revised: 01/21/2016] [Accepted: 01/27/2016] [Indexed: 02/06/2023]
Abstract
Statins are widely prescribed to lower plasma low-density lipoprotein (LDL) cholesterol levels. They also modestly reduce plasma triglyceride (TG), an independent cardiovascular disease risk factor, in most people. The mechanism and inter-individual variability of TG statin response is poorly understood. We measured statin-induced gene expression changes in lymphoblastoid cell lines derived from 150 participants of a simvastatin clinical trial and identified 23 genes (false discovery rate, FDR=15%) with expression changes correlated with plasma TG response. The correlation of insulin-induced gene 1 (INSIG1) expression changes with TG response (rho=0.32, q=0.11) was driven by men (interaction P=0.0055). rs73161338 was associated with INSIG1 expression changes (P=5.4 × 10-5) and TG response in two statin clinical trials (P=0.0048), predominantly in men. A combined model including INSIG1 expression level and splicing changes accounted for 29.5% of plasma TG statin response variance in men (P=5.6 × 10-6). Our results suggest that INSIG1 variation may contribute to statin-induced changes in plasma TG in a sex-specific manner.
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Affiliation(s)
- E Theusch
- Children’s Hospital Oakland Research Institute, Oakland, CA, USA
| | - K Kim
- Children’s Hospital Oakland Research Institute, Oakland, CA, USA
| | - K Stevens
- Children’s Hospital Oakland Research Institute, Oakland, CA, USA
| | - J D Smith
- Department of Genome Sciences, University of Washington, Seattle, WA, USA
| | - Y -D I Chen
- Departments of Pediatrics and Medicine, Los Angeles Biomedical Research Institute at Harbor–UCLA, Torrance, CA, USA
| | - J I Rotter
- Departments of Pediatrics and Medicine, Los Angeles Biomedical Research Institute at Harbor–UCLA, Torrance, CA, USA
| | - D A Nickerson
- Department of Genome Sciences, University of Washington, Seattle, WA, USA
| | - M W Medina
- Children’s Hospital Oakland Research Institute, Oakland, CA, USA
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Holic N, Frin S, Seye AK, Galy A, Fenard D. Improvement of De Novo Cholesterol Biosynthesis Efficiently Promotes the Production of Human Immunodeficiency Virus Type 1-Derived Lentiviral Vectors. Hum Gene Ther Methods 2016; 28:67-77. [PMID: 28042946 DOI: 10.1089/hgtb.2016.150] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The use of lentiviral vectors (LVs) for gene transfer in research, technological, or clinical applications requires the production of large amounts of vector. Mass production of clinical-grade LVs remains a challenge and limits certain perspectives for therapeutic use. Some improvements in LV production protocols have been possible by acting on multiple steps of the production process. The addition of animal-derived cholesterol to the culture medium of producer cells is known to increase the infectivity of LVs. To avoid the use of this animal-derived product in clinical settings, an alternative approach is to increase de novo the production of cholesterol by overexpressing a crucial cholesterogenic enzyme, namely, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). This project evaluates the impact of such an approach on the production, infectivity, and stability of LVs. We demonstrated that the overexpression of human HMGCR isoform 1 (hHMGCR1) in LV producer cells efficiently increased de novo cholesterol biosynthesis and enhanced by 2- to 3-fold the physical and infectious titers of LVs. We also observed that LVs produced in hHMGCR1-overexpressing cells were comparable in stability to LVs produced under classical conditions and were capable of transducing human CD34+ hematopoietic stem/progenitor cells efficiently. Interestingly, we also showed that LV production in the absence of fetal calf serum (FCS) but under hHMGCR1-overexpressing conditions allowed a viral production yield comparable to that achieved under classical conditions in high FCS content, leading the way to the establishment of new LV production protocols on adherent cells without serum.
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Affiliation(s)
- Nathalie Holic
- 1 Généthon , Evry, France
- 2 INSERM , UMR_S951, Généthon, Evry, France
- 3 Université Evry Val d'Essonne , UMR_S951, Evry, France
| | - Sophie Frin
- 1 Généthon , Evry, France
- 2 INSERM , UMR_S951, Généthon, Evry, France
| | - Ababacar K Seye
- 1 Généthon , Evry, France
- 2 INSERM , UMR_S951, Généthon, Evry, France
| | - Anne Galy
- 1 Généthon , Evry, France
- 2 INSERM , UMR_S951, Généthon, Evry, France
- 3 Université Evry Val d'Essonne , UMR_S951, Evry, France
| | - David Fenard
- 1 Généthon , Evry, France
- 2 INSERM , UMR_S951, Généthon, Evry, France
- 3 Université Evry Val d'Essonne , UMR_S951, Evry, France
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36
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The roles of RNA processing in translating genotype to phenotype. NATURE REVIEWS. MOLECULAR CELL BIOLOGY 2016. [PMID: 27847391 DOI: 10.1038/nrm.2016.139.] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
A goal of human genetics studies is to determine the mechanisms by which genetic variation produces phenotypic differences that affect human health. Efforts in this respect have previously focused on genetic variants that affect mRNA levels by altering epigenetic and transcriptional regulation. Recent studies show that genetic variants that affect RNA processing are at least equally as common as, and are largely independent from, those variants that affect transcription. We highlight the impact of genetic variation on pre-mRNA splicing and polyadenylation, and on the stability, translation and structure of mRNAs as mechanisms that produce phenotypic traits. These results emphasize the importance of including RNA processing signals in analyses to identify functional variants.
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Manning KS, Cooper TA. The roles of RNA processing in translating genotype to phenotype. Nat Rev Mol Cell Biol 2016; 18:102-114. [PMID: 27847391 DOI: 10.1038/nrm.2016.139] [Citation(s) in RCA: 141] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
A goal of human genetics studies is to determine the mechanisms by which genetic variation produces phenotypic differences that affect human health. Efforts in this respect have previously focused on genetic variants that affect mRNA levels by altering epigenetic and transcriptional regulation. Recent studies show that genetic variants that affect RNA processing are at least equally as common as, and are largely independent from, those variants that affect transcription. We highlight the impact of genetic variation on pre-mRNA splicing and polyadenylation, and on the stability, translation and structure of mRNAs as mechanisms that produce phenotypic traits. These results emphasize the importance of including RNA processing signals in analyses to identify functional variants.
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Affiliation(s)
- Kassie S Manning
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.,Integrative Molecular and Biomedical Sciences Program, Baylor College of Medicine, Houston, Texas 77030, USA
| | - Thomas A Cooper
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.,Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.,Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.,Integrative Molecular and Biomedical Sciences Program, Baylor College of Medicine, Houston, Texas 77030, USA
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38
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Leduc V, Bourque L, Poirier J, Dufour R. Role of rs3846662 and HMGCR alternative splicing in statin efficacy and baseline lipid levels in familial hypercholesterolemia. Pharmacogenet Genomics 2016; 26:1-11. [PMID: 26466344 DOI: 10.1097/fpc.0000000000000178] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVES To assess the contribution of the rs3846662 polymorphism of HMGCR on serum lipid levels and statin efficacy, we measured in vivo HMGCR mRNA and lipid levels in French Canadian individuals affected by heterozygous familial hypercholesterolemia due to the deletion of more than 15 kb of the LDLR gene. RESULTS Men and women carrying the AA genotype at rs3846662, and no APOE4 allele, had higher levels of total cholesterol (5.43 vs. 4.58 mmol/l, P<0.05) and LDL-cholesterol (5.20 vs. 4.39 mmol/l, P<0.05) at baseline. However, with regard to statin efficacy, the penetrance of the AA genotype was sex dependent. Indeed, the percentage reduction in LDL-cholesterol upon statin treatment was significantly decreased in women with the AA genotype compared with women without it (38.4 vs. 46.2%, P<0.05), whereas this was not observed in men. Although both men and women bearing the AA genotype showed a higher ratio of full-length HMGCR mRNA/total HMGCR mRNA compared with individuals without it (n=37, P<0.05), overall transcription of HMGCR was decreased and increased in men and women carrying this genotype, respectively (n=37, P<0.01 and P<0.05). Finally, in our familial hypercholesterolemia cohort, HMGCR alternative splicing explained between 22 and 55% of the variance in statin response. CONCLUSION rs3846662 polymorphism and the alternative splicing of HMGCR mRNA significantly impact women's response to statin therapy.
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Affiliation(s)
- Valerie Leduc
- aCentre for Studies in Alzheimer's disease prevention bDouglas Mental Health University Institute, McGill University cDepartment of Nutrition, Clinical Research Institute of Montreal (IRCM), Montreal University, Montreal, Quebec, Canada
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Wagner J, Abdel-Rahman SM. Pediatric Statin Administration: Navigating a Frontier with Limited Data. J Pediatr Pharmacol Ther 2016; 21:380-403. [PMID: 27877092 DOI: 10.5863/1551-6776-21.5.380] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Increasingly, children and adolescents with dyslipidemia qualify for pharmacologic intervention. As they are for adults, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins) are the mainstay of pediatric dyslipidemia treatment when lifestyle modifications have failed. Despite the overall success of these drugs, the magnitude of variability in dose-exposure-response profiles contributes to adverse events and treatment failure. In children, the cause of treatment failures remains unclear. This review describes the updated guidelines for screening and management of pediatric dyslipidemia and statin disposition pathway to assist the provider in recognizing scenarios where alterations in dosage may be warranted to meet patients' specific needs.
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Affiliation(s)
- Jonathan Wagner
- Ward Family Heart Center, Children's Mercy Hospital, Kansas City, Missouri ; Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children's Mercy Hospital, Kansas City, Missouri ; Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri
| | - Susan M Abdel-Rahman
- Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children's Mercy Hospital, Kansas City, Missouri ; Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri
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40
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Kim MJ, Yu CY, Theusch E, Naidoo D, Stevens K, Kuang YL, Schuetz E, Chaudhry AS, Medina MW. SUGP1 is a novel regulator of cholesterol metabolism. Hum Mol Genet 2016; 25:3106-3116. [PMID: 27206982 PMCID: PMC5181593 DOI: 10.1093/hmg/ddw151] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2016] [Revised: 05/05/2016] [Accepted: 05/13/2016] [Indexed: 12/19/2022] Open
Abstract
A large haplotype on chromosome 19p13.11 tagged by rs10401969 in intron 8 of SURP and G patch domain containing 1 (SUGP1) is associated with coronary artery disease (CAD), plasma LDL cholesterol levels, and other energy metabolism phenotypes. Recent studies have suggested that TM6SF2 is the causal gene within the locus, but we postulated that this locus could harbor additional CAD risk genes, including the putative splicing factor SUGP1. Indeed, we found that rs10401969 regulates SUGP1 exon 8 skipping, causing non-sense-mediated mRNA decay. Hepatic Sugp1 overexpression in CD1 male mice increased plasma cholesterol levels 20–50%. In human hepatoma cell lines, SUGP1 knockdown stimulated 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) alternative splicing and decreased HMGCR transcript stability, thus reducing cholesterol synthesis and increasing LDL uptake. Our results strongly support a role for SUGP1 as a novel regulator of cholesterol metabolism and suggest that it contributes to the relationship between rs10401969 and plasma cholesterol.
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Affiliation(s)
- Mee J Kim
- Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA
| | - Chi-Yi Yu
- Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA
| | - Elizabeth Theusch
- Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA
| | - Devesh Naidoo
- Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA
| | - Kristen Stevens
- Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA
| | - Yu-Lin Kuang
- Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA
| | - Erin Schuetz
- Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Amarjit S Chaudhry
- Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Marisa W Medina
- Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA
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Mitchel K, Theusch E, Cubitt C, Dosé AC, Stevens K, Naidoo D, Medina MW. RP1-13D10.2 Is a Novel Modulator of Statin-Induced Changes in Cholesterol. ACTA ACUST UNITED AC 2016; 9:223-30. [PMID: 27071970 DOI: 10.1161/circgenetics.115.001274] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Accepted: 03/30/2016] [Indexed: 12/16/2022]
Abstract
BACKGROUND Numerous genetic contributors to cardiovascular disease risk have been identified through genome-wide association studies; however, identifying the molecular mechanism underlying these associations is not straightforward. The Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial of rosuvastatin users identified a sub-genome-wide association of rs6924995, a single-nucleotide polymorphism ≈10 kb downstream of myosin regulatory light chain interacting protein (MYLIP, aka IDOL and inducible degrader of low-density lipoprotein receptor [LDLR]), with LDL cholesterol statin response. Interestingly, although this signal was initially attributed to MYLIP, rs6924995 lies within RP1-13D10.2, an uncharacterized long noncoding RNA. METHODS AND RESULTS Using simvastatin and sham incubated lymphoblastoid cell lines from participants of the Cholesterol and Pharmacogenetics (CAP) simvastatin clinical trial, we found that statin-induced change in RP1-13D10.2 levels differed between cell lines from the tails of the white and black low-density lipoprotein cholesterol response distributions, whereas no difference in MYLIP was observed. RP1-13D10.2 overexpression in Huh7 and HepG2 increased LDLR transcript levels, increased LDL uptake, and decreased media levels of apolipoprotein B. In addition, we found a trend of slight differences in the effects of RP1-13D10.2 overexpression on LDLR transcript levels between hepatoma cells transfected with the rs6924995 A versus G allele and a suggestion of an association between rs6924995 and RP1-10D13.2 expression levels in the CAP lymphoblastoid cell lines. Finally, RP1-13D10.2 expression levels seem to be sterol regulated, consistent with its potential role as a novel lipid regulator. CONCLUSIONS RP1-13D10.2 is a long noncoding RNA that regulates LDLR and may contribute to low-density lipoprotein cholesterol response to statin treatment. These findings highlight the potential role of noncoding RNAs as determinants of interindividual variation in drug response.
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Affiliation(s)
| | | | - Celia Cubitt
- From the Children's Hospital Oakland Research Institute, CA
| | - Andréa C Dosé
- From the Children's Hospital Oakland Research Institute, CA
| | | | - Devesh Naidoo
- From the Children's Hospital Oakland Research Institute, CA
| | - Marisa W Medina
- From the Children's Hospital Oakland Research Institute, CA.
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Abstract
In this review, we lay out 3 areas currently being evaluated for incorporation of genetic information into clinical practice related to atherosclerosis. The first, familial hypercholesterolemia, is the clearest case for utility of genetic testing in diagnosis and potentially guiding treatment. Already in use for confirmatory testing of familial hypercholesterolemia and for cascade screening of relatives, genetic testing is likely to expand to help establish diagnoses and facilitate research related to most effective therapies, including new agents, such as PCSK9 inhibitors. The second area, adding genetic information to cardiovascular risk prediction for primary prevention, is not currently recommended. Although identification of additional variants may add substantially to prediction in the future, combining known variants has not yet demonstrated sufficient improvement in prediction for incorporation into commonly used risk scores. The third area, pharmacogenetics, has utility for some therapies today. Future utility for pharmacogenetics will wax or wane depending on the nature of available drugs and therapeutic strategies.
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Affiliation(s)
- Nina P. Paynter
- From the Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| | - Paul M Ridker
- From the Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| | - Daniel I. Chasman
- From the Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
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43
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Leduc V, Théroux L, Dea D, Dufour R, Poirier J. Effects of rs3846662 Variants on HMGCR mRNA and Protein Levels and on Markers of Alzheimer's Disease Pathology. J Mol Neurosci 2015; 58:109-19. [PMID: 26541602 DOI: 10.1007/s12031-015-0666-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Accepted: 10/09/2015] [Indexed: 01/23/2023]
Abstract
3-Hydroxy-3-methyglutaryl coenzyme A reductase (HMGCR) is a cholesterol-regulating gene with statin relevance. rs3846662 being involved in regulation of HMGCR alternative splicing, we explored its impact on HMGCR messenger RNA (mRNA) and protein levels in the brain and the associations between those levels and levels of Alzheimer's disease pathological markers. We used brain samples derived from a cohort of 33 non-demented controls and 90 Alzheimer's disease autopsied-confirmed cases. HMGCR mRNA levels were determined in the frontal cortex (n = 114) and cerebellum (n = 110) using Taqman-qPCR, and HMGCR protein levels were determined in the frontal cortex (n = 117) using a commercial enzyme immunoassay. While densities of neurofibrillary tangles and senile plaques were determined in the frontal cortex (n = 74), total tau, phosphorylated Tau, and beta-amyloid 1-42 levels were determined in the frontal cortex (n = 94) and cerebellum (n = 91) using commercial enzyme immunoassays. Despite an increase in full-length HMGCR mRNA ratio in the frontal cortex of women carrying the AA genotype, there were no associations between rs3846662 and HMGCR mRNA or protein levels. An increased Δ13 HMGCR mRNA ratio was associated with increased levels of HMGCR proteins and neurofibrillary tangles in the frontal cortex but with reduced beta-amyloid 1-42 levels in the cerebellum, suggesting a brain cell type- or a disease progression-dependent association.
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Affiliation(s)
- Valerie Leduc
- Centre for Studies on Prevention of Alzheimer's Disease (StoP-AD Centre), Douglas Mental Health University Institute, 6875 Lasalle, Verdun, Quebec, H4H 1R3, Canada.,Institut de Recherches Cliniques de Montréal, Department of Nutrition, Université de Montréal, Montréal, Quebec, Canada
| | - Louise Théroux
- Centre for Studies on Prevention of Alzheimer's Disease (StoP-AD Centre), Douglas Mental Health University Institute, 6875 Lasalle, Verdun, Quebec, H4H 1R3, Canada
| | - Doris Dea
- Centre for Studies on Prevention of Alzheimer's Disease (StoP-AD Centre), Douglas Mental Health University Institute, 6875 Lasalle, Verdun, Quebec, H4H 1R3, Canada
| | - Robert Dufour
- Institut de Recherches Cliniques de Montréal, Department of Nutrition, Université de Montréal, Montréal, Quebec, Canada
| | - Judes Poirier
- Centre for Studies on Prevention of Alzheimer's Disease (StoP-AD Centre), Douglas Mental Health University Institute, 6875 Lasalle, Verdun, Quebec, H4H 1R3, Canada. .,Centre for Studies in the Prevention of Alzheimer's Disease, McGill University, Montréal, Quebec, Canada.
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Leduc V, De Beaumont L, Théroux L, Dea D, Aisen P, Petersen RC, Dufour R, Poirier J. HMGCR is a genetic modifier for risk, age of onset and MCI conversion to Alzheimer's disease in a three cohorts study. Mol Psychiatry 2015; 20:867-73. [PMID: 25023145 PMCID: PMC4318698 DOI: 10.1038/mp.2014.81] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Revised: 05/26/2014] [Accepted: 06/18/2014] [Indexed: 01/03/2023]
Abstract
Several retrospective epidemiological studies report that utilization of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibitors called statins at mid-life can reduce the risk of developing sporadic Alzheimer's disease (AD) by as much as 70%. Conversely, the administration of these inhibitors in clinically diagnosed subjects with AD confers little or no benefits over time. Here, we investigated the association between AD and HMGCR rs3846662, a polymorphism known to be involved in the regulation of HMGCR exon 13 skipping, in a founder population and in two distinct mixed North American populations of converting mild cognitively impaired (MCI) subjects (Alzheimer's disease Cooperative study (ADCS) and Alzheimer's disease Neuroimaging Initiative (ADNI) cohorts). Targeting more specifically women, the G allele negative (G-) AD subjects exhibit delayed age of onset of AD (P=0.017) and significantly reduced risk of AD (OR: 0.521; P=0.0028), matching the effect size reported by the apolipoprotein E type 2 variant. Stratification for APOE4 in a large sample of MCI patients from the ADCS cohort revealed a significant protective effect of G negative carriers on AD conversion 3 years after MCI diagnosis (odds ratio (OR): 0.554; P=0.041). Conversion rate among APOE4 carriers with the HMGCR's G negative allele was markedly reduced (from 76% to 27%) to levels similar to APOE4 non-carriers (27.14%), which strongly indicate protection. Conversion data from the independent ADNI cohort also showed significantly reduced MCI or AD conversion among APOE4 carriers with the protective A allele (P=0.005). In conclusion, HMGCR rs3846662 acts as a potent genetic modifier for AD risk, age of onset and conversion.
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Affiliation(s)
- Valerie Leduc
- Douglas Mental Health University Institute
- Institut de recherches cliniques de Montréal, Department of Nutrition, Université de Montréal
| | | | | | - Doris Dea
- Douglas Mental Health University Institute
| | - Paul Aisen
- Department of Neurosciences, University of California San Diego
| | | | | | - Robert Dufour
- Institut de recherches cliniques de Montréal, Department of Nutrition, Université de Montréal
| | - Judes Poirier
- Douglas Mental Health University Institute
- Centre for Studies in Aging, McGill University
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Shahabi P, Dubé MP. Cardiovascular pharmacogenomics; state of current knowledge and implementation in practice. Int J Cardiol 2015; 184:772-795. [DOI: 10.1016/j.ijcard.2015.02.025] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Revised: 02/17/2015] [Accepted: 02/21/2015] [Indexed: 02/07/2023]
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Brown CC, Havener TM, Medina MW, Jack JR, Krauss RM, McLeod HL, Motsinger-Reif AA. Genome-wide association and pharmacological profiling of 29 anticancer agents using lymphoblastoid cell lines. Pharmacogenomics 2015; 15:137-46. [PMID: 24444404 DOI: 10.2217/pgs.13.213] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
AIM Association mapping with lymphoblastoid cell lines (LCLs) is a promising approach in pharmacogenomics research, and in the current study we utilized LCLs to perform association mapping for 29 chemotherapy drugs. MATERIALS & METHODS Currently, we use LCLs to perform genome-wide association mapping of the cytotoxic response of 520 European-Americans to 29 different anticancer drugs; the largest LCL study to date. A novel association approach using a multivariate analysis of covariance design was employed with the software program MAGWAS, testing for differences in the dose-response profiles between genotypes without making assumptions about the response curve or the biologic mode of association. Additionally, by classifying 25 of the 29 drugs into eight families according to structural and mechanistic relationships, MAGWAS was used to test for associations that were shared across each drug family. Finally, a unique algorithm using multivariate responses and multiple linear regressions across pairs of response curves was used for unsupervised clustering of drugs. RESULTS Among the single-drug studies, suggestive associations were obtained for 18 loci, 12 within/near genes. Three of these, MED12L, CHN2 and MGMT, have been previously implicated in cancer pharmacogenomics. The drug family associations resulted in four additional suggestive loci (three contained within/near genes). One of these genes, HDAC4, associated with the DNA alkylating agents, shows possible clinical interactions with temozolomide. For the drug clustering analysis, 18 of 25 drugs clustered into the appropriate family. CONCLUSION This study demonstrates the utility of LCLs in identifying genes that have clinical importance in drug response and for assigning unclassified agents to specific drug families, and proposes new candidate genes for follow-up in a large number of chemotherapy drugs.
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Affiliation(s)
- Chad C Brown
- Bioinformatics Research Center, Department of Statistics, North Carolina State University, Raleigh, NC 27607, USA
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Naidoo D, Wu AC, Brilliant MH, Denny J, Ingram C, Kitchner TE, Linneman JG, McGeachie MJ, Roden DM, Shaffer CM, Shah A, Weeke P, Weiss ST, Xu H, Medina MW. A polymorphism in HLA-G modifies statin benefit in asthma. THE PHARMACOGENOMICS JOURNAL 2014; 15:272-7. [PMID: 25266681 PMCID: PMC4379135 DOI: 10.1038/tpj.2014.55] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Revised: 07/04/2014] [Accepted: 08/13/2014] [Indexed: 11/16/2022]
Abstract
Several reports have shown that statin treatment benefits patients with asthma, however inconsistent effects have been observed. The mir-152 family (148a, 148b and 152) has been implicated in asthma. These microRNAs suppress HLA-G expression, and rs1063320, a common SNP in the HLA-G 3’UTR which is associated with asthma risk, modulates miRNA binding. We report that statins up-regulate mir-148b and 152, and affect HLA-G expression in an rs1063320 dependent fashion. In addition, we found that individuals who carried the G minor allele of rs1063320 had reduced asthma related exacerbations (emergency department visits, hospitalizations or oral steroid use) compared to non-carriers (p=0.03) in statin users ascertained in the Personalized Medicine Research Project at the Marshfield Clinic (n=421). These findings support the hypothesis that rs1063320 modifies the effect of statin benefit in asthma, and thus may contribute to variation in statin efficacy for the management of this disease.
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Affiliation(s)
- D Naidoo
- Atherosclerosis Research, Children's Hospital Oakland Research Institute, Oakland, CA, USA
| | - A C Wu
- Department of Population Medicine, Harvard Medical School, Boston, MA, USA
| | - M H Brilliant
- Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI, USA
| | - J Denny
- 1] Department of Medical Bioinformatics, Vanderbilt University School of Medicine, Nashville, TN, USA [2] Department of Medicine, Vanderbilt University, Nashville, TN, USA
| | - C Ingram
- Department of Medicine, Vanderbilt University, Nashville, TN, USA
| | - T E Kitchner
- Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI, USA
| | - J G Linneman
- Biomedical Informatics Research Center, Marshfield Clinic Research Foundation, Marshfield, WI, USA
| | - M J McGeachie
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - D M Roden
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - C M Shaffer
- Department of Medicine, Vanderbilt University, Nashville, TN, USA
| | - A Shah
- Department of Medicine, Vanderbilt University, Nashville, TN, USA
| | - P Weeke
- 1] Department of Medicine, Vanderbilt University, Nashville, TN, USA [2] Department of Cardiology, Copenhagen University Hospital, Gentofte, Denmark
| | - S T Weiss
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - H Xu
- School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - M W Medina
- Atherosclerosis Research, Children's Hospital Oakland Research Institute, Oakland, CA, USA
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Stormo C, Kringen MK, Lyle R, Olstad OK, Sachse D, Berg JP, Piehler AP. RNA-sequencing analysis of HepG2 cells treated with atorvastatin. PLoS One 2014; 9:e105836. [PMID: 25153832 PMCID: PMC4143339 DOI: 10.1371/journal.pone.0105836] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2013] [Accepted: 07/30/2014] [Indexed: 01/28/2023] Open
Abstract
The cholesterol-lowering drug atorvastatin is among the most prescribed drug in the world. Alternative splicing in a number of genes has been reported to be associated with variable statin response. RNA-seq has proven to be a powerful technique for genome-wide splice variant analysis. In the present study, we sought to investigate atorvastatin responsive splice variants in HepG2 cells using RNA-seq analysis to identify novel candidate genes implicated in cholesterol homeostasis and in the statin response. HepG2 cells were treated with 10 µM atorvastatin for 24 hours. RNA-seq and exon array analyses were performed. The validation of selected genes was performed using Taqman gene expression assays. RNA-seq analysis identified 121 genes and 98 specific splice variants, of which four were minor splice variants to be differentially expressed, 11 were genes with potential changes in their splicing patterns (SYCP3, ZNF195, ZNF674, MYD88, WHSC1, KIF16B, ZNF92, AGER, FCHO1, SLC6A12 and AKAP9), and one was a gene (RAP1GAP) with differential promoter usage. The IL21R transcript was detected to be differentially expressed via RNA-seq and RT-qPCR, but not in the exon array. In conclusion, several novel candidate genes that are affected by atorvastatin treatment were identified in this study. Further studies are needed to determine the biological significance of the atorvastatin responsive splice variants that have been uniquely identified using RNA-seq.
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Affiliation(s)
- Camilla Stormo
- Department of Medical Biochemistry, Oslo University Hospital, Ullevål, Oslo, Norway
| | | | - Robert Lyle
- Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway
| | | | - Daniel Sachse
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Jens P. Berg
- Department of Medical Biochemistry, Oslo University Hospital, Ullevål, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
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Pradas-Juni M, Nicod N, Fernández-Rebollo E, Gomis R. Differential transcriptional and posttranslational transcription factor 7-like regulation among nondiabetic individuals and type 2 diabetic patients. Mol Endocrinol 2014; 28:1558-70. [PMID: 25058603 DOI: 10.1210/me.2014-1065] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Human genetic studies have revealed that the T minor allele of single nucleotide polymorphism rs7903146 in the transcription factor 7-like 2 (TCF7L2) gene is strongly associated with an increased risk of diabetes by 30%-40%. Molecular and clinical studies are of great importance for understanding how this unique variation in TCF7L2 influences type 2 diabetes (T2D) onset and progression. At the molecular level, some studies have been performed in diabetic mice and pancreatic islets from healthy human donors. Whereas TCF7L2 mRNA levels are up-regulated in islets, protein levels are down-regulated. We performed studies on TCF7L2 splicing, mRNA expression, and protein levels in immortalized human lymphocytes from nondiabetic individuals and T2D patients carrying the C/C or the at-risk T/T genotype. Our results show differential expression of TCF7L2 splice variants between nondiabetic and T2D patients carrying the at-risk genotype, as well as differences in protein levels. Therefore, we investigated the regulation of splice variants, and our results propose that splicing of exon 4 is under control of the serine-arginine-rich factor transformer 2 β (TRA2B). Finally, we studied the endoplasmic reticulum stress pathways, looking for a posttranslational explanation. We saw a shift in the activation of these pathways between nondiabetic individuals and T2D patients carrying the at-risk genotype. These results suggest that, in human immortalized lymphocytes carrying the at-risk T/T genotype, first the differential expression of TCF7L2 splice variants implies a regulation, at least for exon 4, by TRA2B and second, the differential protein levels between both T/T carriers point to a different activation of endoplasmic reticulum stress pathways.
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Affiliation(s)
- M Pradas-Juni
- Diabetes and Obesity Research Laboratory (M.P.-J., N.N., E.F-R., R.G.), Institut d'Investigacions Biomèdiques August Pi i Sunyer, 08036 Barcelona, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Diseases (M.P.-J., N.N., E.F.-R., R.G.), 08017 Barcelona, Spain; Department of Medicine (R.G.), University of Barcelona, 08036 Barcelona, Spain; and Hospital Clínic de Barcelona (R.G.), 08036 Barcelona, Spain
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Medina MW, Bauzon F, Naidoo D, Theusch E, Stevens K, Schilde J, Schubert C, Mangravite LM, Rudel LL, Temel RE, Runz H, Krauss RM. Transmembrane protein 55B is a novel regulator of cellular cholesterol metabolism. Arterioscler Thromb Vasc Biol 2014; 34:1917-23. [PMID: 25035345 DOI: 10.1161/atvbaha.113.302806] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE Interindividual variation in pathways affecting cellular cholesterol metabolism can influence levels of plasma cholesterol, a well-established risk factor for cardiovascular disease. Inherent variation among immortalized lymphoblastoid cell lines from different donors can be leveraged to discover novel genes that modulate cellular cholesterol metabolism. The objective of this study was to identify novel genes that regulate cholesterol metabolism by testing for evidence of correlated gene expression with cellular levels of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) mRNA, a marker for cellular cholesterol homeostasis, in a large panel of lymphoblastoid cell lines. APPROACH AND RESULTS Expression array profiling was performed on 480 lymphoblastoid cell lines established from participants of the Cholesterol and Pharmacogenetics (CAP) statin clinical trial, and transcripts were tested for evidence of correlated expression with HMGCR as a marker of intracellular cholesterol homeostasis. Of these, transmembrane protein 55b (TMEM55B) showed the strongest correlation (r=0.29; P=4.0E-08) of all genes not previously implicated in cholesterol metabolism and was found to be sterol regulated. TMEM55B knockdown in human hepatoma cell lines promoted the decay rate of the low-density lipoprotein receptor, reduced cell surface low-density lipoprotein receptor protein, impaired low-density lipoprotein uptake, and reduced intracellular cholesterol. CONCLUSIONS Here, we report identification of TMEM55B as a novel regulator of cellular cholesterol metabolism through the combination of gene expression profiling and functional studies. The findings highlight the value of an integrated genomic approach for identifying genes that influence cholesterol homeostasis.
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Affiliation(s)
- Marisa W Medina
- From the Children's Hospital Oakland Research Institute, CA (M.W.M., F.B., D.N., E.T., K.S., R.M.K.); Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany (J.S., H.R.); Sage Bionetworks, Seattle, WA (L.M.M.); Section on Lipid Sciences, Department of Pathology, Wake Forest University Health Sciences, Winston-Salem, NC (L.L.R., R.E.T.); and Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany (C.S., H.R.).
| | - Frederick Bauzon
- From the Children's Hospital Oakland Research Institute, CA (M.W.M., F.B., D.N., E.T., K.S., R.M.K.); Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany (J.S., H.R.); Sage Bionetworks, Seattle, WA (L.M.M.); Section on Lipid Sciences, Department of Pathology, Wake Forest University Health Sciences, Winston-Salem, NC (L.L.R., R.E.T.); and Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany (C.S., H.R.)
| | - Devesh Naidoo
- From the Children's Hospital Oakland Research Institute, CA (M.W.M., F.B., D.N., E.T., K.S., R.M.K.); Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany (J.S., H.R.); Sage Bionetworks, Seattle, WA (L.M.M.); Section on Lipid Sciences, Department of Pathology, Wake Forest University Health Sciences, Winston-Salem, NC (L.L.R., R.E.T.); and Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany (C.S., H.R.)
| | - Elizabeth Theusch
- From the Children's Hospital Oakland Research Institute, CA (M.W.M., F.B., D.N., E.T., K.S., R.M.K.); Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany (J.S., H.R.); Sage Bionetworks, Seattle, WA (L.M.M.); Section on Lipid Sciences, Department of Pathology, Wake Forest University Health Sciences, Winston-Salem, NC (L.L.R., R.E.T.); and Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany (C.S., H.R.)
| | - Kristen Stevens
- From the Children's Hospital Oakland Research Institute, CA (M.W.M., F.B., D.N., E.T., K.S., R.M.K.); Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany (J.S., H.R.); Sage Bionetworks, Seattle, WA (L.M.M.); Section on Lipid Sciences, Department of Pathology, Wake Forest University Health Sciences, Winston-Salem, NC (L.L.R., R.E.T.); and Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany (C.S., H.R.)
| | - Jessica Schilde
- From the Children's Hospital Oakland Research Institute, CA (M.W.M., F.B., D.N., E.T., K.S., R.M.K.); Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany (J.S., H.R.); Sage Bionetworks, Seattle, WA (L.M.M.); Section on Lipid Sciences, Department of Pathology, Wake Forest University Health Sciences, Winston-Salem, NC (L.L.R., R.E.T.); and Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany (C.S., H.R.)
| | - Christian Schubert
- From the Children's Hospital Oakland Research Institute, CA (M.W.M., F.B., D.N., E.T., K.S., R.M.K.); Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany (J.S., H.R.); Sage Bionetworks, Seattle, WA (L.M.M.); Section on Lipid Sciences, Department of Pathology, Wake Forest University Health Sciences, Winston-Salem, NC (L.L.R., R.E.T.); and Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany (C.S., H.R.)
| | - Lara M Mangravite
- From the Children's Hospital Oakland Research Institute, CA (M.W.M., F.B., D.N., E.T., K.S., R.M.K.); Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany (J.S., H.R.); Sage Bionetworks, Seattle, WA (L.M.M.); Section on Lipid Sciences, Department of Pathology, Wake Forest University Health Sciences, Winston-Salem, NC (L.L.R., R.E.T.); and Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany (C.S., H.R.)
| | - Lawrence L Rudel
- From the Children's Hospital Oakland Research Institute, CA (M.W.M., F.B., D.N., E.T., K.S., R.M.K.); Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany (J.S., H.R.); Sage Bionetworks, Seattle, WA (L.M.M.); Section on Lipid Sciences, Department of Pathology, Wake Forest University Health Sciences, Winston-Salem, NC (L.L.R., R.E.T.); and Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany (C.S., H.R.)
| | - Ryan E Temel
- From the Children's Hospital Oakland Research Institute, CA (M.W.M., F.B., D.N., E.T., K.S., R.M.K.); Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany (J.S., H.R.); Sage Bionetworks, Seattle, WA (L.M.M.); Section on Lipid Sciences, Department of Pathology, Wake Forest University Health Sciences, Winston-Salem, NC (L.L.R., R.E.T.); and Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany (C.S., H.R.)
| | - Heiko Runz
- From the Children's Hospital Oakland Research Institute, CA (M.W.M., F.B., D.N., E.T., K.S., R.M.K.); Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany (J.S., H.R.); Sage Bionetworks, Seattle, WA (L.M.M.); Section on Lipid Sciences, Department of Pathology, Wake Forest University Health Sciences, Winston-Salem, NC (L.L.R., R.E.T.); and Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany (C.S., H.R.)
| | - Ronald M Krauss
- From the Children's Hospital Oakland Research Institute, CA (M.W.M., F.B., D.N., E.T., K.S., R.M.K.); Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany (J.S., H.R.); Sage Bionetworks, Seattle, WA (L.M.M.); Section on Lipid Sciences, Department of Pathology, Wake Forest University Health Sciences, Winston-Salem, NC (L.L.R., R.E.T.); and Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany (C.S., H.R.)
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