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Kim JY, Cho YS. Identification of shared genetic risks underlying metabolic syndrome and its related traits in the Korean population. Front Genet 2024; 15:1417262. [PMID: 39050255 PMCID: PMC11266026 DOI: 10.3389/fgene.2024.1417262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Accepted: 06/20/2024] [Indexed: 07/27/2024] Open
Abstract
Introduction: Observational studies have demonstrated strong correlations between metabolic syndrome (MetS) and its related traits. To gain insight into the genetic architecture and molecular mechanism of MetS, we investigated the shared genetic basis of MetS and its related traits and further tested their causal relationships. Methods: Using summary statistics from genome-wide association analyses of about 72,000 subjects from the Korean Genome and Epidemiological Study (KoGES), we conducted genome-wide multi-trait analyses to quantify the overall genetic correlation and Mendelian randomization analyses to infer the causal relationships between traits of interest. Results: Genetic correlation analyses revealed a significant correlation of MetS with its related traits, such as obesity traits (body mass index and waist circumference), lipid traits (triglyceride and high-density lipoprotein cholesterol), glycemic traits (fasting plasma glucose and hemoglobin A1C), and blood pressure (systolic and diastolic). Mendelian randomization analyses further demonstrated that the MetS-related traits showing significant overall genetic correlation with MetS could be genetically determined risk factors for MetS. Discussion: Our study suggests a shared genetic basis of MetS and its related traits and provides novel insights into the biological mechanisms underlying these complex traits. Our findings further inform public health interventions by supporting the important role of the management of metabolic risk factors such as obesity, unhealthy lipid profiles, diabetes, and high blood pressure in the prevention of MetS.
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Affiliation(s)
| | - Yoon Shin Cho
- Department of Biomedical Science, Hallym University, Chuncheon, Gangwon, Republic of Korea
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Perera SD, Wang J, McIntyre AD, Hegele RA. Variability of longitudinal triglyceride phenotype in patients heterozygous for pathogenic APOA5 variants. J Clin Lipidol 2023; 17:659-665. [PMID: 37586912 DOI: 10.1016/j.jacl.2023.08.003] [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: 06/11/2023] [Revised: 07/15/2023] [Accepted: 08/03/2023] [Indexed: 08/18/2023]
Abstract
BACKGROUND Biallelic pathogenic variants in APOA5 are an infrequent cause of familial chylomicronemia syndrome characterized by severe, refractory hypertriglyceridemia (HTG), and fasting plasma triglyceride (TG) >10 mmol/L (>875 mg/dL). The TG phenotype of heterozygous individuals with one copy of a pathogenic APOA5 variant is less familiar. We evaluated the longitudinal TG phenotype of individuals with a single pathogenic APOA5 variant allele. METHODS Medically stable outpatients from Ontario, Canada were selected for study based on having: 1) a rare pathogenic APOA5 variant in a single allele; and 2) at least three serial fasting TG measurements obtained over >1.5 years of follow-up. RESULTS Seven patients were followed for a mean of 5.3 ± 3.7 years. Fasting TG levels varied widely both within and between patients. Three patients displayed at least one normal TG measurement (<2.0 mmol/L or <175 mg/dL). All patients displayed mild-to-moderate HTG (2 to 9.9 mmol/L or 175 to 875 mg/dL) at multiple time points. Five patients displayed at least one severe HTG measurement. 10%, 54%, and 36% of all TG measurements were in normal, mild-to-moderate, and severe HTG ranges, respectively. CONCLUSIONS Heterozygosity for pathogenic variants in APOA5 is associated with highly variable TG phenotypes both within and between patients. Heterozygosity confers susceptibility to elevated TG levels, with secondary factors likely modulating the phenotypic severity.
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Affiliation(s)
- Shehan D Perera
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Jian Wang
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Adam D McIntyre
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Robert A Hegele
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
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Gunn KH, Neher SB. Structure of dimeric lipoprotein lipase reveals a pore adjacent to the active site. Nat Commun 2023; 14:2569. [PMID: 37142573 PMCID: PMC10160067 DOI: 10.1038/s41467-023-38243-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 04/24/2023] [Indexed: 05/06/2023] Open
Abstract
Lipoprotein lipase (LPL) hydrolyzes triglycerides from circulating lipoproteins, releasing free fatty acids. Active LPL is needed to prevent hypertriglyceridemia, which is a risk factor for cardiovascular disease (CVD). Using cryogenic electron microscopy (cryoEM), we determined the structure of an active LPL dimer at 3.9 Å resolution. This structure reveals an open hydrophobic pore adjacent to the active site residues. Using modeling, we demonstrate that this pore can accommodate an acyl chain from a triglyceride. Known LPL mutations that lead to hypertriglyceridemia localize to the end of the pore and cause defective substrate hydrolysis. The pore may provide additional substrate specificity and/or allow unidirectional acyl chain release from LPL. This structure also revises previous models on how LPL dimerizes, revealing a C-terminal to C-terminal interface. We hypothesize that this active C-terminal to C-terminal conformation is adopted by LPL when associated with lipoproteins in capillaries.
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Affiliation(s)
- Kathryn H Gunn
- Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, 27599, USA
| | - Saskia B Neher
- Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, 27599, USA.
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Gunn KH, Neher SB. Structure of Dimeric Lipoprotein Lipase Reveals a Pore for Hydrolysis of Acyl Chains. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.21.533650. [PMID: 36993689 PMCID: PMC10055231 DOI: 10.1101/2023.03.21.533650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/31/2023]
Abstract
Lipoprotein lipase (LPL) hydrolyzes triglycerides from circulating lipoproteins, releasing free fatty acids. Active LPL is needed to prevent hypertriglyceridemia, which is a risk factor for cardiovascular disease (CVD). Using cryogenic electron microscopy (cryoEM), we determined the structure of an active LPL dimer at 3.9 Ã… resolution. This is the first structure of a mammalian lipase with an open, hydrophobic pore adjacent to the active site. We demonstrate that the pore can accommodate an acyl chain from a triglyceride. Previously, it was thought that an open lipase conformation was defined by a displaced lid peptide, exposing the hydrophobic pocket surrounding the active site. With these previous models after the lid opened, the substrate would enter the active site, be hydrolyzed and then released in a bidirectional manner. It was assumed that the hydrophobic pocket provided the only ligand selectivity. Based on our structure, we propose a new model for lipid hydrolysis, in which the free fatty acid product travels unidirectionally through the active site pore, entering and exiting opposite sides of the protein. By this new model, the hydrophobic pore provides additional substrate specificity and provides insight into how LPL mutations in the active site pore may negatively impact LPL activity, leading to chylomicronemia. Structural similarity of LPL to other human lipases suggests that this unidirectional mechanism could be conserved but has not been observed due to the difficulty of studying lipase structure in the presence of an activating substrate. We hypothesize that the air/water interface formed during creation of samples for cryoEM triggered interfacial activation, allowing us to capture, for the first time, a fully open state of a mammalian lipase. Our new structure also revises previous models on how LPL dimerizes, revealing an unexpected C-terminal to C-terminal interface. The elucidation of a dimeric LPL structure highlights the oligomeric diversity of LPL, as now LPL homodimer, heterodimer, and helical filament structures have been elucidated. This diversity of oligomerization may provide a form of regulation as LPL travels from secretory vesicles in the cell, to the capillary, and eventually to the liver for lipoprotein remnant uptake. We hypothesize that LPL dimerizes in this active C-terminal to C-terminal conformation when associated with mobile lipoproteins in the capillary.
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Teng Z, Zhu Y, Lin D, Hao Q, Yue Q, Yu X, Sun S, Jiang L, Lu S. Deciphering the chromatin spatial organization landscapes during BMMSC differentiation. J Genet Genomics 2023; 50:264-275. [PMID: 36720443 DOI: 10.1016/j.jgg.2023.01.009] [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: 11/03/2022] [Revised: 01/18/2023] [Accepted: 01/18/2023] [Indexed: 01/31/2023]
Abstract
The differentiation imbalance in bone marrow mesenchymal stem cells (BMMSCs) is critical for the development of bone density diseases as the population ages. BMMSCs are precursor cells for osteoblasts and adipocytes; however, the chromatin organization landscapes during BMMSC differentiation remain elusive. In this study, we systematically delineate the four-dimensional (4D) genome and dynamic epigenetic atlas of BMMSCs by RNA sequencing (RNA-seq), assay for transposase-accessible chromatin sequencing (ATAC-seq), and high-throughput chromosome conformation capture (Hi-C). The structure analyses reveal 17.5% common and 28.5%-30% specific loops among BMMSCs, osteoblasts, and adipocytes. The subsequent correlation of genome-wide association studies (GWAS) and expression quantitative trait locus (eQTL) data with multi-omics analysis reveal 274 genes and 3634 single nucleotide polymorphisms (SNPs) associated with bone degeneration and osteoporosis (OP). We hypothesize that SNP mutations affect transcription factor (TF) binding sites, thereby affecting changes in gene expression. Furthermore, 26 motifs, 260 TFs, and 291 SNPs are identified to affect the eQTL. Among these genes, DAAM2, TIMP2, and TMEM241 were found to be essential for diseases such as bone degeneration and OP and may serve as potential drug targets.
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Affiliation(s)
- Zhaowei Teng
- Department of Orthopedics, The First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, China; Key Laboratory of Yunnan Provincial Innovative Application of Traditional Chinese Medicine, The First People's Hospital of Yunnan Province, Kunming, Yunnan 650032, China; Clinical Medical Research Center, The First People's Hospital of Yunnan Province, Kunming, Yunnan 650032, China.
| | - Yun Zhu
- The Sixth Affiliated Hospital of Kunming Medical University, Yuxi, Yunnan 653100, China
| | - Da Lin
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, Hubei 430070, China
| | - Qinggang Hao
- Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming, Yunnan 650504, China
| | - Qiaoning Yue
- The Sixth Affiliated Hospital of Kunming Medical University, Yuxi, Yunnan 653100, China
| | - Xiaochao Yu
- The Sixth Affiliated Hospital of Kunming Medical University, Yuxi, Yunnan 653100, China
| | - Shuo Sun
- The Sixth Affiliated Hospital of Kunming Medical University, Yuxi, Yunnan 653100, China
| | - Lihong Jiang
- Key Laboratory of Yunnan Provincial Innovative Application of Traditional Chinese Medicine, The First People's Hospital of Yunnan Province, Kunming, Yunnan 650032, China.
| | - Sheng Lu
- Department of Orthopedics, The First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650032, China.
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Perera SD, Wang J, McIntyre AD, Dron JS, Hegele RA. The longitudinal triglyceride phenotype in heterozygotes with LPL pathogenic variants. J Clin Lipidol 2023; 17:87-93. [PMID: 36476373 DOI: 10.1016/j.jacl.2022.11.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 11/07/2022] [Accepted: 11/14/2022] [Indexed: 11/23/2022]
Abstract
BACKGROUND Biallelic pathogenic variants in lipoprotein lipase (LPL) cause familial chylomicronemia syndrome with severe hypertriglyceridemia (HTG), defined as plasma triglycerides (TG) > 10 mmol/L (> 885 mg/dL). TG levels in individuals with one copy of a pathogenic LPL gene variant is less familiar; some assume that the phenotype is intermediate between homozygotes and controls. OBJECTIVE We undertook an evaluation of the longitudinal TG phenotype of individuals heterozygous for pathogenic LPL variants. METHODS Medically stable outpatients were evaluated based on having: (1) a single copy of a rare pathogenic LPL variant; and (2) serial fasting TG measurements obtained over > 1.5 years of follow-up. RESULTS Fifteen patients with a single pathogenic LPL variant were followed for a mean of 10.3 years (range 1.5 to 30.3 years). TG levels varied widely both within and between patients. One patient had normal TG levels < 2.0 mmol/L (< 175 mg/dL) continuously, while four patients had at least one normal TG level. Most patients fluctuated between mild-to-moderate and severe HTG: five patients had only mild-to-moderate HTG, with TG levels ranging from 2.0 to 9.9 mmol/L (175 to 885 mg/dL), while 6 patients had at least one instance of severe HTG. Of the 203 total TG measurements from these patients, 14.8%, 67.0% and 18.2% were in the normal, mild-to-moderate and severe HTG ranges, respectively. CONCLUSION The heterozygous LPL deficient phenotype is highly variable both within and between patients. Heterozygosity confers susceptibility to a wide range of TG phenotypes, with severity likely depending on secondary factors.
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Affiliation(s)
- Shehan D Perera
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, 4288A-1151 Richmond Street North, London, Ontario N6A 5B7, Canada (Perera, Wang, McIntyre and Hegele); Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada (Perera and Hegele)
| | - Jian Wang
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, 4288A-1151 Richmond Street North, London, Ontario N6A 5B7, Canada (Perera, Wang, McIntyre and Hegele)
| | - Adam D McIntyre
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, 4288A-1151 Richmond Street North, London, Ontario N6A 5B7, Canada (Perera, Wang, McIntyre and Hegele)
| | - Jacqueline S Dron
- Center for Genomic Medicine, Massachusetts General Hopsital, Boston, Massachusetts, USA (Dron)
| | - Robert A Hegele
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, 4288A-1151 Richmond Street North, London, Ontario N6A 5B7, Canada (Perera, Wang, McIntyre and Hegele); Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada (Perera and Hegele); Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada (Hegele).
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Hwang WJ, Lim HH, Kim YM, Chang MY, Kil HR, Kim JY, Song WJ, Levy HL, Kim SZ. Pancreatic involvement in patients with inborn errors of metabolism. Orphanet J Rare Dis 2021; 16:37. [PMID: 33472655 PMCID: PMC7819202 DOI: 10.1186/s13023-021-01685-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 01/06/2021] [Indexed: 11/10/2022] Open
Abstract
Background Repeated inflammation of the pancreas can cause pancreatitis or diabetes. It is well recognized that the organic acidemias may be complicated by pancreatitis but less recognized are other metabolic disorders in which pancreatitis can occur. This study shows that long-term follow-up of patients with various metabolic disorders in Korea revealed several with episodes of isolated pancreatitis or diabetes concomitantly with pancreatitis. Results and discussion In this study, two patients with methylmalonic aciduria (MMA), two with propionic acidemia (PPA), one with fatty acid oxidation disorder (FAOD), and one with hyperornithinemia, gyrate atrophy, and juvenile onset diabetes mellitus (DM) were clinically followed for up to 10 – 21 years. Two Korean siblings with MMA showed recurrent pancreatitis from the age of 15 and 19, respectively. The frequency of admission due to pancreatitis was up to 11 times. One patient with MMA developed diabetes mellitus at the age of 20. The other patient with MMA developed recurrent pancreatitis at 4 years and diabetes at 8 years of age. One of the patients with PPA presented with diabetic ketoacidosis. The other PPA patient died of cardiac arrest at age 10. The patient with FAOD presented with pancreatitis at 10 years and died at the age of 15 years due to cardiac arrest. A 35-year-old woman with hyperornithinemia/gyrate atrophy was diagnosed with juvenile onset diabetes at the age of 7 years. No pancreatitis occurred during the follow-up period. Conclusions We conclude that various metabolic disorders can trigger acute or chronic pancreatitis. Proper and prompt multidisciplinary management of metabolic derangement is crucial for preventing pancreatic damage. Further clinical and investigational studies are required to elucidate the pathogenesis of pancreatitis and diabetes mellitus in patients with inborn errors in metabolism.
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Affiliation(s)
- Woo Jin Hwang
- Department of Pediatrics, College of Medicine, Chungnam National University, Daejeon, Korea
| | - Han Hyuk Lim
- Department of Pediatrics, College of Medicine, Chungnam National University, Daejeon, Korea
| | - Yoo-Mi Kim
- Department of Pediatrics, College of Medicine, Chungnam National University, Daejeon, Korea
| | - Mea Young Chang
- Department of Pediatrics, College of Medicine, Chungnam National University, Daejeon, Korea
| | - Hong Ryang Kil
- Department of Pediatrics, College of Medicine, Chungnam National University, Daejeon, Korea
| | - Jae Young Kim
- Department of Pediatrics, Gyeongsang National University Hospital, Changwon-si, Gyeongsangnam-do, Korea
| | | | - Harvey L Levy
- Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, USA
| | - Sook-Za Kim
- Department of Pediatrics, College of Medicine, Chungnam National University, Daejeon, Korea. .,Korea Genetics Research Center, Cheongju, Korea.
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Whole exome sequencing for non-selective pediatric patients with hyperlipidemia. Gene 2020; 768:145310. [PMID: 33217533 DOI: 10.1016/j.gene.2020.145310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 10/21/2020] [Accepted: 11/12/2020] [Indexed: 11/20/2022]
Abstract
BACKGROUND Hyperlipidemia is a group of conditions with abnormally elevated levels of any or all lipids or lipoproteins in the blood. It is highly heterogeneous both genetically and clinically, which contributes to diagnostic challenges and results in many patients to be underdiagnosed and undertreated in China. Precise diagnosis and early management are critical to reduce the incidence of potential coronary artery disease and cardiovascular disease. RESULTS We performed a single center study to demonstrate the clinical utility of the genome-first approach by whole exome sequencing (WES) for 12 pediatric patients with abnormal lipids or lipoproteins levels. In vitro experiments were performed in COS-7 cells to further evaluate the biological function of the novel variants. We identified ten pathogenic and likely pathogenic variants and three of them were novel. Molecular cause was uncovered in five (41.7%) patients including three lipoprotein lipase deficiency patients, one hypercholesterolemia patient and one sitosterolemia patient. We also found three patients with rare variants of uncertain significance. Copy number variant (CNV) analysis with WES data did not reveal any potential hyperlipidemia related CNVs in all patients. CONCLUSION We expanded the mutation and phenotype spectra of familial hyperlipidemia. Our study demonstrated the effectiveness of genome-first approach for evaluation pediatric hyperlipidemia patients and showed that WES can be used as the first-tier test for patients with suspected Mendelian hyperlipidemia disorder.
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Li XY, Pu N, Chen WW, Shi XL, Zhang GF, Ke L, Ye B, Tong ZH, Wang YH, Liu G, Chen JM, Yang Q, Li WQ, Li JS. Identification of a novel LPL nonsense variant and further insights into the complex etiology and expression of hypertriglyceridemia-induced acute pancreatitis. Lipids Health Dis 2020; 19:63. [PMID: 32264896 PMCID: PMC7140582 DOI: 10.1186/s12944-020-01249-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 03/31/2020] [Indexed: 12/24/2022] Open
Abstract
Background Hypertriglyceridemia (HTG) is a leading cause of acute pancreatitis. HTG can be caused by either primary (genetic) or secondary etiological factors, and there is increasing appreciation of the interplay between the two kinds of factors in causing severe HTG. Objectives The main aim of this study was to identify the genetic basis of hypertriglyceridemia-induced acute pancreatitis (HTG-AP) in a Chinese family with three affected members (the proband, his mother and older sister). Methods The entire coding and flanking sequences of LPL, APOC2, APOA5, GPIHBP1 and LMF1 genes were analyzed by Sanger sequencing. The newly identified LPL nonsense variant was subjected to functional analysis by means of transfection into HEK-293 T cells followed by Western blot and activity assays. Previously reported pathogenic LPL nonsense variants were collated and compared with respect to genotype and phenotype relationship. Results We identified a novel nonsense variant, p.Gln118* (c.351C > T), in the LPL gene, which co-segregated with HTG-AP in the Chinese family. We provided in vitro evidence that this variant resulted in a complete functional loss of the affected LPL allele. We highlighted a role of alcohol abuse in modifying the clinical expression of the disease in the proband. Additionally, our survey of 12 previously reported pathogenic LPL nonsense variants (in 20 carriers) revealed that neither serum triglyceride levels nor occurrence of HTG-AP was distinguishable among the three carrier groups, namely, simple homozygotes, compound heterozygotes and simple heterozygotes. Conclusions Our findings, taken together, generated new insights into the complex etiology and expression of HTG-AP.
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Affiliation(s)
- Xiao-Yao Li
- Surgical Intensive Care Unit (SICU), Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.,Department of Intensive Care Unit, The Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Na Pu
- Surgical Intensive Care Unit (SICU), Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Wei-Wei Chen
- Surgical Intensive Care Unit (SICU), Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.,Department of Gastroenterology, Subei People's Hospital, Clinical Medical College of Yangzhou University, Yangzhou, China
| | - Xiao-Lei Shi
- Surgical Intensive Care Unit (SICU), Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Guo-Fu Zhang
- Surgical Intensive Care Unit (SICU), Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Lu Ke
- Surgical Intensive Care Unit (SICU), Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Bo Ye
- Surgical Intensive Care Unit (SICU), Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Zhi-Hui Tong
- Surgical Intensive Care Unit (SICU), Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yu-Hui Wang
- Key laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Institute of Cardiovascular Sciences, Health Science Center, Peking University, Beijing, China
| | - George Liu
- Key laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Institute of Cardiovascular Sciences, Health Science Center, Peking University, Beijing, China
| | - Jian-Min Chen
- Inserm, EFS, University of Brest, UMR 1078, GGB, F-29200, Brest, France
| | - Qi Yang
- Surgical Intensive Care Unit (SICU), Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
| | - Wei-Qin Li
- Surgical Intensive Care Unit (SICU), Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
| | - Jie-Shou Li
- Surgical Intensive Care Unit (SICU), Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
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Hayne CK, Yumerefendi H, Cao L, Gauer JW, Lafferty MJ, Kuhlman B, Erie DA, Neher SB. We FRET so You Don't Have To: New Models of the Lipoprotein Lipase Dimer. Biochemistry 2018; 57:241-254. [PMID: 29303250 PMCID: PMC5860654 DOI: 10.1021/acs.biochem.7b01009] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Lipoprotein lipase (LPL) is a dimeric enzyme that is responsible for clearing triglyceride-rich lipoproteins from the blood. Although LPL plays a key role in cardiovascular health, an experimentally derived three-dimensional structure has not been determined. Such a structure would aid in understanding mutations in LPL that cause familial LPL deficiency in patients and help in the development of therapeutic strategies to target LPL. A major obstacle to structural studies of LPL is that LPL is an unstable protein that is difficult to produce in the quantities needed for nuclear magnetic resonance or crystallography. We present updated LPL structural models generated by combining disulfide mapping, computational modeling, and data derived from single-molecule Förster resonance energy transfer (smFRET). We pioneer the technique of smFRET for use with LPL by developing conditions for imaging active LPL and identifying positions in LPL for the attachment of fluorophores. Using this approach, we measure LPL-LPL intermolecular interactions to generate experimental constraints that inform new computational models of the LPL dimer structure. These models suggest that LPL may dimerize using an interface that is different from the dimerization interface suggested by crystal packing contacts seen in structures of pancreatic lipase.
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Affiliation(s)
- Cassandra K. Hayne
- Department of Biochemistry and Biophysics, University of North Carolina - Chapel Hill
| | - Hayretin Yumerefendi
- Department of Biochemistry and Biophysics, University of North Carolina - Chapel Hill
| | - Lin Cao
- Department of Biochemistry and Biophysics, University of North Carolina - Chapel Hill
| | - Jacob W. Gauer
- Department of Chemistry, University of North Carolina at Chapel Hill
| | - Michael J. Lafferty
- Department of Biochemistry and Biophysics, University of North Carolina - Chapel Hill
| | - Brian Kuhlman
- Department of Biochemistry and Biophysics, University of North Carolina - Chapel Hill
| | - Dorothy A. Erie
- Department of Chemistry, University of North Carolina at Chapel Hill
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
| | - Saskia B. Neher
- Department of Biochemistry and Biophysics, University of North Carolina - Chapel Hill
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Rodrigues R, Artieda M, Tejedor D, Martínez A, Konstantinova P, Petry H, Meyer C, Corzo D, Sundgreen C, Klor HU, Gouni-Berthold I, Westphal S, Steinhagen-Thiessen E, Julius U, Winkler K, Stroes E, Vogt A, Hardt P, Prophet H, Otte B, Nordestgaard BG, Deeb SS, Brunzell JD. Pathogenic classification of LPL gene variants reported to be associated with LPL deficiency. J Clin Lipidol 2015; 10:394-409. [PMID: 27055971 DOI: 10.1016/j.jacl.2015.12.015] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Accepted: 12/21/2015] [Indexed: 01/01/2023]
Abstract
BACKGROUND Lipoprotein lipase (LPL) deficiency is a serious lipid disorder of severe hypertriglyceridemia (SHTG) with chylomicronemia. A large number of variants in the LPL gene have been reported but their influence on LPL activity and SHTG has not been completely analyzed. Gaining insight into the deleterious effect of the mutations is clinically essential. METHODS We used gene sequencing followed by in-vivo/in-vitro and in-silico tools for classification. We classified 125 rare LPL mutations in 33 subjects thought to have LPL deficiency and in 314 subjects selected for very SHTG. RESULTS Of the 33 patients thought to have LPL deficiency, only 13 were homozygous or compound heterozygous for deleterious mutations in the LPL gene. Among the 314 very SHTG patients, 3 were compound heterozygous for pathogenic mutants. In a third group of 51,467 subjects, from a general population, carriers of common variants, Asp9Asn and Asn291Ser, were associated with mild increase in triglyceride levels (11%-35%). CONCLUSION In total, 39% of patients clinically diagnosed as LPL deficient had 2 deleterious variants. Three patients selected for very SHTG had LPL deficiency. The deleterious mutations associated with LPL deficiency will assist in the diagnosis and selection of patients as candidates for the presently approved LPL gene therapy.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Hans U Klor
- Director of the German HITRIG, Third Medical Department and Policlinic, Giessen University Hospital, Justus-Liebig-University of Giessen, Giessen, Germany
| | - Ioanna Gouni-Berthold
- Center for Endocrinology, Diabetes and Preventive Medicine, University of Cologne, Cologne, Germany
| | - Sabine Westphal
- Institute of Clinical Chemistry, Lipid Clinic, Magdeburg, Germany
| | | | - Ulrich Julius
- Universitätsklinikum Carl Gustav Carus an der Technischen Universität, Medizinische Klinik III, Dresden, Germany
| | - Karl Winkler
- Institute of Clinical Chemistry and Laboratory Medicine and Lipid Outpatient Clinic, University Hospital Freiburg, Freiburg, Germany
| | - Erik Stroes
- Department of Vascular Medicine, Amsterdam Medical Center/University of Amsterdam, Amsterdam, The Netherlands
| | - Anja Vogt
- LMU Klinikum der Universität München, Medizinische Klinik und Poliklinik 4, München, Germany
| | - Phillip Hardt
- Gießen and Marburg University Hospital, Giessen, Germany
| | | | - Britta Otte
- Universitätsklinikum Münster, Medizinische Klinik D, Med. Clinic, Münster, Münster, Germany
| | - Borge G Nordestgaard
- Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Samir S Deeb
- Department of Medicine (Division of Medical Genetics), University of Washington, Seattle, WA, USA; Department of Genome Sciences, University of Washington, Seattle, WA, USA
| | - John D Brunzell
- Department of Medicine (Division of Metabolism, Endocrinology and Nutrition), University of Washington, Seattle, WA, USA
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Charlesworth A, Steger A, Crook MA. Acute pancreatitis associated with severe hypertriglyceridaemia; A retrospective cohort study. Int J Surg 2015; 23:23-7. [PMID: 26391596 DOI: 10.1016/j.ijsu.2015.08.080] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2015] [Revised: 08/07/2015] [Accepted: 08/19/2015] [Indexed: 01/22/2023]
Abstract
AIM Acute Pancreatitis (AP) secondary to hypertriglyceridaemia (HTG) is a rare association of which little is known in the literature. This study investigates patient characteristics and outcomes (reoccurrence and mortality) in those presenting with AP secondary to HTG in one of the largest reported British cohorts. METHODS A retrospective observational case note review of all patients treated at our institution between 2004 and 2012. Data are expressed as mean and standard deviation if parametric and as median and range if non-parametric. Full fasting lipid profiles and patient demographics were recorded to elucidate further the cause of the severe hypertriglyceridaemia (>10 mmol/L fasting). RESULTS There were 784 patients admitted with AP admitted to our institution within the study period. APHTG was present in 18 patients (2.3%). Peak serum triglyceride concentration was 43.9 mmol/L, SD 18.9 mmol/L. Serum amylase activity was 'falsely' low (with raised urine amylase) in about 10% of the patients with acute pancreatitis and hypertriglyceridaemia. 67% of our patients had type 2 diabetes mellitus or impaired glucose tolerance, 28% had a fatty liver and 50% displayed alcohol excess all these conditions are known to be associated with HTG There was a 94.5% reduction in serum triglyceride between presentation and last follow-up visit. There were also no deaths or recurrent episodes of AP during the study period. CONCLUSIONS APHTG was present in 2.3% of patients presenting with AP. The reoccurrence and mortality rates were zero in this cohort. This may in part be due to aggressive serum triglyceride lowering by a multi-disciplinary team. Early clinical recognition is vital to provide targeted treatment and to try and reduce further episodes of AP.
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Affiliation(s)
- Annika Charlesworth
- Dept of Gastroenterology, University Hospital Lewisham, Lewisham, London, SE13 6LH, United Kingdom
| | - Adrian Steger
- Dept of Surgery, University Hospital Lewisham, Lewisham, London, SE13 6LH, United Kingdom
| | - Martin A Crook
- Department of Clinical Biochemistry, University Hospital Lewisham, Lewisham, London, SE13 6LH, United Kingdom.
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13
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Willecke F, Scerbo D, Nagareddy P, Obunike JC, Barrett TJ, Abdillahi ML, Trent CM, Huggins LA, Fisher EA, Drosatos K, Goldberg IJ. Lipolysis, and not hepatic lipogenesis, is the primary modulator of triglyceride levels in streptozotocin-induced diabetic mice. Arterioscler Thromb Vasc Biol 2014; 35:102-10. [PMID: 25395613 DOI: 10.1161/atvbaha.114.304615] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
OBJECTIVE Diabetic hypertriglyceridemia is thought to be primarily driven by increased hepatic de novo lipogenesis. However, experiments in animal models indicated that insulin deficiency should decrease hepatic de novo lipogenesis and reduce plasma triglyceride levels. APPROACH AND RESULTS To address the discrepancy between human data and genetically altered mouse models, we investigated whether insulin-deficient diabetic mice had triglyceride changes that resemble those in diabetic humans. Streptozotocin-induced insulin deficiency increased plasma triglyceride levels in mice. Contrary to the mouse models with impaired hepatic insulin receptor signaling, insulin deficiency did not reduce hepatic triglyceride secretion and de novo lipogenesis-related gene expression. Diabetic mice had a marked decrease in postprandial triglycerides clearance, which was associated with decreased lipoprotein lipase and peroxisome proliferator-activated receptor α mRNA levels in peripheral tissues and decreased lipoprotein lipase activity in skeletal muscle, heart, and brown adipose tissue. Diabetic heterozygous lipoprotein lipase knockout mice had markedly elevated fasting plasma triglyceride levels and prolonged postprandial triglycerides clearance. CONCLUSIONS Insulin deficiency causes hypertriglyceridemia by decreasing peripheral lipolysis and not by an increase in hepatic triglycerides production and secretion.
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Affiliation(s)
- Florian Willecke
- From the Division of Endocrinology, Diabetes and Metabolism, New York University School of Medicine, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Department of Medicine, Columbia University, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Saha Cardiovascular Research Center, University of Kentucky, Lexington (P.N.); Department of Biological Sciences, New York City College of Technology, City University of New York, Brooklyn (J.C.O.); Division of Cardiology and the Marc and Ruti Bell Program in Vascular Biology, Department of Medicine, New York University School of Medicine, New York (T.J.B., E.A.F.); and Department of Pharmacology, Temple University School of Medicine, Center for Translational Medicine, Philadelphia, PA (K.D.)
| | - Diego Scerbo
- From the Division of Endocrinology, Diabetes and Metabolism, New York University School of Medicine, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Department of Medicine, Columbia University, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Saha Cardiovascular Research Center, University of Kentucky, Lexington (P.N.); Department of Biological Sciences, New York City College of Technology, City University of New York, Brooklyn (J.C.O.); Division of Cardiology and the Marc and Ruti Bell Program in Vascular Biology, Department of Medicine, New York University School of Medicine, New York (T.J.B., E.A.F.); and Department of Pharmacology, Temple University School of Medicine, Center for Translational Medicine, Philadelphia, PA (K.D.)
| | - Prabhakara Nagareddy
- From the Division of Endocrinology, Diabetes and Metabolism, New York University School of Medicine, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Department of Medicine, Columbia University, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Saha Cardiovascular Research Center, University of Kentucky, Lexington (P.N.); Department of Biological Sciences, New York City College of Technology, City University of New York, Brooklyn (J.C.O.); Division of Cardiology and the Marc and Ruti Bell Program in Vascular Biology, Department of Medicine, New York University School of Medicine, New York (T.J.B., E.A.F.); and Department of Pharmacology, Temple University School of Medicine, Center for Translational Medicine, Philadelphia, PA (K.D.)
| | - Joseph C Obunike
- From the Division of Endocrinology, Diabetes and Metabolism, New York University School of Medicine, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Department of Medicine, Columbia University, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Saha Cardiovascular Research Center, University of Kentucky, Lexington (P.N.); Department of Biological Sciences, New York City College of Technology, City University of New York, Brooklyn (J.C.O.); Division of Cardiology and the Marc and Ruti Bell Program in Vascular Biology, Department of Medicine, New York University School of Medicine, New York (T.J.B., E.A.F.); and Department of Pharmacology, Temple University School of Medicine, Center for Translational Medicine, Philadelphia, PA (K.D.)
| | - Tessa J Barrett
- From the Division of Endocrinology, Diabetes and Metabolism, New York University School of Medicine, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Department of Medicine, Columbia University, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Saha Cardiovascular Research Center, University of Kentucky, Lexington (P.N.); Department of Biological Sciences, New York City College of Technology, City University of New York, Brooklyn (J.C.O.); Division of Cardiology and the Marc and Ruti Bell Program in Vascular Biology, Department of Medicine, New York University School of Medicine, New York (T.J.B., E.A.F.); and Department of Pharmacology, Temple University School of Medicine, Center for Translational Medicine, Philadelphia, PA (K.D.)
| | - Mariane L Abdillahi
- From the Division of Endocrinology, Diabetes and Metabolism, New York University School of Medicine, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Department of Medicine, Columbia University, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Saha Cardiovascular Research Center, University of Kentucky, Lexington (P.N.); Department of Biological Sciences, New York City College of Technology, City University of New York, Brooklyn (J.C.O.); Division of Cardiology and the Marc and Ruti Bell Program in Vascular Biology, Department of Medicine, New York University School of Medicine, New York (T.J.B., E.A.F.); and Department of Pharmacology, Temple University School of Medicine, Center for Translational Medicine, Philadelphia, PA (K.D.)
| | - Chad M Trent
- From the Division of Endocrinology, Diabetes and Metabolism, New York University School of Medicine, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Department of Medicine, Columbia University, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Saha Cardiovascular Research Center, University of Kentucky, Lexington (P.N.); Department of Biological Sciences, New York City College of Technology, City University of New York, Brooklyn (J.C.O.); Division of Cardiology and the Marc and Ruti Bell Program in Vascular Biology, Department of Medicine, New York University School of Medicine, New York (T.J.B., E.A.F.); and Department of Pharmacology, Temple University School of Medicine, Center for Translational Medicine, Philadelphia, PA (K.D.)
| | - Lesley A Huggins
- From the Division of Endocrinology, Diabetes and Metabolism, New York University School of Medicine, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Department of Medicine, Columbia University, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Saha Cardiovascular Research Center, University of Kentucky, Lexington (P.N.); Department of Biological Sciences, New York City College of Technology, City University of New York, Brooklyn (J.C.O.); Division of Cardiology and the Marc and Ruti Bell Program in Vascular Biology, Department of Medicine, New York University School of Medicine, New York (T.J.B., E.A.F.); and Department of Pharmacology, Temple University School of Medicine, Center for Translational Medicine, Philadelphia, PA (K.D.)
| | - Edward A Fisher
- From the Division of Endocrinology, Diabetes and Metabolism, New York University School of Medicine, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Department of Medicine, Columbia University, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Saha Cardiovascular Research Center, University of Kentucky, Lexington (P.N.); Department of Biological Sciences, New York City College of Technology, City University of New York, Brooklyn (J.C.O.); Division of Cardiology and the Marc and Ruti Bell Program in Vascular Biology, Department of Medicine, New York University School of Medicine, New York (T.J.B., E.A.F.); and Department of Pharmacology, Temple University School of Medicine, Center for Translational Medicine, Philadelphia, PA (K.D.)
| | - Konstantinos Drosatos
- From the Division of Endocrinology, Diabetes and Metabolism, New York University School of Medicine, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Department of Medicine, Columbia University, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Saha Cardiovascular Research Center, University of Kentucky, Lexington (P.N.); Department of Biological Sciences, New York City College of Technology, City University of New York, Brooklyn (J.C.O.); Division of Cardiology and the Marc and Ruti Bell Program in Vascular Biology, Department of Medicine, New York University School of Medicine, New York (T.J.B., E.A.F.); and Department of Pharmacology, Temple University School of Medicine, Center for Translational Medicine, Philadelphia, PA (K.D.)
| | - Ira J Goldberg
- From the Division of Endocrinology, Diabetes and Metabolism, New York University School of Medicine, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Department of Medicine, Columbia University, New York (F.W., D.S., M.L.A., C.M.T., L.A.H., I.J.G.); Saha Cardiovascular Research Center, University of Kentucky, Lexington (P.N.); Department of Biological Sciences, New York City College of Technology, City University of New York, Brooklyn (J.C.O.); Division of Cardiology and the Marc and Ruti Bell Program in Vascular Biology, Department of Medicine, New York University School of Medicine, New York (T.J.B., E.A.F.); and Department of Pharmacology, Temple University School of Medicine, Center for Translational Medicine, Philadelphia, PA (K.D.).
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Bays HE, Tighe AP, Sadovsky R, Davidson MH. Prescription omega-3 fatty acids and their lipid effects: physiologic mechanisms of action and clinical implications. Expert Rev Cardiovasc Ther 2014; 6:391-409. [DOI: 10.1586/14779072.6.3.391] [Citation(s) in RCA: 177] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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15
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Brunschwiler C, Heine D, Kappeler S, Conde-Petit B, Nyström L. Direct measurement of rice bran lipase activity for inactivation kinetics and storage stability prediction. J Cereal Sci 2013. [DOI: 10.1016/j.jcs.2013.06.007] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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16
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Weston N, Fernando U, Baskar V. Hypertriglyceridaemia-induced pancreatitis. BMJ Case Rep 2013; 2013:bcr-2013-008722. [PMID: 23446049 DOI: 10.1136/bcr-2013-008722] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Hypertriglyceridaemia is the third most common cause of acute pancreatitis but is relatively rare and therefore requires a high level of clinical suspicion to be diagnosed. We discuss the case of a 46-year-old man who initially presented to the accident and emergency department with suspected first presentation of diabetic ketoacidosis (DKA) and a normal amylase but who did not respond to DKA treatment. Further history revealed significant cardiovascular risk factors, examination showed an evidence of hyperlipidaemia and investigations revealed acute pancreatitis secondary to hypertriglyceridaemia. We discuss the causes of hypertriglyceridaemia, the difficulty in differentiating primary versus secondary hypertriglyceridaemia, possible pathogenesis and current evidence-based treatments.
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17
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Reaven GM. Insulin Resistance, Compensatory Hyperinsulinemia, and Coronary Heart Disease: Syndrome X Revisited. Compr Physiol 2011. [DOI: 10.1002/cphy.cp070238] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Abstract
Hereditary chronic pancreatitis (HCP) is a rare disease in which chronic pancreatitis develops in childhood. HCP has autosomal dominant inheritance with approximately 80% penetrance. Diagnostic criteria are not universally agreed upon but the EUROPAC trial defined it as two first-degree relatives or at least 3 second-degree relatives in two or more generations, with chronic pancreatitis for which there is no other etiology. The gene for HCP was originally identified on chromosome 7 and subsequently many other genes have been reported to be associated with HCP. To date, no single genetic alteration has been found that is necessary for the development of HCP. In a recent study, 81% of patients with HCP were found to have a mutation of the PRSS1 gene. Patients with HCP are at risk for developing exocrine and endocrine insufficiency and there is a 50-fold increased risk of pancreatic cancer in HCP patients as compared with the general population.
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19
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Abstract
Acute pancreatitis and chronic pancreatitis are complex inflammatory disorders of the pancreas with unpredictable severity, complications, and clinical courses. Growing evidence for genetic risk and modifying factors, plus strong evidence that only a minority of patients with these disorders are heavy alcohol drinkers, has revolutionized our concept of these diseases. Once considered a self-inflicted injury, pancreatitis is now recognized as a complex inflammatory condition like inflammatory bowel disease. Genetic linkage and candidate gene studies have identified six pancreas-targeting factors that are associated with changes in susceptibility to acute and/or chronic pancreatitis, including cationic trypsinogen (PRSS1), anionic trypsinogen (PRSS2), serine protease inhibitor Kazal 1 (SPINK1), cystic fibrosis transmembrane conductance regulator (CFTR), chymotrypsinogen C (CTRC) and calcium-sensing receptor (CASR). Patients with mutations in these genes are at increased risk of pancreatitis caused by a variety of stresses including hyperlipidemia and hypercalcemia. Multiple studies are reporting new polymorphisms, as well as complex gene x gene and gene x environmental interactions.
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Affiliation(s)
- David C Whitcomb
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
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20
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Abstract
While the precise definition of hypertriglyceridaemia remains contentious, the condition is becoming more common in western populations as the prevalence of obesity and diabetes mellitus rise. Although there is strong epidemiological evidence that hypertriglyceridaemia is an independent risk factor for cardiovascular disease, it is has been difficult to demonstrate this by drug intervention studies, as drugs that reduce triglycerides also raise high density lipoprotein cholesterol. Precise target values have also been difficult to agree, although several of the new guidelines for coronary risk management now include triglycerides. The causes of hypertriglyceridaemia are numerous. The more severe forms have a genetic basis, and may lead to an increased risk of pancreatitis. Several types of hypertriglyceridaemia are familial and are associated with increased cardiovascular risk. Secondary causes of hypertriglyceridaemia are also numerous and it is important to exclude these before starting treatment with specific triglyceride-lowering agents. Lifestyle management is also very effective and includes weight reduction, restricted alcohol and fat intake and exercise.
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21
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Abstract
Pancreatitis (necroinflammation of the pancreas) has both acute and chronic manifestations. Gallstones are the major cause of acute pancreatitis, whereas alcohol is associated with acute as well as chronic forms of the disease. Cases of true idiopathic pancreatitis are steadily diminishing as more genetic causes of the disease are discovered. The pathogenesis of acute pancreatitis has been extensively investigated over the past four decades; the general current consensus is that the injury is initiated within pancreatic acinar cells subsequent to premature intracellular activation of digestive enzymes. Repeated attacks of acute pancreatitis have the potential to evolve into chronic disease characterized by fibrosis and loss of pancreatic function. Our knowledge of the process of scarring has advanced considerably with the isolation and study of pancreatic stellate cells, now established as the key cells in pancreatic fibrogenesis. The present review summarizes recent developments in the field particularly with respect to the progress made in unraveling the molecular mechanisms of acute and chronic pancreatic injury secondary to gallstones, alcohol and genetic factors. It is anticipated that continued research in the area will lead to the identification and characterization of molecular pathways that may be therapeutically targeted to prevent/inhibit the initiation and progression of the disease.
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Affiliation(s)
- Alain Vonlaufen
- Pancreatic Research Group, South Western Sydney Clinical School, Liverpool Hospital and The University of New South Wales, Sydney, Australia
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22
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Association of APOA5 −1131T>C and S19W gene polymorphisms with both mild hypertriglyceridemia and hyperchylomicronemia in type 2 diabetic patients. Clin Chim Acta 2008; 394:99-103. [DOI: 10.1016/j.cca.2008.04.013] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2008] [Revised: 04/19/2008] [Accepted: 04/19/2008] [Indexed: 11/30/2022]
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Abstract
OBJECTIVES The aim of this study was to assess retrospectively the prevalence and the predictive factors of acute pancreatitis (AP) in a population of patients referred in our endocrinology department for evaluation of very high triglyceride (TG) levels. METHODS One hundred twenty-nine patients (119 with type IV phenotypes and 10 with type V phenotypes according to Fredrickson's classification) were referred to our hospital between 2000 and 2005. RESULTS Twenty-six subjects (20.2% of the population) presented with AP. This population was significantly younger at diagnosis of hyperlipidemia (32 vs 40 years, P < 0.001) and at age of investigation (43 vs 48 years, P = 0.05) and had maximum TG levels greater than the population without AP (44.7 vs 24.5, P < 0.001). Subjects of the third tertile of TG levels had a 4.0-fold increased risk (95% confidence interval, 1.3-12.3) of AP compared with the first tertile. Severe pancreatitis (need for intensive care, C-reactive protein >150 mg/L, or Balthazar score >C) was observed in 71.5% of the patients. CONCLUSIONS Twenty percent of patients with severe hypertriglyceridemia experience at least 1 attack of AP. Pancreatitis seems to occur in young patients at higher levels of TG than previously thought (85% of patients >30 g/L) and is associated with a severe clinical course.
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24
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Abstract
Hereditary chronic pancreatitis (HCP) is a very rare form of early-onset chronic pancreatitis. Apart from young age at diagnosis and a slower progression, the clinical course, morphological features and laboratory findings of HCP do not differ from those of patients with alcoholic chronic pancreatitis. Diagnostic criteria and treatment of HCP also resemble those of chronic pancreatitis of other causes. The clinical presentation is highly variable and includes chronic abdominal pain, impairment of endocrine and exocrine pancreatic function, nausea and vomiting, maldigestion, diabetes, pseudocysts, bile-duct and duodenal obstruction, and rarely pancreatic cancer. Fortunately, the disease is mild in most patients. Mutations in the PRSS1 gene, encoding cationic trypsinogen, play a causative role in chronic pancreatitis. It has been shown that the PRSS1 mutations increase autocatalytic conversion of trypsinogen to active trypsin, and thus probably cause premature, intrapancreatic trypsinogen activation, disturbing the intrapancreatic balance of proteases and their inhibitors. Other genes--such as the anionic trypsinogen (PRSS2), the serine protease inhibitor Kazal type 1 (SPINK1), and the cystic fibrosis transmembrane conductance regulator (CFTR)--have also been found to be associated with chronic pancreatitis (idiopathic and hereditary). Genetic testing should only be performed in carefully selected patients by direct DNA sequencing, and antenatal diagnosis should not be encouraged. Treatment focuses on enzyme and nutritional supplementation, pain management, pancreatic diabetes, and local organ complications such as pseudocysts and bile-duct or duodenal obstruction. The disease course and prognosis of patients with HCP is unpredictable. The risk of pancreatic cancer is elevated. Therefore, HCP patients should strongly avoid environmental risk factors for pancreatic cancer.
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25
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Lee J, Goldberg IJ. Hypertriglyceridemia-induced pancreatitis created by oral estrogen and in vitro fertilization ovulation induction. J Clin Lipidol 2008; 2:63-6. [PMID: 19190717 PMCID: PMC2350225 DOI: 10.1016/j.jacl.2007.11.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Hypertriglyceridemia is one of the known causes of pancreatitis. Estrogen treatment can aggravate hypertriglyceridemia by increasing very low density lipoprotein secretion and reducing hepatic triglyceride lipase. In this paper, we present 3 patients who developed severe hypertriglyceridemia with conditions that increased estrogen. Two patients were found to have genetic lipoprotein lipase deficiency and were treated with birth control pills. The third was a patient with polycystic ovary disease who was receiving ovulation induction therapy for in vitro fertilization.
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Affiliation(s)
- Jee Lee
- Division of Preventive Medicine and Nutrition, Columbia University, New York, NY 10032
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26
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Rosendahl J, Bödeker H, Mössner J, Teich N. Hereditary chronic pancreatitis. Orphanet J Rare Dis 2007; 2:1. [PMID: 17204147 PMCID: PMC1774562 DOI: 10.1186/1750-1172-2-1] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2006] [Accepted: 01/04/2007] [Indexed: 12/19/2022] Open
Abstract
Hereditary chronic pancreatitis (HCP) is a very rare form of early onset chronic pancreatitis. With the exception of the young age at diagnosis and a slower progression, the clinical course, morphological features and laboratory findings of HCP do not differ from those of patients with alcoholic chronic pancreatitis. As well, diagnostic criteria and treatment of HCP resemble that of chronic pancreatitis of other causes. The clinical presentation is highly variable and includes chronic abdominal pain, impairment of endocrine and exocrine pancreatic function, nausea and vomiting, maldigestion, diabetes, pseudocysts, bile duct and duodenal obstruction, and rarely pancreatic cancer. Fortunately, most patients have a mild disease. Mutations in the PRSS1 gene, encoding cationic trypsinogen, play a causative role in chronic pancreatitis. It has been shown that the PRSS1 mutations increase autocatalytic conversion of trypsinogen to active trypsin, and thus probably cause premature, intrapancreatic trypsinogen activation disturbing the intrapancreatic balance of proteases and their inhibitors. Other genes, such as the anionic trypsinogen (PRSS2), the serine protease inhibitor, Kazal type 1 (SPINK1) and the cystic fibrosis transmembrane conductance regulator (CFTR) have been found to be associated with chronic pancreatitis (idiopathic and hereditary) as well. Genetic testing should only be performed in carefully selected patients by direct DNA sequencing and antenatal diagnosis should not be encouraged. Treatment focuses on enzyme and nutritional supplementation, pain management, pancreatic diabetes, and local organ complications, such as pseudocysts, bile duct or duodenal obstruction. The disease course and prognosis of patients with HCP is unpredictable. Pancreatic cancer risk is elevated. Therefore, HCP patients should strongly avoid environmental risk factors for pancreatic cancer.
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Affiliation(s)
- Jonas Rosendahl
- Medizinische Klinik und Poliklinik II, Universität Leipzig, Germany
| | - Hans Bödeker
- Medizinische Klinik und Poliklinik II, Universität Leipzig, Germany
| | - Joachim Mössner
- Medizinische Klinik und Poliklinik II, Universität Leipzig, Germany
| | - Niels Teich
- Medizinische Klinik und Poliklinik II, Universität Leipzig, Germany
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27
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Abstract
Hypertriglyceridemia is an established cause of pancreatitis. In a case-based approach, we present a review of hypertriglyceridemia and how it can cause pancreatitis. We outline how to investigate and manage such patients. A 35 year old man presented to the emergency department with abdominal pain and biochemical evidence of acute pancreatitis. There was no history of alcohol consumption and biliary imaging was normal. The only relevant past medical history was that of mild hyperlipidemia, treated with diet alone. Physical exam revealed epigastric tenderness, right lateral rectus palsy, lipemia retinalis, bitemporal hemianopsia and a delay in the relaxation phase of his ankle reflexes. Subsequent laboratory investigation revealed marked hypertriglyceridemia and panhypopituarism. An enhanced CT scan of the head revealed a large suprasellar mass impinging on the optic chiasm and hypothalamus. The patient was treated supportively; thyroid replacement and lipid lowering agents were started. He underwent a successful resection of a craniopharyngioma. Post-operatively, the patient did well on hormone replacement therapy. He has had no further attacks of pancreatitis. This case highlights many of the factors involved in the regulation of triglyceride metabolism. We review the common causes of hypertriglyceridemia and the proposed mechanisms resulting in pancreatitis. The incidence and management of hypertriglyceridemia-induced pancreatitis are also discussed.
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Affiliation(s)
- S-Ian Gan
- Division of Gastroenterology and Endocrinology, Foothills Hospital, University of Calgary, Calgary, Alberta, Canada
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Lerch MM, Zenker M, Turi S, Mayerle J. Developmental and metabolic disorders of the pancreas. Endocrinol Metab Clin North Am 2006; 35:219-41, vii. [PMID: 16632089 DOI: 10.1016/j.ecl.2006.02.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
The pancreas is an important exocrine and endocrine organ that develops from the dorsal and ventral anlagen during embryogenesis and arises from the endodermal lining of the duodenum within the first month of human embryonic life. A number of developmental disorders can either lead to anatomic abnormalities of the pancreas and its ducts, or can be part of complex disorders that affect multiorgan systems. Other genetic changes can lead to metabolic abnormalities that affect the pancreas exclusively or increase the lifetime risk for developing pancreatitis or pancreatic diabetes. This article reviews some of the developmental and metabolic disorders that can affect the endocrine and exocrine pancreas.
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Affiliation(s)
- Markus M Lerch
- Department of Gastroenterology, Endocrinology and Nutrition, Ernst-Moritz-Arndt-University, Friedrich-Loeffler-Strasse 23A, Greifswald 17485, Germany.
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Woodman RJ, Chew GT, Watts GF. Mechanisms, Significance and Treatment of Vascular Dysfunction in Type 2 Diabetes Mellitus. Drugs 2005; 65:31-74. [PMID: 15610050 DOI: 10.2165/00003495-200565010-00003] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Endothelial dysfunction and increased arterial stiffness occur early in the pathogenesis of diabetic vasculopathy. They are both powerful independent predictors of cardiovascular risk. Advances in non-invasive methodologies have led to widespread clinical investigation of these abnormalities in diabetes mellitus, generating a wealth of new knowledge concerning the mechanisms of vascular dysfunction, risk factor associations and potential treatment targets. Endothelial dysfunction primarily reflects decreased availability of nitric oxide (NO), a critical endothelium-derived vasoactive factor with vasodilatory and anti-atherosclerotic properties. Techniques for assessing endothelial dysfunction include ultrasonographic measurement of flow-mediated vasodilatation of the brachial artery and plethysmography measurement of forearm blood flow responses to vasoactive agents. Arterial stiffness may be assessed using pulse wave analysis to generate measures of pulse wave velocity, arterial compliance and wave reflection. The pathogenesis of endothelial dysfunction in type 2 diabetes is multifactorial, with principal contributors being oxidative stress, dyslipidaemia and hyperglycaemia. Elevated blood glucose levels drive production of reactive oxidant species (ROS) via multiple pathways, resulting in uncoupling of mitochondrial oxidative phosphorylation and endothelial NO synthase (eNOS) activity, reducing NO availability and generating further ROS. Hyperglycaemia also contributes to accelerated arterial stiffening by increasing formation of advanced glycation end-products (AGEs), which alter vessel wall structure and function. Diabetic dyslipidaemia is characterised by accumulation of triglyceride-rich lipoproteins, small dense low-density lipoprotein (LDL) particles, reduced high-density lipoprotein (HDL)-cholesterol and increased postprandial free fatty acid flux. These lipid abnormalities contribute to increasing oxidative stress and may directly inhibit eNOS activity. Although lipid-regulating agents such as HMG-CoA reductase inhibitors (statins), fibric acid derivatives (fibrates) and fish oils are used to treat diabetic dyslipidaemia, their impact on vascular function is less clear. Studies in type 2 diabetes have yielded inconsistent results, but this may reflect sampling variation and the potential over-riding influence of oxidative stress, dysglycaemia and insulin resistance on endothelial dysfunction. Results of positive intervention trials suggest that improvement in vascular function is mediated by both lipid and non-lipid mechanisms, including anti-inflammatory, anti-oxidative and direct effects on the arterial wall. Other treatments, such as renin-angiotensin-aldosterone system antagonists, insulin sensitisers and lifestyle-based interventions, have shown beneficial effects on vascular function in type 2 diabetes. Novel approaches, targeting eNOS and AGEs, are under development, as are new lipid-regulating therapies that more effectively lower LDL-cholesterol and raise HDL-cholesterol. Combination therapy may potentially increase therapeutic efficacy and permit use of lower doses, thereby reducing the risk of adverse drug effects and interactions. Concomitant treatments that specifically target oxidative stress may also improve endothelial dysfunction in diabetes. Vascular function studies can be used to explore the therapeutic potential and mechanisms of action of new and established interventions, and provide useful surrogate measures for cardiovascular endpoints in clinical trials.
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Affiliation(s)
- Richard J Woodman
- School of Medicine and Pharmacology, University of Western Australia, and West Australian Heart Research Institute, Perth, Western Australia, Australia
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Cai G, Cole SA, Freeland-Graves JH, MacCluer JW, Blangero J, Comuzzie AG. Genome-wide scans reveal quantitative trait Loci on 8p and 13q related to insulin action and glucose metabolism: the San Antonio Family Heart Study. Diabetes 2004; 53:1369-74. [PMID: 15111508 DOI: 10.2337/diabetes.53.5.1369] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Type 2 diabetes is a complex disease that arises from physiological disruptions of the body's sensitivity to insulin and ability to metabolize glucose. Multipoint linkage analyses for insulin sensitivity phenotypes were conducted in 1,280 Mexican Americans from 41 families who participated in the San Antonio Family Heart Study. A significant linkage signal (logarithm of odds [LOD] = 2.98) affecting corrected insulin response to glucose was detected on chromosome 13q between D13787 and D13S252, in the region where the MODY-4 gene has previously been mapped. Another signal on chromosome 13 was observed at D13S285 (LOD = 1.86), where the insulin receptor substrate 2 gene resides. Significant linkage (LOD = 3.09) for insulin response to glucose was found on chromosome 8 between D8S1130 and D8S1106, near the lipoprotein lipase and macrophage scavenger receptor genes. Multipoint analysis of abdominal skinfold with an LOD of 2.68 showed signals in the same region. There was also suggestive evidence for linkage of quantitative insulin sensitivity check index and fasting glucose to a previously reported location at D9S301 (LOD = 2.19). These results indicate that chromosomal locations on 8p and 13q might harbor genes that affect a variety of insulin- and glucose-related phenotypes that contribute to the observed variations in these important risk factors for diabetes in Mexican Americans.
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Affiliation(s)
- Guowen Cai
- Department of Genetics, Southwest Foundation for Biomedical Research, 7620 NW Loop 410, San Antonio, TX 78227-5301, USA
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Abstract
The venues opened to all by the remarkable studies of the genome are just starting to become manifest; they can now distinguish different variants of a disease; they are given the tools to better understand the pathophysiology of illness; they hope to be able to provide better treatment alternatives to our patients. The examples described in this review demonstrate the applicability of these concepts to pancreatic disorders. Researchers may be just scratching the surface at this time, but the potential is enormous. Many philosophic and ethical questions need to be answered as physicians move along: Should all family members of an index case be screened? Who should pay for testing? Who should get results? But, without the participation of so many patients, their family members, and numerous volunteers, researchers would not have witnessed the bridging of so many gaps as they have so far. All of us may now look forward to the application of this incredible knowledge to the therapeutic solutions so eagerly awaited.
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Affiliation(s)
- Véronique Morinville
- Division of Gastroenterology and Nutrition, McGill University Health Center, Montreal Children's Hospital, 2300 Tupper Street #D562, Montreal, QC H3H 1P3 Canada
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Jap TS, Jenq SF, Wu YC, Chiu CY, Cheng HM. Mutations in the lipoprotein lipase gene as a cause of hypertriglyceridemia and pancreatitis in Taiwan. Pancreas 2003; 27:122-6. [PMID: 12883259 DOI: 10.1097/00006676-200308000-00003] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
INTRODUCTION Familial lipoprotein lipase (LPL) deficiency is inherited as an autosomal recessive trait and is characterized by chylomicronemia, eruptive xanthoma, hepatosplenomegaly, and recurrent pancreatitis. AIMS AND METHODOLOGY Two unrelated Chinese of Han descent with hypertriglyceridemia were enrolled in this study, and another six Han Chinese with no family history of hypertriglyceridemia and diabetes were recruited as normal controls. LPL activity was determined with use of an artificial substrate of 14C-trioleine and Arabic gum, and release of 14C free fatty acid was determined by the liquid-liquid partitioning system. LPL mass was measured by enzyme immunoassay. Genomic DNA was extracted from EDTA-preserved whole blood, and PCR was used to amplify the nine coding exons and the minimal promoter of the LPL gene. RESULTS DNA sequence analysis revealed that mutations were identified in both patients; one patient had compound heterozygous mutations in codon 252 [CTG(Leu) --> GTG(Val)] and in codon 264 [TGC(Cys) --> TGa(Ter)] of exon 6, and the other patient had homozygous L252V mutation. These subjects had > or =90% reduction in LPL mass and > or =60% reduction in LPL activity. CONCLUSION The mutated and truncated LPLs caused hypertriglyceridemia in these patients in Taiwan with hypertriglyceridemia and pancreatitis.
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Affiliation(s)
- Tjin-Shing Jap
- Section of Biochemistry, Department of Pathology and Laboratory Medicine, Veterans General Hospital-Taipei, Taiwan, ROC.
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Abstract
BACKGROUND The pathogenesis of chronic pancreatitis (CP) remains poorly understood. Recently, molecular biology has identified the genetic background for many patients with hereditary CP. In addition, a number of studies have focused on the detection of proto-oncogenes and tumour suppressor gene mutations in the pathogenesis of CP. So far, the use of these mutations (with the exception of mutations causing hereditary CP), as diagnostic and prognostic markers is still controversial. DISCUSSION It is well known that the risk of pancreatic cancer in patients with CP, especially the hereditary form, is high. At present, there is insufficient evidence to show a clear relationship between the development of pancreatic cancer and certain mutations. New biotechnological methods, such as DNA array expression analysis, expand our knowledge of the molecular pathogenesis of this disease and may help to develop specific diagnostic, prognostic and therapeutic tools. However, until long-term studies examine the safety and efficacy of certain genetic markers, long-term follow-up of patients with CP who harbour mutations is needed.
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Affiliation(s)
- D Paramythiotis
- Department of General Surgery, University of HeidelbergHeidelbergGermany
| | - J Kleeff
- Department of General Surgery, University of HeidelbergHeidelbergGermany
| | - J Schmidt
- Department of General Surgery, University of HeidelbergHeidelbergGermany
| | - Mw Büchler
- Department of General Surgery, University of HeidelbergHeidelbergGermany
| | - H Friess
- Department of General Surgery, University of HeidelbergHeidelbergGermany
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Simon P, Weiss FU, Zimmer KP, Koch HG, Lerch MM. Acute and chronic pancreatitis in patients with inborn errors of metabolism. Pancreatology 2002; 1:448-56. [PMID: 12120223 DOI: 10.1159/000055846] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Acute and chronic recurrent pancreatitis have been reported in patients with a variety of inborn errors of metabolism. Among these are hyperlipidaemias, various disorders of branched-chain amino acid degradation, homocystinuria, haemolytic disorders, acute intermittent porphyria and several amino acid transporter defects. Some of these disease entities are exceedingly rare. In most of these disorders, pancreatitis is not very common and, with the exception of lipoprotein lipase and apolipoprotein C-II deficiency, is neither the leading nor the clinically most distressing manifestation of the underlying metabolic defect. The majority of these syndromes are, however, inherited, and often entire kindreds are carriers of well-defined germline mutations that can, to varying degrees, be associated with pancreatitis. We have reviewed the clinical, biochemical and genetic characteristics of those inborn errors of metabolism because interesting information can be gained from the in regard to the pathophysiology of pancreatitis and because they need to be distinguished from other hereditary causes of the disease.
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Affiliation(s)
- P Simon
- Departments of Medicine B and Pediatrics, Westfälische Wilhelms-Universität, Münster, Albert-Schweitzer-Strasse 33, D-48129 Münster, Germany
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Abstract
The utilization of recent advances in molecular and genomic technologies and progress in pancreatic imaging techniques provided remarkable insight into genetic, environmental, immunologic, and pathobiological factors leading to chronic pancreatitis. Translation of these advances into clinical practice demands a reassessment of current approaches to diagnosis, classification, and staging. We conclude that an adequate pancreatic biopsy must be the gold standard against which all diagnostic approaches are judged. Although computed tomography remains the initial test of choice for the diagnosis of chronic pancreatitis, the roles of endoscopic retrograde pancreatography, endoscopic ultrasonography, and magnetic resonance imaging are considered. Once chronic pancreatitis is diagnosed, proper classification becomes important. Major predisposing risk factors to chronic pancreatitis may be categorized as either (1) toxic-metabolic, (2) idiopathic, (3) genetic, (4) autoimmune, (5) recurrent and severe acute pancreatitis, or (6) obstructive (TIGAR-O system). After classification, staging of pancreatic function, injury, and fibrosis becomes the next major concern. Further research is needed to determine the clinical and natural history of chronic pancreatitis developing in the context of various risk factors. New methods are needed for early diagnosis of chronic pancreatitis, and new therapies are needed to determine whether interventions will delay or prevent the progression of the irreversible damage characterizing end-stage chronic pancreatitis.
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Affiliation(s)
- B Etemad
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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Gilbert B, Rouis M, Griglio S, de Lumley L, Laplaud P. Lipoprotein lipase (LPL) deficiency: a new patient homozygote for the preponderant mutation Gly188Glu in the human LPL gene and review of reported mutations: 75 % are clustered in exons 5 and 6. ANNALES DE GENETIQUE 2001; 44:25-32. [PMID: 11334614 DOI: 10.1016/s0003-3995(01)01037-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
We have investigated the lipoprotein lipase (LPL) gene of a 2-year-old patient presenting classical features of the familial LPL deficiency including undetectable LPL activity. DNA sequence analysis of exon 5 identified the patient as a homozygote for the Gly188Glu mutation, frequently involved in this disease. A review of cases of LPL deficiency with molecular study of the LPL gene showed a total number of 221 reported mutations involved in this disease. Gly188Glu was involved in 23.5 % of cases and 74.6 % of mutations were clustered in exons 5 and 6. Based on these observations, we propose a method of screening for mutations in this gene.
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Affiliation(s)
- B Gilbert
- Unité de génétique, hôpital Dupuytren, Limoges, France.
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37
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Foubert L, Bruin T, De Gennes JL, Ehrenborg E, Furioli J, Kastelein J, Benlian P, Hayden M. A single Ser259Arg mutation in the gene for lipoprotein lipase causes chylomicronemia in Moroccans of Berber ancestry. Hum Mutat 2000; 10:179-85. [PMID: 9298816 DOI: 10.1002/(sici)1098-1004(1997)10:3<179::aid-humu1>3.0.co;2-e] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Lipoprotein lipase (LPL) is the rate-limiting enzyme for the hydrolysis of triglyceride-rich lipoproteins. Numerous LPL gene mutations have been described as a cause of familial chylomicronemia in various populations. In general, allelic heterogeneity is observed in LPL deficiency in different populations. However, a founder effect has been reported in certain populations, such as French Canadians. Although familial chylomicronemia is observed in Morocco, the molecular basis for the disease remains unknown. Here, we report two unrelated Moroccan families of Berber ancestry, ascertained independently in Holland and France. In both probands, familial chylomicronemia manifested in infancy and was complicated with acute pancreatitis at age 2 years. Both probands were homozygous for a Ser259Arg mutation, which results in the absence of LPL catalytic activity both in vivo and in vitro. In heterozygous relatives, a partial decrease in plasma LPL activity was observed, sometimes associated with combined hyperlipidemia. This mutation previously unreported in other populations segregated on an identical haplotype, rarely observed in Caucasians, in both families. Therefore, LPL deficiency is a cause of familial chylomicronemia in Morocco and may result from a founder effect in patients of Berber ancestry.
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Affiliation(s)
- L Foubert
- Medical Genetics, University of British Columbia, Vancouver, Canada
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38
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Cohn JA, Bornstein JD, Jowell PS. Cystic fibrosis mutations and genetic predisposition to idiopathic chronic pancreatitis. Med Clin North Am 2000; 84:621-31, ix. [PMID: 10872419 DOI: 10.1016/s0025-7125(05)70245-5] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Idiopathic chronic pancreatitis is a leading cause of chronic pancreatitis. Work from this and other groups has shown that idiopathic chronic pancreatitis is associated with mutations of the cystic fibrosis gene (CFTR). Many idiopathic pancreatitis patients have compound heterozygote genotypes in which both copies of the CFTR gene are abnormal. In these patients, the pancreatic disease can be viewed as a mild variant of cystic fibrosis, in which there is sufficient residual CFTR function to prevent lung disease. This article summarizes the evidence associating these abnormal CFTR genotypes with idiopathic chronic pancreatitis and reviews the implications of this association for the pathogenesis, classification, and prevention of pancreatitis.
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Affiliation(s)
- J A Cohn
- Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
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39
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Mann WA, Meyer N, Berg D, Greten H, Beisiegel U. Lipoprotein lipase compensates for the defective function of apo E variants in vitro by interacting with proteoglycans and lipoprotein receptors. Atherosclerosis 1999; 145:61-9. [PMID: 10428296 DOI: 10.1016/s0021-9150(99)00015-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Lipoprotein lipase (LPL) and apolipoprotein E (apo E) independently enhance binding and uptake of lipoproteins to cells. A coordinate effect of LPL and apo E has been previously described in human hepatozytes where simultaneous addition of both proteins resulted in an additive increase of chylomicron binding and uptake. The role of lipoprotein receptors and proteoglycans in this coordinate effect was now analysed using various cell types and heparinase treatment. To investigate a pathophysiological relevance, the effect of LPL and normal apo E-3 was compared to LPL and four apo E variants, associated with type III hyperlipoproteinemia (HLP). Apo E-3 and LPL increased the binding and uptake of chylomicrons and beta-very low density lipoproteins (VLDL) in an additive way in all cell types analysed, except proteoglycan deficient Chinese hamster ovary (CHO)-cells. Heparinase treatment almost completely abolished the effect of apo E and LPL. Addition of LPL to the apo E variants resulted in significant compensation of their defective function in mediating beta-VLDL binding to low density lipoprotein (LDL)-receptor defective fibroblasts. These findings indicate that the coordinate effect of apo E and LPL is mediated by proteoglycans and lipoprotein receptors, independent of the LDL receptor. LPL may compensate for the defective function of apo E variants by enhancing lipoprotein binding to these receptors. Defects in this mechanism may explain how mutations in the LPL molecule contribute to the manifestation of type III HLP in addition to the presence of a defective apo E.
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Affiliation(s)
- W A Mann
- Medical Clinic, University Hospital Eppendorf, Hamburg, Germany.
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40
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Hammell AB, Taylor RC, Peltz SW, Dinman JD. Identification of Putative Programmed −1 Ribosomal Frameshift Signals in Large DNA Databases. Genome Res 1999. [DOI: 10.1101/gr.9.5.417] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The cis-acting elements that promote efficient ribosomal frameshifting in the −1 (5′) direction have been well characterized in several viral systems. Results from many studies have convincingly demonstrated that the basic molecular mechanisms governing programmed −1 ribosomal frameshifting are almost identical from yeast to humans. We are interested in testing the hypothesis that programmed −1 ribosomal frameshifting can be used to control cellular gene expression. Toward this end, a computer program was designed to search large DNA databases for consensus −1 ribosomal frameshift signals. The results demonstrated that consensus programmed −1 ribosomal frameshift signals can be identified in a substantial number of chromosomally encoded mRNAs and that they occur with frequencies from two- to sixfold greater than random in all of the databases searched. A preliminary survey of the databases resulting from the computer searches found that consensus frameshift signals are present in at least 21 homologous genes from different species, 2 of which are nearly identical, suggesting evolutionary conservation of function. We show that four previously described missense alleles of genes that are linked to human diseases would disrupt putative programmed −1 ribosomal frameshift signals, suggesting that the frameshift signal may be involved in the normal expression of these genes. We also demonstrate that signals found in the yeastRAS1 and the human CCR5 genes were able to promote significant levels of programmed −1 ribosomal frameshifting. The significance of these frameshifting signals in controlling gene expression is not known, however.
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41
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Hammell AB, Taylor RC, Peltz SW, Dinman JD. Identification of putative programmed -1 ribosomal frameshift signals in large DNA databases. Genome Res 1999; 9:417-27. [PMID: 10330121 PMCID: PMC310776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/12/2023]
Abstract
The cis-acting elements that promote efficient ribosomal frameshifting in the -1 (5') direction have been well characterized in several viral systems. Results from many studies have convincingly demonstrated that the basic molecular mechanisms governing programmed -1 ribosomal frameshifting are almost identical from yeast to humans. We are interested in testing the hypothesis that programmed -1 ribosomal frameshifting can be used to control cellular gene expression. Toward this end, a computer program was designed to search large DNA databases for consensus -1 ribosomal frameshift signals. The results demonstrated that consensus programmed -1 ribosomal frameshift signals can be identified in a substantial number of chromosomally encoded mRNAs and that they occur with frequencies from two- to sixfold greater than random in all of the databases searched. A preliminary survey of the databases resulting from the computer searches found that consensus frameshift signals are present in at least 21 homologous genes from different species, 2 of which are nearly identical, suggesting evolutionary conservation of function. We show that four previously described missense alleles of genes that are linked to human diseases would disrupt putative programmed -1 ribosomal frameshift signals, suggesting that the frameshift signal may be involved in the normal expression of these genes. We also demonstrate that signals found in the yeast RAS1 and the human CCR5 genes were able to promote significant levels of programmed -1 ribosomal frameshifting. The significance of these frameshifting signals in controlling gene expression is not known, however.
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Affiliation(s)
- A B Hammell
- Department of Molecular Genetics and Microbiology, University of Medicine and Dentistry of New Jersey (UMDNJ), Robert Wood Johnson Medical School, and The Graduate Programs in Molecular Bioscience Rutgers/UMDNJ, Piscataway, New Jersey 08854, USA
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42
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Watts GF, Playford DA. Dyslipoproteinaemia and hyperoxidative stress in the pathogenesis of endothelial dysfunction in non-insulin dependent diabetes mellitus: an hypothesis. Atherosclerosis 1998; 141:17-30. [PMID: 9863535 DOI: 10.1016/s0021-9150(98)00170-1] [Citation(s) in RCA: 80] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Endothelial dysfunction in non-insulin dependent (Type 2) diabetes mellitus (NIDDM) has implications for the pathogenesis of the two major complications, macrovascular disease and microangiopathy. Endothelial dysfunction is a consequence of a disturbance in the L-arginine/nitric oxide pathway. Its occurrence in NIDDM is well supported by both in vitro and in vivo studies. NIDDM results in diverse abnormalities in lipoprotein metabolism, the most significant being hypertriglyceridaemia which is associated with increased plasma concentrations of small dense LDL and low levels of HDL. Dysglycaemia results in hyperoxidative stress and increased formation of advanced-glycosylation endproducts, both of which enhance the oxidative modification of lipoprotein particles. Based on extensive in vitro studies and on human data, we generate the hypothesis that the development of endothelial dysfunction in NIDDM is a consequence of the effect of dyslipoproteinaemia, in particular increased circulatory concentrations of modified small dense LDL and of hyperoxidative stress on the formation, action and disposal of nitric oxide, by diverse molecular mechanisms; HDL is proposed to have a protective effect on these processes through its enzymic antioxidant properties. The hypothesis proposed is simple, testable and consistent with wide sources of evidence. The practical implications of the hypothesis and the existing opportunities for the prevention and reversal of endothelial dysfunction in NIDDM are also reviewed and discussed.
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Affiliation(s)
- G F Watts
- Department of Medicine, University of Western Australia, Royal Perth Hospital, Australia
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43
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Abstract
The chylomicronemia syndrome is a disorder characterized by severe hypertriglyceridemia and fasting chylomicronemia. Genetic causes of the syndrome are rare and include deficiency of lipoprotein lipase (LPL), apolipoprotein C-II, and familial inhibitor of LPL. Patients with familial forms of hypertriglyceridemia in combination with secondary acquired disorders account for most individuals presenting with chylomicronemia. The clinical manifestations--lipid and other biochemical abnormalities--as well as treatment options for chylomicronemic patients are discussed.
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Affiliation(s)
- S Santamarina-Fojo
- Section of Molecular Biology, Molecular Disease Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA
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44
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Semenkovich CF, Coleman T, Daugherty A. Effects of heterozygous lipoprotein lipase deficiency on diet-induced atherosclerosis in mice. J Lipid Res 1998. [DOI: 10.1016/s0022-2275(20)32538-4] [Citation(s) in RCA: 51] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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45
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Nordestgaard BG, Abildgaard S, Wittrup HH, Steffensen R, Jensen G, Tybjaerg-Hansen A. Heterozygous lipoprotein lipase deficiency: frequency in the general population, effect on plasma lipid levels, and risk of ischemic heart disease. Circulation 1997; 96:1737-44. [PMID: 9323055 DOI: 10.1161/01.cir.96.6.1737] [Citation(s) in RCA: 92] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Patients with mutations on both alleles of the lipoprotein lipase gene resulting in complete lipoprotein lipase deficiency exhibit the chylomicronemia syndrome with severe hypertriglyceridemia and increased risk of pancreatitis and possibly of ischemic heart disease. This study examined frequency, lipid levels, and risk of ischemic heart disease for heterozygous carriers of lipoprotein lipase mutations known to cause the chylomicronemia syndrome in the homozygous state. METHODS AND RESULTS Two mutations were screened for in 9259 individuals in a general population sample and in 948 patients with verified ischemic heart disease. The percent frequencies of heterozygous individuals with the Gly188-->Glu and Ile194-->Thr substitutions in the general population were 0.06% (95% CI, 0.04% to 0.23%) and 0% (95% CI, 0.00% to 0.12%), respectively. The Gly188-->Glu substitution was associated with an increase in plasma triglycerides of 0.8+/-0.3 mmol/L (mean+/-SEM) and a decrease in plasma HDL cholesterol, apo A-I, and glucose levels of 0.45+/-0.07 mmol/L, 17+/-6 mg/dL, and 1.1+/-0.2 mmol/L, respectively. On multiple logistic regression analysis allowing for age, sex, plasma cholesterol, plasma lipoprotein (a), hypertension, diabetes mellitus, smoking, and body mass index, both plasma triglycerides and HDL cholesterol levels were independent predictors of ischemic heart disease. Finally, the Gly188-->Glu substitution was more common among patients with verified ischemic heart disease (percent frequency of heterozygous individuals, 0.32%) than among individuals from the general population (odds ratio, 4.9; 95% CI, 1.2 to 19.6). The effects of the Gly188-->Glu substitution were more pronounced than those of the common Asn291-->Ser substitution. CONCLUSIONS Heterozygous lipoprotein lipase deficiency due to the Gly188-->Glu substitution appears to increase plasma triglycerides and reduce HDL levels and may thereby predispose carriers to ischemic heart disease.
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Affiliation(s)
- B G Nordestgaard
- Department of Clinical Biochemistry, Herlev University Hospital, Denmark
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46
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Hokanson JE. Lipoprotein lipase gene variants and risk of coronary disease: a quantitative analysis of population-based studies. INTERNATIONAL JOURNAL OF CLINICAL & LABORATORY RESEARCH 1997; 27:24-34. [PMID: 9144024 DOI: 10.1007/bf02827239] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The purpose of this study is to quantify the magnitude of the association between common variants in the lipoprotein lipase gene and coronary disease, based on published population-based studies. Fourteen studies, representing 15,708 subjects, report allelic distribution for lipoprotein lipase gene variants among coronary disease patients and control subjects. Patient outcomes included clinical coronary disease events and documented coronary disease based on angiography. Allele frequencies are estimated for disease and non-disease groups within each study. A 2 x 2 contingency table is used to compute individual study odds ratios and 95% confidence intervals, relating the presence of the rare allele to disease status. Mantel-Haenszel-stratified analysis of each allelic variant results in a summary odds ratio and 95% confidence interval for the association between each rare allele in the lipoprotein lipase gene and coronary disease. The lipoprotein lipase D9N allele has a summary odds ratio of 1.59 (95% confidence interval 1.03-2.55), indicating a 59% increase in risk of coronary disease for carriers with this allelic variant. The lipoprotein lipase N291S allele showed no association with coronary disease (summary odds ratio 0.93, 95% confidence interval 0.73-1.19). The summary odds ratio for lipoprotein lipase S447Ter allele is 0.81 (95% confidence interval 0.65-1.0), indicating a marginal negative association between this variant and coronary disease. The common lipoprotein lipase Pvu II polymorphism shows no relation to coronary disease (summary odds ratio 0.90, 95% confidence interval 0.80-1.01). The rare allele of the lipoprotein lipase HindIII polymorphism is negatively associated with coronary disease (summary odds ratio 0.84, 95% confidence interval 0.73-0.96). The lipoprotein lipase D9N allele is associated with high levels of triglyceride and low levels of high-density lipoprotein. Similar atherogenic lipid levels are observed in subjects with structural mutations lipoprotein lipase C188E and P207L. Carriers of the S447Ter allele have low levels of triglyceride. The lipoprotein, lipase gene variants which decrease lipoprotein lipase catalytic activity are associated with familial combined hyperlipidemia, but not the elevation of apolipoprotein B seen in this disorder. In conclusion, allelic variants in the lipoprotein lipase gene are associated with altered lipid levels and differential coronary disease risk.
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Affiliation(s)
- J E Hokanson
- Department of Medicine, School of Public Health and Community Medicine, University of Washington, Seattle, USA
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Sprecher DL, Harris BV, Stein EA, Bellet PS, Keilson LM, Simbartl LA. Higher triglycerides, lower high-density lipoprotein cholesterol, and higher systolic blood pressure in lipoprotein lipase-deficient heterozygotes. A preliminary report. Circulation 1996; 94:3239-45. [PMID: 8989135 DOI: 10.1161/01.cir.94.12.3239] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
BACKGROUND Heterozygous lipoprotein lipase (LPL) deficiency has been associated with familial hypertriglyceridemia and familial combined hyperlipidemia. Studies of heterozygotes with LPL gene defects at amino acid residues 188 and 207 showed higher triglycerides (TG) and lower HDL cholesterol (HDL-C), with no elevation in LDL cholesterol (LDL-C). Other LPL defects may reveal alternate clinical phenotypes. METHODS AND RESULTS We evaluated three families with defects at amino acid residues 64, 194, and 188. Thirty-eight heterozygotes (8 with defect 64, 14 with defect 194, and 16 with defect 188) and 95 family members without defects were studied. Plasma lipid, lipoprotein, and apolipoprotein (apo) values were measured, as well as blood pressure. Pooled carriers demonstrated higher systolic blood pressure (SBP) (127 versus 116 mm Hg, P < .0001) and TG (160 versus 125 mg/dL, P = .004) and lower HDL-C (44 versus 52 mg/dL, P = .001) than did noncarriers. A comparison of the 188 carriers and noncarriers revealed the most striking phenotypic characteristics, with lower HDL-C (36 versus 51 mg/dL, P < .0001) and HDL-C/(apo A-I + apo A-II) (0.21 versus 0.24, P = .002) and higher TG (206 versus 123 mg/dL, P = .0003), SBP (132 versus 116 mm Hg, P = .0004), and apo B/LDL-C (1.12 versus 0.93, P < .0001). CONCLUSIONS These data confirm past observations that LPL deficient heterozygotes trend toward lower HDL-C and higher TG levels while potentially expressing higher SBP. These data also implicate the specific LPL gene defect as a contributing factor to the variable expression of HDL-C, TG, and SBP.
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Zhang H, Henderson H, Gagne SE, Clee SM, Miao L, Liu G, Hayden MR. Common sequence variants of lipoprotein lipase: standardized studies of in vitro expression and catalytic function. BIOCHIMICA ET BIOPHYSICA ACTA 1996; 1302:159-66. [PMID: 8695666 DOI: 10.1016/0005-2760(96)00059-8] [Citation(s) in RCA: 81] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
We have assessed the functional activity of three common sequence variants of human lipoprotein lipase (LPL). Two of these, Asn291Ser and Asp9Asn arise from missense mutations while the third, Ser447Ter, derives from a nonsense mutation, truncating LPL by two residues. As previous in vitro studies have produced conflicting results, we have re-analyzed the catalytic function of these variants using the COS cell transfection system, under optimized and standardized experimental protocols. We found the Asn291Ser variant to manifest with a decrease in catalytic activity (57% of normal) due to a reduction in secretion and stability of the active homodimeric form. The Asp9Asn variant also showed a significant decrease in catalytic activity (85% of normal), but this was found to be due to a decreased rate of secretion only, as the homodimeric form was stable. The findings for these mutants contrasted with those of the Ser447Ter truncation variant which proved to be catalytically normal; this variant also manifested normal homodimer stability. The truncated variant did however, present with a higher total secreted mass level (131%) than control LPL. This was most likely due to enhanced secretion of the monomeric form. None of these mutations exhibited defects in binding affinity to cell surface proteoglycans. Each of these variants deviated significantly from normal as regards to their secreted activity or mass levels in the COS cell transfection system.
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Affiliation(s)
- H Zhang
- Department of Medical Genetics, University of British Columbia, Vancouver, Canada
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Rouis M, Lohse P, Dugi KA, Lohse P, Beg OU, Ronan R, Talley GD, Brunzell JD, Santamarina-Fojo S. Homozygosity for two point mutations in the lipoprotein lipase (LPL) gene in a patient with familial LPL deficiency: LPL(Asp9–>Asn, Tyr262–>His). J Lipid Res 1996. [DOI: 10.1016/s0022-2275(20)37606-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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Georges JL, Régis-Bailly A, Salah D, Rakotovao R, Siest G, Visvikis S, Tiret L. Family study of lipoprotein lipase gene polymorphisms and plasma triglyceride levels. Genet Epidemiol 1996; 13:179-92. [PMID: 8722745 DOI: 10.1002/(sici)1098-2272(1996)13:2<179::aid-gepi4>3.0.co;2-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
To better characterize the role of the lipoprotein lipase (LPL) gene in the determination of triglyceride levels in healthy subjects, a study was performed in 193 nuclear families (384 parents, means age = 42.0 +/- 5.2 years; 399 offspring, mean age = 14.6 +/- 4.3 years) volunteering to have a free health checkup examination. The pattern of familial resemblance was compatible with a zero correlation between spouses, a weak father-offspring correlation (0.099 +/- 0.054; P < 0.07), and significant mother-offspring (0.235 +/- 0.053; P < 10(-4)) and sib-sib (0.294 +/- 0.064; P < 10(-4)) correlations. Associations of triglyceride levels with the LPL HindIII and PvuII polymorphisms were investigated by a familial measured genotype analysis, specifying sex- and age-dependent polymorphism effects. The effects associated with both polymorphisms were significant only in fathers, the H+ and P+ alleles being associated with raised triglyceride levels. The HindIII and PvuII polymorphisms explained 3.5% and 3%, respectively, of the variability of triglycerides in fathers. The relationship was weakened after prior adjustment on body mass index, but remained significant for PvuII. Because of the lack of effect in mothers and offspring, the polymorphisms did not contribute to the covariance of triglyceride levels in relatives. In conclusion, this family study showed a weak relationship of the HindIII and PvuII polymorphisms to plasma triglyceride levels in young healthy male subjects. The effects detectable only in fathers suggest a possible modulation of the LPL expression by hormonal or lifestyle factors.
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Affiliation(s)
- J L Georges
- Institut National de la Santé et de la Recherche Médicale (INSERM) U258, Paris, France
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