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Pareek S, Gupta RK, Sharma A, Gulati S. Human Leukocyte Antigen-DQ Genotyping in Pediatric Celiac Disease. Pediatr Gastroenterol Hepatol Nutr 2023; 26:50-57. [PMID: 36816433 PMCID: PMC9911170 DOI: 10.5223/pghn.2023.26.1.50] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 08/12/2022] [Accepted: 09/18/2022] [Indexed: 01/15/2023] Open
Abstract
PURPOSE The purpose of this study was to determine the pattern of human leukocyte antigen (HLA)-DQ genotype in children diagnosed with celiac disease (CD) (biopsy proven), and to compare this with a control group; and secondarily, to correlate HLA genotypes with clinical profiles of CD. METHODS This cross-sectional comparative observational study included 26 controls and 52 patients diagnosed with CD who presented at Sir Padampat Mother and Child Health Institute, Jaipur, from May, 2017 to October, 2018. HLA DQ genotype was assessed for each patients and correlated with clinical profiles. RESULTS HLA DQ2/DQ8 genotypes were significantly more common in CD (present in 100.0% cases) than in controls (23.1%) in Northern India (Rajasthan). When HLA DQ2.5 and DQ8 were present together, individuals had significantly more atypical presentations and severe findings on duodenal biopsy. Similarly, patients with the HLA DQ 2.5 genotype were also predisposed to more severe endoscopic findings, while HLA DQ2.2 predisposed them to less severe biopsy findings. HLA DQ8 was significantly associated with later age at diagnosis (>5 years) and shorter stature. The highest HLA DQ relative risk (RR) for CD development was associated with HLA DQ2.5 and DQ2.2 in combination, followed by HLA DQ2.5 and DQ8 in combination, while HLA DQx.5 and HLA DQ2.2 together had the lowest risk. CONCLUSION HLA DQ2/DQ8 genotypes are strongly associated with pediatric CD patients in northern India. These genotypes and their combinations may be associated with different clinical presentations of CD, and may help predict severity of CD.
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Affiliation(s)
- Stuti Pareek
- Department of Pediatric Medicine, Sawai Man Singh Medical College, Jaipur, India
| | - Raj Kumar Gupta
- Department of Pediatric Medicine, Sawai Man Singh Medical College, Jaipur, India
| | - Abhinav Sharma
- Department of Pediatric Medicine, Sawai Man Singh Medical College, Jaipur, India
| | - Sandhya Gulati
- Department of Pathology, Sawai Man Singh Medical College, Jaipur, India
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2
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Childebayeva A, Rohrlach AB, Barquera R, Rivollat M, Aron F, Szolek A, Kohlbacher O, Nicklisch N, Alt KW, Gronenborn D, Meller H, Friederich S, Prüfer K, Deguilloux MF, Krause J, Haak W. Population Genetics and Signatures of Selection in Early Neolithic European Farmers. Mol Biol Evol 2022; 39:6586604. [PMID: 35578825 PMCID: PMC9171004 DOI: 10.1093/molbev/msac108] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Human expansion in the course of the Neolithic transition in western Eurasia has been one of the major topics in ancient DNA research in the last 10 years. Multiple studies have shown that the spread of agriculture and animal husbandry from the Near East across Europe was accompanied by large-scale human expansions. Moreover, changes in subsistence and migration associated with the Neolithic transition have been hypothesized to involve genetic adaptation. Here, we present high quality genome-wide data from the Linear Pottery Culture site Derenburg-Meerenstieg II (DER) (N = 32 individuals) in Central Germany. Population genetic analyses show that the DER individuals carried predominantly Anatolian Neolithic-like ancestry and a very limited degree of local hunter-gatherer admixture, similar to other early European farmers. Increasing the Linear Pottery culture cohort size to ∼100 individuals allowed us to perform various frequency- and haplotype-based analyses to investigate signatures of selection associated with changes following the adoption of the Neolithic lifestyle. In addition, we developed a new method called Admixture-informed Maximum-likelihood Estimation for Selection Scans that allowed us test for selection signatures in an admixture-aware fashion. Focusing on the intersection of results from these selection scans, we identified various loci associated with immune function (JAK1, HLA-DQB1) and metabolism (LMF1, LEPR, SORBS1), as well as skin color (SLC24A5, CD82) and folate synthesis (MTHFR, NBPF3). Our findings shed light on the evolutionary pressures, such as infectious disease and changing diet, that were faced by the early farmers of Western Eurasia.
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Affiliation(s)
- Ainash Childebayeva
- Archaeogenetics Department, Max Planck Institute for the Science of Human History, Kahlaische Straße 10, D-07745 Jena, Germany.,Archaeogenetics Department, Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, D-04103 Leipzig, Germany
| | - Adam Benjamin Rohrlach
- Archaeogenetics Department, Max Planck Institute for the Science of Human History, Kahlaische Straße 10, D-07745 Jena, Germany.,Archaeogenetics Department, Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, D-04103 Leipzig, Germany.,ARC Centre of Excellence for Mathematical and Statistical Frontiers, School of Mathematical Sciences, The University of Adelaide, Adelaide, Australia
| | - Rodrigo Barquera
- Archaeogenetics Department, Max Planck Institute for the Science of Human History, Kahlaische Straße 10, D-07745 Jena, Germany.,Archaeogenetics Department, Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, D-04103 Leipzig, Germany
| | - Maïté Rivollat
- Archaeogenetics Department, Max Planck Institute for the Science of Human History, Kahlaische Straße 10, D-07745 Jena, Germany.,Université de Bordeaux, CNRS, PACEA-UMR 5199, 33615 Pessac, France
| | - Franziska Aron
- Archaeogenetics Department, Max Planck Institute for the Science of Human History, Kahlaische Straße 10, D-07745 Jena, Germany
| | - András Szolek
- Applied Bioinformatics, Dept. of Computer Science, University of Tübingen, Tübingen, Germany.,Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany
| | - Oliver Kohlbacher
- Applied Bioinformatics, Dept. of Computer Science, University of Tübingen, Tübingen, Germany.,Institute for Bioinformatics and Medical Informatics, University of Tübingen, Tübingen, Germany.,Translational Bioinformatics, University Hospital Tübingen, Tübingen, Germany.,Biomolecular Interactions, Max Planck Institute for Developmental Biology, Tübingen, Germany
| | - Nicole Nicklisch
- Center of Natural and Cultural Human History, Danube Private University, Krems-Stein, Austria.,State Office for Heritage Management and Archaeology Saxony-Anhalt - State Museum of Prehistory, Halle (Saale), Germany
| | - Kurt W Alt
- Center of Natural and Cultural Human History, Danube Private University, Krems-Stein, Austria.,State Office for Heritage Management and Archaeology Saxony-Anhalt - State Museum of Prehistory, Halle (Saale), Germany
| | - Detlef Gronenborn
- Römisch-Germanisches Zentralmuseum, Leibniz Research Institute for Archaeology, Ernst-Ludwig-Platz 2, 55116 Mainz, Germany
| | - Harald Meller
- State Office for Heritage Management and Archaeology Saxony-Anhalt - State Museum of Prehistory, Halle (Saale), Germany
| | - Susanne Friederich
- State Office for Heritage Management and Archaeology Saxony-Anhalt - State Museum of Prehistory, Halle (Saale), Germany
| | - Kay Prüfer
- Archaeogenetics Department, Max Planck Institute for the Science of Human History, Kahlaische Straße 10, D-07745 Jena, Germany.,Archaeogenetics Department, Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, D-04103 Leipzig, Germany
| | | | - Johannes Krause
- Archaeogenetics Department, Max Planck Institute for the Science of Human History, Kahlaische Straße 10, D-07745 Jena, Germany.,Archaeogenetics Department, Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, D-04103 Leipzig, Germany
| | - Wolfgang Haak
- Archaeogenetics Department, Max Planck Institute for the Science of Human History, Kahlaische Straße 10, D-07745 Jena, Germany.,Archaeogenetics Department, Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, D-04103 Leipzig, Germany
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3
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Kurppa K, Agardh D. Pediatric coeliac disease. COELIAC DISEASE AND GLUTEN-RELATED DISORDERS 2022:23-41. [DOI: 10.1016/b978-0-12-821571-5.00002-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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4
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Guandalini S, Discepolo V. Celiac Disease. TEXTBOOK OF PEDIATRIC GASTROENTEROLOGY, HEPATOLOGY AND NUTRITION 2022:525-548. [DOI: 10.1007/978-3-030-80068-0_40] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Autoimmune Diseases of Digestive Organs-A Multidisciplinary Challenge: A Focus on Hepatopancreatobiliary Manifestation. J Clin Med 2021; 10:jcm10245796. [PMID: 34945093 PMCID: PMC8705412 DOI: 10.3390/jcm10245796] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 12/04/2021] [Accepted: 12/07/2021] [Indexed: 12/11/2022] Open
Abstract
It is well known that some pathological conditions, especially of autoimmune etiology, are associated with the HLA (human leukocyte antigen) phenotype. Among these diseases, we include celiac disease, inflammatory bowel disease, autoimmune enteropathy, autoimmune hepatitis, primary sclerosing cholangitis and primary biliary cholangitis. Immunoglobulin G4-related diseases (IgG4-related diseases) constitute a second group of autoimmune gastrointestinal, hepatobiliary and pancreatic illnesses. IgG4-related diseases are systemic and rare autoimmune illnesses. They often are connected with chronic inflammation and fibrotic reaction that can occur in any organ of the body. The most typical feature of these diseases is a mononuclear infiltrate with IgG4-positive plasma cells and self-sustaining inflammatory response. In this review, we focus especially upon the hepatopancreatobiliary system, autoimmune pancreatitis and IgG4-related sclerosing cholangitis. The cooperation of the gastroenterologist, radiologist, surgeon and histopathologist is crucial for establishing correct diagnoses and appropriate treatment, especially in IgG4 hepatopancreatobiliary diseases.
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Tolone C, Piccirillo M, Dolce P, Alfiero S, Arenella M, Sarnataro M, Iardino P, Pucciarelli A, Strisciuglio C. Celiac disease in pediatric patients according to HLA genetic risk classes: a retrospective observational study. Ital J Pediatr 2021; 47:107. [PMID: 33952340 PMCID: PMC8097774 DOI: 10.1186/s13052-021-01052-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 04/21/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Celiac disease (CD) is an autoimmune enteropathy in which HLA-DQ haplotypes define susceptibility. Our aim was to evaluate if belonging to a certain HLA-DQ class risk could be associated to the clinical, serological and histological presentation of CD. METHODS We performed a retrospective observational monocentric study including all 300 patients diagnosed with CD, who underwent HLA typing. Clinical, serological and histological data was collected from clinical records and their association with HLA-DQ class risk was verified through statistical tests. RESULTS In our sample mean age at onset was 6.7 ± 4.2 years, with a prevalence of females (n = 183; 61%), typical symptoms (n = 242; 80.6%) and anti-tTG IgA ≥ 100 U/mL (n = 194; 64.7%). Family history was present only in 19% (n = 57) of patients, and it was not significantly associated with any of the clinical and demographical data analyzed or the belonging to a certain HLA-DQ class risk. We found in the male population more frequently a coexistence of CD and atopic syndrome (males: n = 47; 40.2%; females: n = 50; 27.3%; p = 0.020). Early age of onset, instead, was associated with typical symptoms (m = 6.4 ± 4; p = 0.045) and elevated liver enzymes (m = 5 ± 3.8; p < 0.001), while later age of onset was associated with presence of other autoimmune diseases (m = 8.2 ± 4; p = 0.01). We observed statistically significant influences of HLA class risk on antibodies and liver enzymes levels: G1, G4 and G2 classes showed more frequently anti-tTG IgA ≥ 100 U/mL (n = 44; 80%, n = 16; 69.6%, n = 48; 67.6% respectively; p-value = 0.037), and in patients from G2 class we found enhanced liver enzymes (n = 28; 39.4%; p-value = 0.005). HLA class risk was still significantly associated with anti-tTG ≥ 100 (p = 0.044) and with hypertransaminasemia (p = 0.010) after a multiple logistic regression adjusted for the effect of gender, age at onset and family history. CONCLUSIONS We failed to prove an association between HLA-DQ genotypes and the clinical features in our CD pediatric patients. Although, our results suggest an effect of the DQB1-02 allele not only on the level of antibodies to tTG, but possibly also on liver involvement.
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Affiliation(s)
- Carlo Tolone
- Department of Pediatrics, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Marisa Piccirillo
- Department of Pediatrics, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Pasquale Dolce
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - Salvatore Alfiero
- Department of Pediatrics, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Mattia Arenella
- Department of Pediatrics, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Marina Sarnataro
- Department of Pediatrics, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Patrizia Iardino
- UOC Clinic and Molecular Pathology, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Alessia Pucciarelli
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
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Espino L, Núñez C. The HLA complex and coeliac disease. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2020; 358:47-83. [PMID: 33707057 DOI: 10.1016/bs.ircmb.2020.09.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The Human Leukocyte Antigen (HLA) has a crucial role in the development and pathogenesis of coeliac disease (CD). The genes HLA-DQA1 and HLA-DQB1, both lying in this region and encoding the HLA-DQ heterodimer, are the main genetic predisposing factors to CD. Approximately 90% of CD patients carry the heterodimer HLA-DQ2.5, leaving only a small proportion of patients with lower risk heterodimers (HLA-DQ8, HLA-DQ2.2 or HLA-DQ7.5). These HLA-DQ molecules act as receptors present in the surface of antigen presenting cells and show high affinity for deamidated gluten peptides, which bind and present to CD4+ T cells. This triggers the immunological reaction that evolves into CD. Since specific HLA genetics is present in almost the totality of CD patients, HLA typing has a very high negative predictive value, and it can be used to support diagnosis in specific scenarios. HLA risk has been associated to different CD-related features, such as age at onset, clinical outcomes, antibody levels and grade of histological lesion; but further research is needed. HLA-DQ genotypes have been also suggested to modulate the composition of the gut microbiota.
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Affiliation(s)
- Laura Espino
- Laboratorio de investigación en Genética de enfermedades complejas, Hospital Clínicos San Carlos, IdISSC, Madrid, Spain
| | - Concepción Núñez
- Laboratorio de investigación en Genética de enfermedades complejas, Hospital Clínicos San Carlos, IdISSC, Madrid, Spain.
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8
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Koskimaa S, Kivelä L, Arvola T, Hiltunen P, Huhtala H, Kaukinen K, Kurppa K. Clinical characteristics and long-term health in celiac disease patients diagnosed in early childhood: Large cohort study. Dig Liver Dis 2020; 52:1315-1322. [PMID: 32900652 DOI: 10.1016/j.dld.2020.08.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 07/12/2020] [Accepted: 08/06/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Early detection of celiac disease could theoretically prevent most of the disease-associated complications, but long-term effects of this approach are unclear. AIMS To investigate features at diagnosis and adulthood health in celiac disease patients diagnosed in early childhood in 1965-2014. METHODS Medical data on 978 pediatric patients were collected and study questionnaires sent to 559 adult patients who were diagnosed in childhood. Results were compared between patients diagnosed in early (≤3.0 years) and later (3.1-17.9 years) childhood. RESULTS Early diagnosed patients (n=131) had more often total villous atrophy (37% vs 25%, p=0.001), gastrointestinal presentation (61% vs 47%, p<0.001), growth disturbances (70% vs 32%, p=0.001) and severe symptoms (30% vs 9%, p<0.001) and were less often screen-detected (10% vs 27%, p<0.001) at diagnosis than those diagnosed later (n=847). Among 239 adult responders, early diagnosed patients (n=36) had fewer comorbidities (33% vs 53%, p=0.034) but considered their health less often good/excellent (69% vs 84%, p=0.029). The groups were comparable in current age, dietary adherence, symptoms and health-related quality of life. CONCLUSION Despite more severe initial presentation, the long-term health in early diagnosed patients was mostly comparable or even better to those diagnosed later in childhood. Poorer self-perceived health suggests a need for support during the transition to adulthood care.
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Affiliation(s)
- Sara Koskimaa
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland; Center for Child Health Research, Tampere University and Department of Pediatrics, Tampere University Hospital, Tampere, Finland
| | - Laura Kivelä
- Center for Child Health Research, Tampere University and Department of Pediatrics, Tampere University Hospital, Tampere, Finland; University of Helsinki and Helsinki University Hospital, Children's Hospital, and Pediatric Research Center, Helsinki, Finland.
| | - Taina Arvola
- Department of Pediatrics, Hospital District of Kanta-Häme, Hämeenlinna, Finland
| | - Pauliina Hiltunen
- Center for Child Health Research, Tampere University and Department of Pediatrics, Tampere University Hospital, Tampere, Finland
| | - Heini Huhtala
- Faculty of Social Sciences, Tampere University, Tampere, Finland
| | - Katri Kaukinen
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland; Department of Internal Medicine, Tampere University Hospital, Tampere, Finland; Celiac Disease Research Center, Tampere University, Tampere, Finland
| | - Kalle Kurppa
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland; Center for Child Health Research, Tampere University and Department of Pediatrics, Tampere University Hospital, Tampere, Finland; The University Consortium of Seinäjoki, and Department of Pediatrics, Seinäjoki Central Hospital, Seinäjoki, Finland
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Lee J, Smith WM, Goldstein DA. Birdshot chorioretinopathy presenting in a teenager. Am J Ophthalmol Case Rep 2020; 19:100807. [PMID: 32695925 PMCID: PMC7365988 DOI: 10.1016/j.ajoc.2020.100807] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 06/01/2020] [Accepted: 06/29/2020] [Indexed: 11/17/2022] Open
Abstract
Purpose To describe clinical features of the youngest patient with well-documented HLA-A29-positive birdshot chorioretinopathy (BCR). Observations A 17-year-old female presented with poor night vision and floaters. Examination revealed bilateral vitritis, retinal vasculitis, and numerous cream-colored ovoid lesions in the fundus. Fluorescein angiography revealed bilateral optic disc leakage, large vessel leakage and diffuse capillary ferning. There were hundreds of small hypocyanescent spots evenly distributed in the posterior pole of both eyes on indocyanine green angiography. Workup was positive for HLA-A29.2. Systemic immunosuppression with adalimumab 40mg/0.4mL was initiated every two weeks and escalated to weekly dosing. The patient's early age of disease onset prompted evaluation of her parents. The mother's exam was normal and she was HLA-A29 negative. Examination of the father revealed peripapillary choroidal lesions as well as hypocyanescent spots on ICG. HLA-typing revealed the presence of HLA-A29.2. Conclusions and Importance BCR rarely occurs in the pediatric population. We present the youngest patient with well-documented BCR in the literature to highlight that this disease deserves consideration even in young patients. Interestingly, choroidal lesions were also found in an asymptomatic parent with HLA-A29.2 positivity.
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Affiliation(s)
- Jennifer Lee
- Uveitis Service, Northwestern University, Feinberg School of Medicine, Department of Ophthalmology, Chicago, IL, USA
| | - Wendy M Smith
- Uveitis Service, Mayo Clinic, Department of Ophthalmology, Rochester, MN, USA
| | - Debra A Goldstein
- Uveitis Service, Northwestern University, Feinberg School of Medicine, Department of Ophthalmology, Chicago, IL, USA
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Poddighe D, Rebuffi C, De Silvestri A, Capittini C. Carrier frequency of HLA-DQB1*02 allele in patients affected with celiac disease: A systematic review assessing the potential rationale of a targeted allelic genotyping as a first-line screening. World J Gastroenterol 2020; 26:1365-1381. [PMID: 32256023 PMCID: PMC7109277 DOI: 10.3748/wjg.v26.i12.1365] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 03/10/2020] [Accepted: 03/22/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Celiac Disease (CD) is an immune-mediated disorder, in which the HLA immunogenetic background (DQ2 and DQ8 heterodimers) and environmental trigger (gluten) are well established. Indeed, both factors are necessary – but not sufficient – to develop CD. However, it is very likely that CD is underdiagnosed in both developing and developed countries, due to several aspects, including the fact that a lot of patients present mild and/or atypical symptoms, without the presence of any recognized risk factors. Therefore, the possibility and feasibility of widened screening strategies to identify CD patients are debated.
AIM To provide further evidence of the main epidemiological importance of HLA-DQB1*02 allele in the population of CD patients.
METHODS We performed a systematic search in PubMed, EMBASE, Cochrane, Web of Science and Scopus databases, in order to produce a systematic review assessing the carrier frequency of HLA-DQB1*02 allele in the celiac population. Following the PRISMA guidelines, we retrieved all the original articles describing CD patients’ HLA-DQB1 genotype in such a way that could allow to assess the HLA-DQB1*02 carrier frequency among CD patients, along with the evidence of the appropriate diagnostic work-up to achieve a correct and final diagnosis of CD.
RESULTS The final output of this systematic search in the medical literature consisted of 38 studies providing the appropriate HLA-DQB1 genotype information of the respective CD population. According to this systematic review, including a pool of 4945 HLA-DQ genotyped CD patients, the HLA-DQB1*02 carrier frequency was 94.94%, meaning that only 5.06% of CD patients were completely lacking this allelic variant. Interestingly, if we consider only the studies whereby the prevalence of CD patients affected with type 1 diabetes mellitus was supposed or clearly established to be very low, the frequency of non-HLA-DQB1*02 carriers among CD patients dropped to 3.65%.
CONCLUSION Such a high carrier frequency of the HLA-DQB1*02 allelic variant (which is > 95%-96% in CD patients without risk factors, like type 1 diabetes mellitus comorbidity) might be exploited to consider a cost-effective and widened screening approach. If a sustainable strategy could be implemented through a low-cost targeted genetic test to detect the individual presence of HLA-DQB1*02 allele, an appropriate algorithm for serological screening in individuals resulting to be genetically predisposed to CD, might be considered.
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Affiliation(s)
- Dimitri Poddighe
- Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan 010000, Kazakhstan
| | - Chiara Rebuffi
- Grant Office and Scientific Documentation Center, Fondazione IRCCS Policlinico San Matteo, Pavia 27100, Italy
| | - Annalisa De Silvestri
- Scientific Direction, Clinical Epidemiology and Biometric Unit, Fondazione IRCCS Policlinico San Matteo, Pavia 27100, Italy
| | - Cristina Capittini
- Scientific Direction, Clinical Epidemiology and Biometric Unit, Fondazione IRCCS Policlinico San Matteo, Pavia 27100, Italy
- Department of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia, Pavia 27100, Italy
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Zwiers A, van Wanrooij RL, Dieckman T, Nijeboer P, Kraal G, Bouma G. Celiac disease associated SNP rs17810546 is located in a gene silencing region. Gene 2020; 726:144165. [DOI: 10.1016/j.gene.2019.144165] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2019] [Accepted: 10/08/2019] [Indexed: 12/19/2022]
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Cabrera CM, Sánchez-Godoy L, Navas-López VM. Is the double gene dose of DQ2.5 or DQ2.5/DQ2.2 an involved factor in the clinical features of celiac disease? Scand J Gastroenterol 2019; 54:960-964. [PMID: 31361165 DOI: 10.1080/00365521.2019.1647283] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Objectives: Celiac disease (CD) is barely known if the quantitative effect of DQB1*02 (DQ2) double dose in antigen presentation to T-cells has translation into the clinic. For this, we have conducted a case-control study in a cohort of two hundred and nineteen patients with CD. Material and methods: For the control group, individuals were enrolled with single dose of DQ2, carrying DQ2.5 heterodimers in heterozygous state (n = 109). The cases with CD were diving into three groups: cases with overall DQ2 double dose (n = 110), DQ2.5 homozygous (n = 33) and DQ2.5/DQ2.2 heterozygous (n = 77). Prevalence and associations of demographic, laboratory, histological and clinical characteristics between the control group and cases were studied. Results: No differences were found for the total of 16 variables analyzed between the control group and overall DQ2 double dose as well as DQ2.5 homozygous cases. In contrast to DQ2.5/DQ2.2, heterozygous cases presented a protection factor for developing allergy to airway allergens regarding the control group (OR = 0.210, p = .019). Conclusions: To date, this negative association has not been described. Further studies will be necessary to elucidate the implication of this protection factor in CD. Since, until now the association between CD and allergic diseases has been poorly studied.
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Affiliation(s)
- Carmen M Cabrera
- Immunology Section, Department of Hematology, Carlos Haya Regional University Hospital , Málaga , Spain
| | - Lorenzo Sánchez-Godoy
- Clinical Laboratory Service, Carlos Haya Regional University Hospital , Málaga , Spain
| | - Víctor M Navas-López
- Pediatric Gastroenterology and Nutrition Unit, Carlos Haya Regional University Hospital , Málaga , Spain
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13
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Martínez-Ojinaga E, Fernández-Prieto M, Molina M, Polanco I, Urcelay E, Núñez C. Influence of HLA on clinical and analytical features of pediatric celiac disease. BMC Gastroenterol 2019; 19:91. [PMID: 31196071 PMCID: PMC6567567 DOI: 10.1186/s12876-019-1014-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Accepted: 06/06/2019] [Indexed: 12/12/2022] Open
Abstract
Background Celiac disease (CD) is triggered by gluten and related prolamines in genetically susceptible individuals. We aimed to investigate the influence of HLA-DQ genotypes in clinical, serological and histological features related to CD. Methods A retrospective observational study was performed including 463 Spanish patients with biopsy-proven CD. Clinical, serological, histological and HLA-DQ genetic data were collected from each participant. The presence of a family history of CD was also considered. Bivariate (chi-square tests or the Fisher’s exact test) and multivariate (logistic regression after adjusting for age and sex) analyses were performed to assess the association between clinical and laboratory parameters with HLA-DQ. Results A predominance of females (62%), classical clinical presentation (86%) and positive anti-transglutaminase 2/endomysium antibodies (99%) was observed in our sample, with a mean age at onset of 2.6 ± 0.1 years. Five percent of our patients were first-degree relatives of subjects with CD, with HLA-DQ genetics showing increased homozygosity of HLA-DQ2.5 (p = 0.03) and HLA-DQ8 (p = 0.09). In the non-CD family history group, an association between delayed disease onset and HLA-DQ8 carriage was observed (p < 0.001), besides an influence of HLA-DQB1*02 gene dosage on clinical presentation and severity of histological damage (after adjusting for age and sex, p = 0.05 and p = 0.02, respectively) and a trend towards presence of specific antibodies (p = 0.09). These associations could not be evaluated properly in the group of patients with affected first-degree relatives due to the small sample size. Conclusions HLA-DQ genotypic frequencies differ slightly between CD patients depending on their family history of CD. In patients lacking CD first-degree relatives, carriage of HLA-DQ2.5 with double dose of HLA-DQB1*02 seems to be associated with classical clinical presentation and more severe histological damage.
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Affiliation(s)
- Eva Martínez-Ojinaga
- Servicio de Gastroenterología y Nutrición Pediátrica, Hospital Universitario La Paz, Madrid, Spain
| | - Marta Fernández-Prieto
- Laboratorio de investigación en Genética de enfermedades complejas, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), C/ Profesor Martín Lagos s/n 28040, Madrid, Spain
| | - Manuel Molina
- Servicio de Gastroenterología y Nutrición Pediátrica, Hospital Universitario La Paz, Madrid, Spain
| | - Isabel Polanco
- Servicio de Gastroenterología y Nutrición Pediátrica, Hospital Universitario La Paz, Madrid, Spain
| | - Elena Urcelay
- Laboratorio de investigación en Genética de enfermedades complejas, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), C/ Profesor Martín Lagos s/n 28040, Madrid, Spain
| | - Concepción Núñez
- Laboratorio de investigación en Genética de enfermedades complejas, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), C/ Profesor Martín Lagos s/n 28040, Madrid, Spain.
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Prevalence of Celiac Disease in a Long-term Study of a Spanish At-genetic-risk Cohort From the General Population. J Pediatr Gastroenterol Nutr 2019; 68:364-370. [PMID: 30418411 DOI: 10.1097/mpg.0000000000002195] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
OBJECTIVES To perform long-term celiac disease (CD) screening in an HLA-DQ2 (+) cohort from the general population and to assess the influence of risk genotypes on its development. METHODS In 2004, an HLA-DQ2 (+) cohort was selected. After the first CD screening at age 2 to 3 years, we performed a follow-up screening 8 to 10 years later. Antitransglutaminase 2 antibodies were determined using a rapid test kit. Results were confirmed by serum IgA antitransglutaminase 2 and IgA endomysial antibody determination. CD diagnosis was carried out by intestinal biopsies. Four HLA-DQ2 genotypic groups were used: G1: DQ2.5/DQ2.5 (G1A) or DQ2.5/ DQ2.2 (G1B); G2: DQ2.2/DQ7.5 (DQ2.5 trans); G3: DQ2.5/ X; G4: DQ2.2/X. RESULTS CD prevalence after 10 years of follow-up was 5.8% (95% confidence interval 3.8-8.7). One of every 3 HLA-DQ2(+) children carried at least 1 haplotype DQ2.2 or DQ7. The homozygous genotype DQ2.5/DQ2.5 and the HLA-DQ2.5 trans genotype increased CD risk 4- and 3-fold, respectively. The homozygous genotype DQ2.5/ DQ2.2 did not increase the CD risk. Children carrying G1 or G2 genotypes were diagnosed with CD earlier and more frequently during the follow-up compare with those carrying G3 or G4 genotypes. Approximately 81% of children with spontaneous antibody negativization after the first screening maintained negative antibodies. CONCLUSIONS A repeated screening of at-risk children during their follow-up allowed us to diagnose new CD cases. In our cohort, HLA- DQ2.5 trans genotype conferred a higher risk in the development of CD than HLA- DQ2.5/DQ2.2. The majority of children with potential CD and CD autoimmunity at 10 years of age remained healthy.
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Bajor J, Szakács Z, Juhász M, Papp M, Kocsis D, Szegedi É, Földi I, Farkas N, Hegyi P, Vincze Á. HLA-DQ2 homozygosis increases tTGA levels at diagnosis but does not influence the clinical phenotype of coeliac disease: A multicentre study. Int J Immunogenet 2019; 46:74-81. [PMID: 30779476 DOI: 10.1111/iji.12415] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Accepted: 01/03/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND PURPOSE Magnitude of gluten-specific T-cell responses in coeliac disease (CD) might be dependent on HLA-DQ2 gene dose. We aimed to investigate the effects of HLA-DQB1*02 allele dose on clinical outcomes. METHODS We reviewed the charts of all coeliac patients attending to three Hungarian university clinics after 1997 and included those patients, who (a) were diagnosed with CD, (b) underwent high-resolution HLA typing and (c) were ≥18 years at the time of data collection. HLA typing was performed to determine DQB1*02 allele dose. Patients were divided into risk groups by DQB1*02 allele dose, as follows: high-, intermediate- and low-risk groups corresponded to a double, single and zero doses, respectively. We used ANOVA and Pearson's chi-squared test to explore association between HLA risk and clinical variables. RESULTS A total of 727 coeliac patients attended the clinics but only 105 (14.4%) patients were eligible for inclusion. High, intermediate and low HLA risk patients comprised 35.3%, 52.3% and 12.3% of the study population, respectively. Double dose of HLA-DQB1*02 was more frequent in patient with high tTGA level (>10 times the upper limit of normal; p = 0.045). Gene dose was not associated with younger age at diagnosis (p = 0.549), gender (p = 0.739), more severe diagnostic histology (p = 0.318), more frequent classical presentation (p = 0.846), anaemia (p = 0.611), metabolic bone disease (p = 0.374), dermatitis herpetiformis (p = 0.381) and autoimmune diseases (p = 0.837). CONCLUSIONS Our study shows a significant gene dose effect in terms of tTGA level at diagnosis, but no significant association between HLA-DQB1*02 allele dose and the clinical outcomes in CD.
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Affiliation(s)
- Judit Bajor
- Division of Gastroenterology, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Zsolt Szakács
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Márk Juhász
- Department of Internal Medicine, St. Margit Hospital, Budapest, Hungary
| | - Mária Papp
- Department of Internal Medicine, Division of Gastroenterology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Dorottya Kocsis
- Second Department of Internal Medicine, Semmelweis University, Budapest, Hungary
| | - Éva Szegedi
- Department of Interventional Gastroenterology, National Institute of Oncology, Budapest, Hungary
| | - Ildikó Földi
- Department of Internal Medicine, Division of Gastroenterology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Nelli Farkas
- Division of Gastroenterology, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary.,Institute of Bioanalysis, Medical School, University of Pécs, Pécs, Hungary
| | - Péter Hegyi
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary.,Hungarian Academy of Sciences, Momentum Gastroenterology Multidisciplinary Research Group, University of Szeged, Szeged, Hungary
| | - Áron Vincze
- Division of Gastroenterology, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
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Bajor J, Szakács Z, Farkas N, Hegyi P, Illés A, Solymár M, Pétervári E, Balaskó M, Pár G, Sarlós P, Szűcs Á, Czimmer J, Szemes K, Huszár O, Varjú P, Vincze Á. Classical celiac disease is more frequent with a double dose of HLA-DQB1*02: A systematic review with meta-analysis. PLoS One 2019; 14:e0212329. [PMID: 30763397 PMCID: PMC6375622 DOI: 10.1371/journal.pone.0212329] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Accepted: 01/21/2019] [Indexed: 12/17/2022] Open
Abstract
Background and aims Experimental data suggest that the HLA-DQ2 gene dose has a strong quantitative effect on clinical outcomes and severity of celiac disease (CD). We aimed to conduct a meta-analysis with systematic review to investigate the association between HLA-DQB1*02 gene doses and the characteristics of CD. Methods We searched seven medical databases for studies discussing HLA-DQB1 gene dose in CD and various disease characteristics, such as clinical presentation, histology, age at diagnosis, and comorbidities. Odds ratios (OR, for categorical variables) and weighted mean differences (for age) were calculated to compare patients with a double dose of HLA-DQB1*02 versus those with single and zero doses. Heterogeneity was tested with I2-statistics and explored by study subgroups (children and adults). Results Twenty-four publications were eligible for meta-analysis. Classical CD was more frequent with a double versus single dose of the HLA-DQB1*02 allele (OR = 1.758, 95%CI: 1.148–2.692, I2 = 0.0%). In pediatric studies, gene dose effect was more prominent (OR = 2.082, 95%CI: 1.189–3.646, I2 = 0.0% and OR = 3.139, 95%CI: 1.142–8.630, I2 = 0.0% for the comparisons of double versus single and double versus zero dose, respectively). Atrophic histology was more prevalent with a double versus zero dose (OR = 2.626, CI: 1.060–6.505, I2 = 21.3%). We observed no gene dose effect regarding diarrhea, age at diagnosis, the severity of villous atrophy, and the association with type 1 diabetes mellitus. Conclusion A double dose of HLA-DQB1*02 gene seems to predispose patients to developing classical CD and villous atrophy. Risk stratification by HLA-DQB1*02 gene dose requires further clarification due to the limited available evidence.
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Affiliation(s)
- Judit Bajor
- Division of Gastroenterology, First Department of Medicine, University of Pécs, Medical School, Pécs, Hungary
- Clinical Medicine Doctoral School, University of Szeged, Szeged, Hungary
| | - Zsolt Szakács
- Clinical Medicine Doctoral School, University of Szeged, Szeged, Hungary
- Institute for Translational Medicine, University of Pécs, Medical School, Pécs, Hungary
| | - Nelli Farkas
- Institute for Translational Medicine, University of Pécs, Medical School, Pécs, Hungary
- Institute of Bioanalysis, University of Pécs, Medical School, Pécs, Hungary
| | - Péter Hegyi
- Division of Gastroenterology, First Department of Medicine, University of Pécs, Medical School, Pécs, Hungary
- Clinical Medicine Doctoral School, University of Szeged, Szeged, Hungary
- Institute for Translational Medicine, University of Pécs, Medical School, Pécs, Hungary
- Hungarian Academy of Sciences-University of Szeged, Momentum Gastroenterology Multidisciplinary Research Group, Szeged, Hungary
| | - Anita Illés
- Division of Gastroenterology, First Department of Medicine, University of Pécs, Medical School, Pécs, Hungary
| | - Margit Solymár
- Institute for Translational Medicine, University of Pécs, Medical School, Pécs, Hungary
| | - Erika Pétervári
- Institute for Translational Medicine, University of Pécs, Medical School, Pécs, Hungary
| | - Márta Balaskó
- Institute for Translational Medicine, University of Pécs, Medical School, Pécs, Hungary
| | - Gabriella Pár
- Division of Gastroenterology, First Department of Medicine, University of Pécs, Medical School, Pécs, Hungary
| | - Patrícia Sarlós
- Division of Gastroenterology, First Department of Medicine, University of Pécs, Medical School, Pécs, Hungary
| | - Ákos Szűcs
- First Department of Surgery, Semmelweis University, Budapest, Hungary
| | - József Czimmer
- Division of Gastroenterology, First Department of Medicine, University of Pécs, Medical School, Pécs, Hungary
| | - Kata Szemes
- Division of Gastroenterology, First Department of Medicine, University of Pécs, Medical School, Pécs, Hungary
| | - Orsolya Huszár
- Hungarian Academy of Sciences-University of Szeged, Momentum Gastroenterology Multidisciplinary Research Group, Szeged, Hungary
| | - Péter Varjú
- Institute for Translational Medicine, University of Pécs, Medical School, Pécs, Hungary
| | - Áron Vincze
- Division of Gastroenterology, First Department of Medicine, University of Pécs, Medical School, Pécs, Hungary
- Clinical Medicine Doctoral School, University of Szeged, Szeged, Hungary
- * E-mail:
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Martínez-Ojinaga E, Molina M, Polanco I, Urcelay E, Núñez C. HLA-DQ distribution and risk assessment of celiac disease in a Spanish center. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2018; 110:421-426. [PMID: 29699404 DOI: 10.17235/reed.2018.5399/2017] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
AIMS celiac disease is a multisystem immune-mediated disease triggered by gluten in genetically susceptible individuals. The HLA-DQ2 and/or HLA-DQ8 heterodimers are encoded by the main genetic predisposing factors and their presence is required for the development of the immunological response that leads to the disease. However, the HLA-conferred risk can differ within different countries. The aim of the study was to analyze the risk of Spanish children to develop celiac disease according to their HLA-DQ genotype. METHODS a retrospective observational case-control study was performed using a sample of 475 celiac patients and 628 controls. RESULTS children carrying the HLA-DQ2.5 had the highest disease risk, especially those with two HLA-DQB1*02 alleles. A similar high risk was observed in HLA-DQ8 homozygous individuals. A risk conferred by HLA-DQ8 in heterozygosity and HLA-DQ2.2 was also found and two patients with celiac disease carried the HLA-DQ7.5 haplotype as the only HLA risk factor. CONCLUSIONS there are four genetic risk categories according to the HLA-DQ genotype. The HLA-DQ7.5 genotype does not confer risk but should not be used to rule out celiac disease when a high suspicion of the disease exists. These findings could be relevant to determine when to perform serological screening in asymptomatic subjects at risk of celiac disease.
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Affiliation(s)
| | | | | | - Elena Urcelay
- Instituto de Investigación Sanitaria Hospital Clínico San Carlos
| | - Concepción Núñez
- Laboratorio de Genética d Enfermedades Autoinmunes, Hospital Clínico San Carlos, España
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Bosca-Watts MM, Minguez M, Planelles D, Navarro S, Rodriguez A, Santiago J, Tosca J, Mora F. HLA-DQ: Celiac disease vs inflammatory bowel disease. World J Gastroenterol 2018; 24:96-103. [PMID: 29358886 PMCID: PMC5757130 DOI: 10.3748/wjg.v24.i1.96] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2017] [Revised: 11/22/2017] [Accepted: 11/27/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To determine the genetic predisposition to celiac disease (CeD) in inflammatory bowel disease (IBD) patients by quantifying the frequency of CeD-related human leucocyte antigen (HLA) (HLA-CeD: HLA-DQ2 and -DQ8) in IBD patients globally, by type of IBD and gender, and by calculating the protective/risk contribution of these haplotypes in the development of the IBD disease.
METHODS We conducted a prospective study with IBD patients from our Unit. Clinical information was gathered and blood was tested for HLA-CeD. The control group was made up of unrelated Valencian organ donors.
RESULTS 1034 subjects were analyzed: 457 IBD [207 ulcerative coliti (UC) and 250 Crohn’s disease (CD)] patients and 577 healthy controls. 39% of the controls and 34% of the patients had HLA-CeD (P = 0.0852). HLA-DQ2 was less frequent in UC patients (P = 0.0287), and HLA-DQ8 in CD (P = 0.0217). In women with UC, the frequency of DQ2.5cis (DQB1*02:01-DQA1*05:01) was reduced ≥ 50% [P = 0.0344; preventive fraction (PF) = 13%]. PFs (7%-14%) were obtained with all HLA-CeD haplotypes. HLA DQB1*02:02-DQA1*02:01 (HLA-DQ2.2) was more frequent in CD patients with respect to controls (P = 0.001) and UC patients (etiological fraction = 15%).
CONCLUSION HLA-CeD is not more frequent in IBD patients, with an even lower frequency of HLA-DQ2 and -DQ8 in UC and CD respectively. HLA-DQ2.5 confers protection from the development of UC, especially in women, and HLA-DQ8 does so for the appearance of CD. HLA-DQ2.2 is present in 34% of the CD patients and may constitute a genetic risk factor for CD development.
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Affiliation(s)
- Marta Maia Bosca-Watts
- IBD Unit, Digestive Disease Department of the University Clinic Hospital of Valencia, University of Valencia, Valencia 46017, Spain
| | - Miguel Minguez
- IBD Unit, Digestive Disease Department of the University Clinic Hospital of Valencia, University of Valencia, Valencia 46017, Spain
| | - Dolores Planelles
- Histocompatibility Department of the Transfusion Center of the Valencian Community, Valencia 46014, Spain
| | - Samuel Navarro
- Pathology Department of the University Clinic Hospital of Valencia, University of Valencia, Valencia 46017, Spain
| | - Alejandro Rodriguez
- Digestive Disease Department of the Hospital Virgen del Castillo of Yecla, Yecla 30510, Spain
| | - Jesus Santiago
- Digestive Disease Department of the Hospital de Manises, Valencia 46940, Spain
| | - Joan Tosca
- IBD Unit, Digestive Disease Department of the University Clinic Hospital of Valencia, University of Valencia, Valencia 46017, Spain
| | - Francisco Mora
- Digestive Disease Department of the University Clinic Hospital of Valencia, University of Valencia, Valencia 46017, Spain
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Marginean CO, Meliţ LE, Mareş RC, Mărginean MO, Voidăzan S, Dobreanu M. Clinical and biological correlations in celiac disease in children: the prospective single experience of a romanian tertiary center: A case-control study (Strobe-Compliant study). Medicine (Baltimore) 2017; 96:e6936. [PMID: 28514313 PMCID: PMC5440150 DOI: 10.1097/md.0000000000006936] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Celiac disease-a chronic inflammatory disease of the intestine-is triggered by gluten or associated protein consumption.The aim of our study was to assess the sensitivity, specificity of the combined anti-transglutaminase 2 (TG2)/deamidated gliadin peptide antibodies (DGP), and antiendomisium antibodies (EMA), to determine the distribution of HLA-DQ2/DQ8 for the 140 tested patients, and also to evaluate the clinical and laboratory characteristics of patients admitted with the suspicion of celiac disease (CD). Children included in the study were divided into: group 1, patients with confirmed CD; group 2, patients with "potential' CD; group 3, control group, patients without CD. We assessed the standard laboratory data, the level of TG2/DGP and EMA antibodies, as well as the distribution of HLA molecules in the selected patients. Histopathological examination was considered the criterion standard for diagnosis in most cases.The sensitivity of TG2/DGP was 85% and the specificity 92%. EMA showed a sensitivity of 82% and a specificity of 98%. The vast majority of patients diagnosed with CD were either HLA-DQ2.5 (encoded by DQA1*05 & DQB1*02) positive (87.5%) or HLA-DQ8 (encoded by DQB1*03:02) positive (12.5%). One patient showed a positivity only for HLA-DQ2.2 (encoded by DQA1*02 & B1*02).Our study showed that the genetic risk for CD was present in more than one-third of the cases without a confirmed diagnosis of CD. Therefore, the awareness of genetic susceptibility for CD is essential because of the fact that these individuals can develop the disease at any point of their lives. The sensitivity of TG2/DGP and EMA were very similar, whereas EMA presented a higher specificity as that of TG2/DGP.
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Affiliation(s)
| | | | | | | | | | - Minodora Dobreanu
- Department of Laboratory Medicine, University of Medicine and Pharmacy Tîrgu Mureş, Romania
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In silico search for modifier genes associated with pancreatic and liver disease in Cystic Fibrosis. PLoS One 2017; 12:e0173822. [PMID: 28339466 PMCID: PMC5365109 DOI: 10.1371/journal.pone.0173822] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Accepted: 02/27/2017] [Indexed: 12/15/2022] Open
Abstract
Cystic Fibrosis is the most common lethal autosomal recessive disorder in the white population, affecting among other organs, the lung, the pancreas and the liver. Whereas Cystic Fibrosis is a monogenic disease, many studies reveal a very complex relationship between genotype and clinical phenotype. Indeed, the broad phenotypic spectrum observed in Cystic Fibrosis is far from being explained by obvious genotype-phenotype correlations and it is admitted that Cystic Fibrosis disease is the result of multiple factors, including effects of the environment as well as modifier genes. Our objective was to highlight new modifier genes with potential implications in the lung, pancreatic and liver outcomes of the disease. For this purpose we performed a system biology approach which combined, database mining, literature mining, gene expression study and network analysis as well as pathway enrichment analysis and protein-protein interactions. We found that IFI16, CCNE2 and IGFBP2 are potential modifiers in the altered lung function in Cystic Fibrosis. We also found that EPHX1, HLA-DQA1, HLA-DQB1, DSP and SLC33A1, GPNMB, NCF2, RASGRP1, LGALS3 and PTPN13, are potential modifiers in pancreas and liver, respectively. Associated pathways indicate that immune system is likely involved and that Ubiquitin C is probably a central node, linking Cystic Fibrosis to liver and pancreatic disease. We highlight here new modifier genes with potential implications in Cystic Fibrosis. Nevertheless, our in silico analysis requires functional analysis to give our results a physiological relevance.
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Hepatitis B Virus Revaccination With Standard Versus Pre-S Vaccine in Previously Immunized Patients With Celiac Disease. J Pediatr Gastroenterol Nutr 2015; 61:400-3. [PMID: 25988560 DOI: 10.1097/mpg.0000000000000856] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Previous studies have suggested that hepatitis B virus (HBV) vaccines may be less immunogenic in individuals with celiac disease (CD). A pre-S vaccine (Sci-B-Vac) has demonstrated superior immunogenicity compared with standard HBV vaccines in several diseases. We compared the short-term immunogenicity of a pre-S vaccine with a HBV vaccine (Engerix B) for repeat vaccination of seronegative, previously immunized patients with CD. METHODS Participants were 1 to 18-year-old children with CD who despite standard HBV vaccines in infancy had nonprotective hepatitis B surface antibody (HBs-Ab) concentrations (≤10 mIU/mL). Patients were randomized to receive either Engerix B or pre-S vaccine. HBs-Ab concentrations were measured 1 month after the first dose. For those who had not responded after 1 dose, measurement was repeated after the third dose. RESULTS Children (n = 82) were analyzed (42 pre-S vaccine and 40 Engerix B). Baseline characteristics were similar for both groups, including gluten-free diet status. Both arms showed high response rates following the first injection: 41 (98%) versus 35 (87%) for pre-S vaccine and Engerix B recipients, respectively (P = 0.08). All other patients responded when measured after dose 3. HBs-Ab concentrations (mIU/mL) were higher in the pre-S vaccine group (median 925, interquartile range [IQR] 424-1000) than the Engerix B group (median 363, IQR 106-996, P = 0.005). Twenty (48%) of the pre-S vaccine recipients were "high responders" (>1000 mIU/mL) versus 10 (25%) in Engerix B recipients (P = 0.008). CONCLUSIONS Both vaccines elicited adequate booster responses in most previously vaccinated patients with CD with nonprotective HBs-Ab concentrations. Pre-S vaccine administration resulted in higher Hbs-Ab concentrations. Our data suggest that a single dose of either vaccine is sufficient to raise titers to protective levels in most patients with CD.
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Agardh D, Lee HS, Kurppa K, Simell V, Aronsson CA, Jörneus O, Hummel M, Liu E, Koletzko S. Clinical features of celiac disease: a prospective birth cohort. Pediatrics 2015; 135:627-34. [PMID: 25733751 PMCID: PMC4379464 DOI: 10.1542/peds.2014-3675] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/22/2014] [Indexed: 01/18/2023] Open
Abstract
OBJECTIVES To investigate clinical features of celiac disease (CD) and their association with risk factors for CD in a genetic risk birth cohort. METHODS Children from 6 clinical centers in 4 countries positive for HLA-DR3-DQ2 or DR4-DQ8 were annually screened for tissue transglutaminase antibodies (tTGA) and assessed for symptoms by questionnaires. Associations of symptoms with anthropometrics, known risk factors for CD, tTGA levels, and mucosal lesions in those biopsied were examined. RESULTS Of 6706 screened children, 914 developed persistent positive tTGA, 406 underwent biopsies, and 340 had CD. Compared with age-matched tTGA-negative children, those with persistent tTGA were more likely to have symptoms at 2 (34% vs 19%, P < .001) and 3 years of age (28% vs 19%, P = .009) but not at 4 years (27% vs 21%, NS). Z-scores for height, weight, and BMI did not differ between groups. In children with persistent tTGA, having ≥ 1 symptom was associated with family history of CD (odds ratio = 2.59, 95% confidence interval, 1.21-5.57) but not with age, gender, or HLA-DR3-DQ2 homozygosity. At seroconversion, tTGA levels were higher in symptomatic than asymptomatic children (P < .001), in those from CD families (P < .001), and in US participants (P < .001) but not associated with age, gender, or HLA genotype. tTGA levels correlated with severity of mucosal lesions both in symptomatic (r = 0.53, P < .001) and asymptomatic children (r = 0.22, P = .01). CONCLUSIONS A majority of children detected with persistent tTGA in screenings are asymptomatic and have normal growth by age 4 years. tTGA levels correlate more strongly with severity of mucosal lesions in symptomatic as compared with asymptomatic children.
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Affiliation(s)
- Daniel Agardh
- The Diabetes and Celiac Disease Unit, Department of Clinical Sciences, Lund University, Malmo, Sweden; Pediatric Epidemiology Center, Department of Pediatrics, Morsani College of Medicine, University of South Florida, Tampa, Florida;
| | - Hye-Seung Lee
- Pediatric Epidemiology Center, Department of Pediatrics, Morsani College of Medicine, University of South Florida, Tampa, Florida
| | - Kalle Kurppa
- Tampere Center for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland
| | - Ville Simell
- Department of Pediatrics, Turku University Hospital, Turku, Finland
| | - Carin Andrén Aronsson
- The Diabetes and Celiac Disease Unit, Department of Clinical Sciences, Lund University, Malmo, Sweden
| | - Ola Jörneus
- The Diabetes and Celiac Disease Unit, Department of Clinical Sciences, Lund University, Malmo, Sweden
| | - Michael Hummel
- Institute of Diabetes Research, Helmholtz Zentrum München, and Klinikum Rechts der Isar, Technische Universität München, and Forschergruppe Diabetes e.V., Neuherberg, Germany
| | - Edwin Liu
- Digestive Health Institute, University of Colorado, Children's Hospital Colorado, Denver, Colorado; and
| | - Sibylle Koletzko
- Dr von Hauner Children's Hospital, Ludwig Maximilian University, Munich, Germany
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Liu E, Lee HS, Aronsson CA, Hagopian WA, Koletzko S, Rewers MJ, Eisenbarth GS, Bingley PJ, Bonifacio E, Simell V, Agardh D. Risk of pediatric celiac disease according to HLA haplotype and country. N Engl J Med 2014; 371:42-9. [PMID: 24988556 PMCID: PMC4163840 DOI: 10.1056/nejmoa1313977] [Citation(s) in RCA: 244] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
BACKGROUND The presence of HLA haplotype DR3-DQ2 or DR4-DQ8 is associated with an increased risk of celiac disease. In addition, nearly all children with celiac disease have serum antibodies against tissue transglutaminase (tTG). METHODS We studied 6403 children with HLA haplotype DR3-DQ2 or DR4-DQ8 prospectively from birth in the United States, Finland, Germany, and Sweden. The primary end point was the development of celiac disease autoimmunity, which was defined as the presence of tTG antibodies on two consecutive tests at least 3 months apart. The secondary end point was the development of celiac disease, which was defined for the purpose of this study as either a diagnosis on biopsy or persistently high levels of tTG antibodies. RESULTS The median follow-up was 60 months (interquartile range, 46 to 77). Celiac disease autoimmunity developed in 786 children (12%). Of the 350 children who underwent biopsy, 291 had confirmed celiac disease; an additional 21 children who did not undergo biopsy had persistently high levels of tTG antibodies. The risks of celiac disease autoimmunity and celiac disease by the age of 5 years were 11% and 3%, respectively, among children with a single DR3-DQ2 haplotype, and 26% and 11%, respectively, among those with two copies (DR3-DQ2 homozygosity). In the adjusted model, the hazard ratios for celiac disease autoimmunity were 2.09 (95% confidence interval [CI], 1.70 to 2.56) among heterozygotes and 5.70 (95% CI, 4.66 to 6.97) among homozygotes, as compared with children who had the lowest-risk genotypes (DR4-DQ8 heterozygotes or homozygotes). Residence in Sweden was also independently associated with an increased risk of celiac disease autoimmunity (hazard ratio, 1.90; 95% CI, 1.61 to 2.25). CONCLUSIONS Children with the HLA haplotype DR3-DQ2, especially homozygotes, were found to be at high risk for celiac disease autoimmunity and celiac disease early in childhood. The higher risk in Sweden than in other countries highlights the importance of studying environmental factors associated with celiac disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).
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Affiliation(s)
- Edwin Liu
- From the Digestive Health Institute, Children's Hospital Colorado (E.L.), and the Barbara Davis Center (E.L., M.J.R., G.S.E.), University of Colorado Denver, Aurora; the Pediatrics Epidemiology Center, University of South Florida, Tampa (H.-S.L.); the Diabetes and Celiac Disease Unit, Department of Clinical Sciences, Lund University, Malmo, Sweden (C.A.A., D.A.); Pacific Northwest Diabetes Research Institute, Seattle (W.A.H.); Dr. von Hauner Children's Hospital, Ludwig Maximilian University, Munich (S.K.), the Center for Regenerative Therapies Dresden, Technische Universitaet Dresden, Dresden (E.B.), and Forschergruppe Diabetes, Helmholz Zentrum München, Neuherberg (E.B.) - all in Germany; the School of Clinical Sciences, University of Bristol, Bristol, United Kingdom (P.J.B.); and the Department of Pediatrics, University of Turku, Turku University Hospital, Turku, Finland (V.S.)
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24
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Delgado JF, Amengual MJ, Veraguas A, Rodríguez E, de Los Santos MM, Guallarte MP. Paediatric celiac patients carrying the HLA-DR7-DQ2 and HLA-DR3-DQ2 haplotypes display small clinical differences. Acta Paediatr 2014; 103:e238-42. [PMID: 24628273 DOI: 10.1111/apa.12605] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2013] [Revised: 01/10/2014] [Accepted: 02/13/2014] [Indexed: 12/12/2022]
Abstract
AIM The aim of this study was to determine the relevance of HLA-DR7-DQ2 typing in a prospective cohort of paediatric coeliac disease patients from Southern Europe. METHODS This cross-sectional study tested 249 paediatric patients with coeliac disease. HLA-DR3-DQ2 was typed in combination with HLA-DR7-DQ2 to screen for the HLA-DQ2 haplotype. The histological, analytical and clinical characteristics of the subjects were recorded. RESULTS A total of 91 coeliac patients were diagnosed: 96.7% carried HLA-DQ2 and 4.4% carried HLA-DQ8. In percentage terms, 80.2% of patients carried HLA-DR3-DQ2 and 34.1% carried HLA-DR7-DQ2. We did not find significant differences between HLA-DR7-DQ2 and HLA-DR3-DQ2 paediatric patients with respect to histological damage and clinical characteristics, except for irritability and weight loss. These characteristics were more frequent in HLA-DQ2trans than in HLA-DQ2cis (22.2% vs. 0.0% [p = 0.035] and 55.6% vs. 21.4% [p = 0.017], respectively). Coeliac-specific autoantibody levels were higher in HLA-DQ2cis than one half of HLA-DQ2trans patients (105.5 vs. 19.2 U/mL, p = 0.014). CONCLUSION Small clinical differences were found between paediatric coeliac patients carrying HLA-DR7-DQ2 and HLA-DR3-DQ2. For a correct screening of HLA-DQ2, at least in our geographical population, the HLA-DR7-DQ2 haplotype should be typed due to its frequency and clinical presentation.
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Affiliation(s)
- Juan F. Delgado
- Immunology Section Laboratory; UDIAT-Centre Diagnòstic; Corporació Sanitària Parc Taulí; Sabadell Spain
- Institut Universitari Parc Taulí-UAB; Universitat Autònoma de Barcelona; Campus d'Excelència Internacional; Bellaterra Spain
| | - María J. Amengual
- Immunology Section Laboratory; UDIAT-Centre Diagnòstic; Corporació Sanitària Parc Taulí; Sabadell Spain
- Institut Universitari Parc Taulí-UAB; Universitat Autònoma de Barcelona; Campus d'Excelència Internacional; Bellaterra Spain
| | - Ana Veraguas
- Immunology Section Laboratory; UDIAT-Centre Diagnòstic; Corporació Sanitària Parc Taulí; Sabadell Spain
- Institut Universitari Parc Taulí-UAB; Universitat Autònoma de Barcelona; Campus d'Excelència Internacional; Bellaterra Spain
| | - Encarnación Rodríguez
- Immunology Section Laboratory; UDIAT-Centre Diagnòstic; Corporació Sanitària Parc Taulí; Sabadell Spain
- Institut Universitari Parc Taulí-UAB; Universitat Autònoma de Barcelona; Campus d'Excelència Internacional; Bellaterra Spain
| | - Mariela M. de Los Santos
- Institut Universitari Parc Taulí-UAB; Universitat Autònoma de Barcelona; Campus d'Excelència Internacional; Bellaterra Spain
- Pediatric Department; Hospital de Sabadell; Corporació Sanitària Parc Taulí; Sabadell Spain
| | - María P. Guallarte
- Institut Universitari Parc Taulí-UAB; Universitat Autònoma de Barcelona; Campus d'Excelència Internacional; Bellaterra Spain
- Pediatric Department; Hospital de Sabadell; Corporació Sanitària Parc Taulí; Sabadell Spain
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Mackinder M, Allison G, Svolos V, Buchanan E, Johnston A, Cardigan T, Laird N, Duncan H, Fraser K, Edwards CA, Craigie I, McGrogan P, Gerasimidis K. Nutritional status, growth and disease management in children with single and dual diagnosis of type 1 diabetes mellitus and coeliac disease. BMC Gastroenterol 2014; 14:99. [PMID: 24885742 PMCID: PMC4046848 DOI: 10.1186/1471-230x-14-99] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Accepted: 05/21/2014] [Indexed: 12/17/2022] Open
Abstract
Background The consequences of subclinical coeliac disease (CD) in Type 1 diabetes mellitus (T1DM) remain unclear. We looked at growth, anthropometry and disease management in children with dual diagnosis (T1DM + CD) before and after CD diagnosis. Methods Anthropometry, glycated haemoglobin (HbA1c) and IgA tissue transglutaminase (tTg) were collected prior to, and following CD diagnosis in 23 children with T1DM + CD. This group was matched for demographics, T1DM duration, age at CD diagnosis and at T1DM onset with 23 CD and 44 T1DM controls. Results No differences in growth or anthropometry were found between children with T1DM + CD and controls at any time point. Children with T1DM + CD, had higher BMI z-score two years prior to, than at CD diagnosis (p < 0.001). BMI z-score change one year prior to CD diagnosis was lower in the T1DM + CD than the T1DM group (p = 0.009). At two years, height velocity and change in BMI z-scores were similar in all groups. No differences were observed in HbA1c between the T1DM + CD and T1DM groups before or after CD diagnosis. More children with T1DM + CD had raised tTg levels one year after CD diagnosis than CD controls (CDx to CDx + 1 yr; T1DM + CD: 100% to 71%, p = 0.180 and CD: 100% to 45%, p < 0.001); by two years there was no difference. Conclusions No major nutrition or growth deficits were observed in children with T1DM + CD. CD diagnosis does not impact on T1DM glycaemic control. CD specific serology was comparable to children with single CD, but those with dual diagnosis may need more time to adjust to gluten free diet.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | - Konstantinos Gerasimidis
- Human Nutrition, School of Medicine, College of Medicine, Veterinary and Life Sciences, Royal Hospital for Sick Children, University of Glasgow, G3 8SJ Glasgow, UK.
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26
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Rostami-Nejad M, Romanos J, Rostami K, Ganji A, Ehsani-Ardakani MJ, Bakhshipour AR, Zojaji H, Mohebbi SR, Zali MR, Wijmenga C. Allele and haplotype frequencies for HLA-DQ in Iranian celiac disease patients. World J Gastroenterol 2014; 20:6302-6308. [PMID: 24876751 PMCID: PMC4033468 DOI: 10.3748/wjg.v20.i20.6302] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2013] [Revised: 12/31/2013] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the distribution of human leukocyte antigen (HLA)-DQ2 and -DQ8 in Iranian celiac disease (CD) patients and compare them to healthy Iranian controls.
METHODS: To predict the HLA-DQA1 and -DQB1 genes, we used six previously reported HLA-tagging single nucleotide polymorphism to determine HLA genotypes in 59 Iranian patients with ‘biopsy-confirmed’ CD and in 151 healthy Iranian individuals. To test the transferability of the method, 50 cases and controls were also typed using a commercial kit that identifies individual carriers of DQ2, DQ7 and DQ8 alleles.
RESULTS: In this pilot study 97% of CD cases (n = 57) and 58% of controls (n = 87) were carriers of HLA-DQ2 and/or HLA-DQ8 heterodimers, either in the homozygous or heterozygous state. The HLA-DQ pattern of these 57 CD patients: heterozygous DQ2.2 (n = 14) and homozygous DQ2.2 (n = 1), heterozygous DQ2.5 (n = 33) and homozygous DQ2.5 (n = 8), heterozygous DQ8 (n = 13) and homozygous DQ8 (n = 2). Two CD patients were negative for both DQ2 and DQ8 (3%).
CONCLUSION: The prevalence of DQ8 in our CD population was higher than that reported in other populations (25.4%). As reported in other populations, our results underline the primary importance of HLA-DQ alleles in the Iranian population’s susceptibility to CD.
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Bozzola M, Bozzola E, Pagani S, Mascolo A, Porto R, Meazza C. Late diagnosis of celiac disease in an asymptomatic infant with growth failure. Ital J Pediatr 2014; 40:4. [PMID: 24428915 PMCID: PMC3896748 DOI: 10.1186/1824-7288-40-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Accepted: 12/31/2013] [Indexed: 01/14/2023] Open
Abstract
The clinical spectrum for celiac disease (CD) is broad and includes cases with either typical (intestinal) or atypical (extraintestinal) features, often making the diagnosis of CD very difficult. We describe the case of a girl presenting with stunted growth and malnourishment. She was evaluated at 14 months for decreased growth rate without any signs of gastrointestinal, renal or endocrine disorders. She was evaluated for CD, but resulted negative for anti-tTG antibodies. At the age of 4.1 years, she exhibited basal dental enamel hypoplasia, iron deficiency anaemia despite repeated iron supplementation, with persistent reduced height (-2.79 SDS), BMI (-0.76 SDS), growth velocity (-1.79 SDS) and delayed bone age (1.5 year). The CD screening was repeated and very high anti-tTG-IgA (128 IU/ml, normal values < 7 IU/ml) and anti-tTG-IgG (77 IU/ml, normal values < 7 IU/ml) values were found. HLA genotyping revealed an HLA DQ2 haplotype. A duodenal biopsy revealed severe villous atrophy with crypt hyperplasia and increased intraepithelial lymphocytes (> 40 IELs/100 epithelial cells) confirming the diagnosis of CD. A gluten-free diet was started and after only four months, her growth velocity increased from 4.83 cm/year (-1.79 SDS) to 6.53 cm/year (-0.15 SDS). In conclusion, we report the development of a positive serology for CD in an asymptomatic child with growth retardation, who previously was investigated for CD and resulted negative. Therefore, when faced with retarded growth in young patients, after excluding other malabsorption conditions and even when CD serological markers are negative, the paediatric endocrinologist should request HLA genotyping, before the intestinal biopsy, in order to check for the presence of risk alleles.
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Affiliation(s)
- Mauro Bozzola
- Internal Medicine and Therapeutics Department, University of Pavia, Fondazione IRCCS San Matteo, Pavia, Italy.
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28
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Verbeek WHM, Schreurs MWJ, Visser OJ, von Blomberg BME, Al-Toma A, Mulder CJJ. Novel approaches in the management of refractory celiac disease. Expert Rev Clin Immunol 2014; 4:205-19. [PMID: 20477051 DOI: 10.1586/1744666x.4.2.205] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- Wieke H M Verbeek
- VU University Medical Center, Department of Gastroenterology and Hepatology, PO Box 7057, 1007 MB, Amsterdam, The Netherlands.
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29
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Poddar U. Pediatric and adult celiac disease: similarities and differences. Indian J Gastroenterol 2013; 32:283-8. [PMID: 23715643 DOI: 10.1007/s12664-013-0339-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2012] [Accepted: 04/14/2013] [Indexed: 02/04/2023]
Abstract
Differences between children and adults in celiac disease (CD) presentation and epidemiology are reviewed here. Clinical manifestations, histological changes, serology, and response to gluten-free diet are similar. Differences exist in epidemiology, type of clinical presentations, coexisting diseases, complications, and association with obesity. CD is two to five times more common in children than in adults. Classical CD with gastrointestinal symptoms is more common in children whereas nonclassical CD dominates in adults. A gene dose phenomenon (double-dose HLA-DQB1 02 allele) is postulated to be responsible for this difference. Coexisting autoimmune diseases like diabetes mellitus type 1, Sjogren's syndrome, and dermatitis herpetiformis are more common in adults than in children (42 % vs. 5 %). The association of overweight/obesity and CD is stronger in adults than in children (22.5 % vs. 14 %). Besides poor compliance, pancreatic insufficiency, bacterial overgrowth, lactose intolerance, irritable bowel syndrome, lymphocytic colitis, and microscopic colitis are considered responsible for nonresponsive CD in adults but not in children. Complications like refractory sprue and small intestinal neoplasms are seen exclusively in adults. Existing diagnostic criteria (modified ESPGHAN) are not suitable for diagnosing CD in adults as the majority of cases are either nonclassical or subclinical CD.
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Affiliation(s)
- Ujjal Poddar
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow 226 014, India.
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30
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Abstract
Patients with celiac disease (CD) lacking both human leukocyte antigen (HLA)-DQ2.5 in cis (DQA1*05:01, DQB1*02:01) or trans (DQA1*05:05, DQB1*02:02) configuration and HLA-DQ8 (DQA1*03:01, DQB1*03:02) are considered to be rare. Therefore, absence of these genotypes is commonly used to exclude the diagnosis of CD. To investigate whether this approach is justified, the HLA-distribution in 155 children with CD was studied. A total of 139 (89.7%) patients carried HLA-DQ2.5. Of the remaining patients, 7 (4.5%) carried HLA-DQ8. Interestingly, the 9 (5.8%) patients lacking HLA-DQ2.5 and HLA-DQ8 carried HLA-DQA1*02:01 and -DQB1*02:02 (HLA-DQ2.2). Therefore, HLA-DQ2.2 should be included as an important HLA-type related to CD.
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Abstract
Celiac disease results from the interplay of genetic, environmental, and immunologic factors. An understanding of the pathophysiology of celiac disease, in which the trigger (wheat, rye, and barley) is known, will undoubtedly reveal basic mechanisms that underlie other autoimmune diseases (eg, type 1 diabetes) that share many common pathogenic perturbations. This review describes seminal findings in each of the 3 domains of the pathogenesis of celiac disease, namely genetics, environmental triggers, and immune dysregulation, with a focus on newer areas of investigation such as non-HLA genetic variants, the intestinal microbiome, and the role of the innate immune system.
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Affiliation(s)
- Sonia S Kupfer
- University of Chicago Celiac Disease Center, Chicago, IL, USA.
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32
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Atypical celiac disease: from recognizing to managing. Gastroenterol Res Pract 2012; 2012:637187. [PMID: 22811701 PMCID: PMC3395124 DOI: 10.1155/2012/637187] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2012] [Accepted: 05/08/2012] [Indexed: 12/23/2022] Open
Abstract
The nonclassic clinical presentation of celiac disease (CD) becomes increasingly common in physician's daily practice, which requires an awareness of its many clinical faces with atypical, silent, and latent forms. Besides the common genetic background (HLA DQ2/DQ8) of the disease, other non-HLA genes are now notably reported with a probable association to atypical forms. The availability of high-sensitive and specific serologic tests such as antitissue transglutuminase, antiendomysium, and more recent antideamidated, gliadin peptide antibodies permits to efficiently uncover a large portion of the submerged CD iceberg, including individuals having conditions associated with a high risk of developing CD (type 1 diabetes, autoimmune diseases, Down syndrome, family history of CD, etc.), biologic abnormalities (iron deficiency anemia, abnormal transaminase levels, etc.), and extraintestinal symptoms (short stature, neuropsychiatric disorders, alopecia, dental enamel hypoplasia, recurrent aphtous stomatitis, etc.). Despite the therapeutic alternatives currently in developing, the strict adherence to a GFD remains the only effective and safe therapy for CD.
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Abstract
The advent of highly sensitive and specific serological markers has led to some protagonists proposing that coeliac disease can be diagnosed without the need for a biopsy. However, this is an area of controversy. Lack of consensus about diagnostic degrees of histological change, paucity of symptoms, antibody-negative disease and immunodeficiency can make diagnosis difficult even with a biopsy. Conversely, an argument can be put forward for a 'no biopsy' approach based on the large number of patients with typical symptoms and positive serology who experience a diagnostic delay. In addition, endoscopy is not without discomfort. This article discusses the use of antibodies and duodenal biopsy within this context. Finally, we propose a pragmatic diagnostic algorithm for clinicians to use when investigating patients for coeliac disease.
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Affiliation(s)
- K E Evans
- Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield, UK.
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34
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El-Akawi ZJ, Al-Hattab DM, Migdady MA. Frequency of HLA-DQA1*0501 and DQB1*0201 alleles in patients with coeliac disease, their first-degree relatives and controls in Jordan. ACTA ACUST UNITED AC 2011; 30:305-9. [PMID: 21118624 DOI: 10.1179/146532810x12858955921195] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND The primary genetic marker associated with coeliac disease (CD) is the HLA-DQ2 molecule, encoded by the DQA1*0501 and DQB1*0201 genes. AIM To investigate the frequency of HLA-DQA1*0501 and DQB1*0201 alleles in Jordanian patients with CD and their first-degree relatives. METHODS An allele-specific DNA-based PCR-sequence-specific primer was used to investigate DQA1*0501 and DQB1*0201 alleles in 44 CD patients, 47 first-degree relatives and 53 healthy controls. RESULTS The mean age of the patients at the time of diagnosis was 13.5 years (range 1-39) and at the time of the study was 19.3 years (range 5-42). The DQA1/B1 (0501; 0201) haplotype was present in 80% of patients and 66% of first-degree relatives compared with 32% of controls (p<0.0001 and <0.01, respectively). The remaining 20% of CD patients who were negative for the DQ2 molecule carried the DQB1*0201 allele only. A statistically significant difference was detected in the DQ2 hetero-dimer frequency between CD patients, their first-degree relatives and controls with a higher frequency in the patients group (p<0.001). CONCLUSION The significant differences in the frequency of DQA1*0501, DQB1*0201 alleles in CD patients and their first-degree relatives compared with the control group demonstrated the important role of these alleles in the development of CD in the Jordanian population.
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Affiliation(s)
- Z J El-Akawi
- Departments of Biochemistry & Molecular Biology, Faculty of Applied Medical Sciences, Jordan University of Science & Technology, Irbid, Jordan.
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Shammaa D, Khansa S, Zaatari G, Mahfouz RAR. Human leukocyte antigen-DQA1 gene allelic distribution: experience of a major tertiary care center in Lebanon. Genet Test Mol Biomarkers 2011; 15:111-3. [PMID: 21198394 DOI: 10.1089/gtmb.2010.0114] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
AIMS DQA1 is a human leukocyte antigen (HLA) class II molecule that is similar to the other class II molecules DR and DP. This study is the first of its kind to describe the distribution of HLA-DQA1 alleles in Lebanon. METHODS HLA-DQA1 typing was detected using the polymerase chain reaction/sequence-specific priming method in 111 Lebanese individuals referred for HLA typing and possible bone marrow donation. RESULTS Our data was compared to that of several populations. Some similarities were found between the Lebanese, Tunisian, Spanish, and Kuwaiti populations. CONCLUSION This very first report from Lebanon will be of great help for later research to study the association of DQA1 alleles with major diseases in the Lebanese population and will add to the published international literature related to this important histocompatibility locus.
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Affiliation(s)
- Dina Shammaa
- Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Beirut, Lebanon
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Hadithi M, Peña AS. Current methods to diagnose the unresponsive and complicated forms of coeliac disease. Eur J Intern Med 2010; 21:247-53. [PMID: 20603030 DOI: 10.1016/j.ejim.2010.01.015] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2008] [Revised: 01/24/2010] [Accepted: 01/29/2010] [Indexed: 02/07/2023]
Abstract
Coeliac disease is a common disorder. Due to the protean manifestations of the disease and the often mild but indolent course, the diagnosis is often missed. The method to diagnose this in principle reversible disease after the introduction of a gluten-free diet has attracted the attention of several scientific disciplines to find the simplest and most patient-friendly test. This has resulted in a noticeable impact on the clinical practice next to a general increased awareness of its existence, its pathogenesis, its course and recent evidence of increased mortality. Amendments made in the diagnostic criteria of coeliac disease over the last half century have simplified the diagnosis. However, the aspect most relevant to the specialist in internal medicine is related to its grave consequences when the disease fails to respond to a gluten-free diet. These refractory cases may culminate in severe complications with sombre endings and malignancy. Fortunately, current technology can offer the specialist in internal medicine more facilities to diagnose the cause of the complicated cases in order to attempt to intervene in the course of disease and hopefully save these patients. We review the available tools that now exist and their indications that can be practiced in a modern clinical setting for the diagnosis of the complicated forms of this disease.
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Affiliation(s)
- M Hadithi
- Department of Gastroenterology, Maasstad Hospital, Postbus 9119, Rotterdam, The Netherlands
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Thomas HJ, Ahmad T, Rajaguru C, Barnardo M, Warren BF, Jewell DP. Contribution of histological, serological, and genetic factors to the clinical heterogeneity of adult-onset coeliac disease. Scand J Gastroenterol 2010; 44:1076-83. [PMID: 19593686 DOI: 10.1080/00365520903100473] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Although the factors predisposing to coeliac disease (CD) are largely understood, it remains unclear what determines the clinical heterogeneity of the disease. The aim of this study was to explore the contribution of histological, serological, and genetic factors to disease presentation. MATERIAL AND METHODS The study was designed as a retrospective chart review of 384 unrelated Caucasian patients diagnosed with CD after the age of 16 at a single UK centre. RESULTS We found that 8.8% of IgA-competent CD patients were endomysial antibody (EMA)-negative. Compared with the EMA-positive group, EMA-negative CD patients had a lower prevalence of iron deficiency (52.0% versus 72.6%, p=0.03) and Marsh IIIb-c lesions (66.7% versus 85.3%, p=0.03). Histological severity at diagnosis correlated with anaemia (p<0.01), folate deficiency (p<0.01), and iron deficiency (p=0.05), but no other laboratory or clinical features. Compared with human leucocyte antigen (HLA)-DQ2.5-positive patients, those carrying HLA-DQ2.2 were similar in terms of all the characteristics we considered, whereas those carrying HLA-DQ8 had a lower frequency of EMA positivity (62.5% versus 92.6%, p<0.01). The proportion of EMA-positive patients increased with frequency of the HLA-DQB1*0201 allele (76.7% versus 92.3% versus 96.4% for 0 versus 1 versus 2 alleles, p<0.01); no other evidence of a gene-dose effect of HLA-DQB1*0201 was observed. CONCLUSIONS Histological severity at diagnosis of CD is associated with anaemia and some micronutrient deficiencies, but no other clinical features. The proportion of EMA-positive patients is higher amongst those carrying HLA-DQ2 than in those carrying HLA-DQ8, and is highest in HLA-DQ2 homozygotes. We found no correlation between frequency of the HLA-DQ alleles encoding HLA-DQ2.5 and CD severity.
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Affiliation(s)
- Harry J Thomas
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
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Mohammadi J, Ramanujam R, Jarefors S, Rezaei N, Aghamohammadi A, Gregersen PK, Hammarström L. IgA deficiency and the MHC: assessment of relative risk and microheterogeneity within the HLA A1 B8, DR3 (8.1) haplotype. J Clin Immunol 2010; 30:138-43. [PMID: 19834793 PMCID: PMC11292587 DOI: 10.1007/s10875-009-9336-2] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2009] [Accepted: 09/24/2009] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Selective IgA deficiency (IgAD; serum IgA concentration of <0.07 g/l) is the most common primary immunodeficiency in Caucasians with an estimated prevalence of 1/600. The frequency of the extended major histocompatibility complex haplotype HLA A1, B8, DR3, DQ2 (the "8.1" haplotype) is increased among patients with IgAD. MATERIALS AND METHODS We carried out a direct measurement of the relative risk of homozygosity of the 8.1 haplotype for IgA deficiency in a population-based sample of 117 B8, DR3 homozygous individuals. RESULTS AND DISCUSSION IgA deficiency was found to be present in 2 of 117 (1.7%) of these subjects, a figure that is concordant with estimates of relative risk from large case-control studies in the Swedish population. These data are consistent with a multiplicative model for the 8.1 haplotype contribution to IgA deficiency and contrasts with prior studies, suggesting a much higher risk for 8.1 homozygosity. Using a dense single nucleotide polymorphism marker analysis of the MHC region in HLA B8, DR3, DQ2 homozygous individuals, we did not observe consistent differences between cases (n = 26) and controls (n = 24). Overall, our results do not support the hypothesis that IgA deficiency is associated with a distinct subgroup of 8.1 related haplotypes, but rather indicate that risk is conferred by the common 8.1 haplotype acting in multiplicative manner.
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Affiliation(s)
- Javad Mohammadi
- Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden
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Abstract
BACKGROUND Coeliac disease (CD) is a genetically driven immunological intolerance to dietary gluten with a wide range of clinical presentations. The aim of this study was to investigate the heritability of the phenotype in CD and the influence on the phenotype of different genes associated with the disease. PATIENTS AND METHODS One hundred and seven families with at least 2 siblings with CD were collected. The patients were grouped in symptom grades on the basis of the clinical presentation, the age at diagnosis, and sex. Stratification analyses of the human leucocyte antigen-DQA1 and human leucocyte antigen-DQB1 genotypes, the CTLA4 +49A/G polymorphism, the CTLA4 haplotype MH30*G:-1147*T:+49*A:CT60*G:CT61*A, and the 5q31-33 loci were done. RESULTS The heritability of the phenotype was estimated to be 0.45. Significant association and linkage was found between the clinical presentation and the CTLA4 +49A/G polymorphism but not for the other genotypes. No correlation was found between genotypes and age at diagnosis or sex. CONCLUSIONS Our results indicate that the heritability is determiner of the phenotype in CD. The CTLA4 +49A/G polymorphism is correlated to the clinical presentation: the AA genotype is associated with clinically silent disease.
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Vermeulen BAN, Hogen Esch CE, Yuksel Z, Koning F, Verduijn W, Doxiadis IIN, Schreuder GMT, Mearin ML. Phenotypic variance in childhood coeliac disease and the HLA-DQ/DR dose effect. Scand J Gastroenterol 2009; 44:40-5. [PMID: 18932050 DOI: 10.1080/00365520802116422] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Coeliac disease (CD) is associated with HLA-DQ2 and DQ8. The clinical picture is variable and certain human leucocyte antigen (HLA) DQ/DR combinations have a higher relative risk (RR) for CD than others. Moreover, the HLA-DQ gene-dose effect has an impact on the strength of the gluten-specific T-cell response and thus may correlate with clinical presentation and severity of CD. The aim of this study was to determine the correlation between HLA-DQ/DR-based genotypes and the variation in phenotypes of the disease. MATERIAL AND METHODS A total of 113 non-related Caucasian children clinically diagnosed with CD during the period 1980-2003 with a known HLA type were included in the study. Patients were divided into four categories according to amount of disease expression predisposing to HLA-DQ2 or HLA-DQ8 molecules and the known RR of their HLA-DR/DQ type for CD: high (DR3DQ2 homozygous and DR3DQ2/DR7DQ2), substantial (DR3DQ2/DR5DQ7 and DR5DQ7/DR7DQ2), moderate (DR3DQ2-DR4DQ8 and DR3DQ2/DR*DQ*) and low (DR7DQ2/DR*DQ*, DR4DQ8- DR*DQ* and DR*DQ*- DR*DQ*). The clinical data and HLA genotypes of these patients were compared. RESULTS The 113 children were diagnosed with CD at a mean age of 4.6 years and boys were significantly older than girls when diagnosed (p=0.01). RR for having CD was highest for the high HLA-risk group (RR 8.1). With the exception of a greater frequency of abdominal distension and fewer non-gastrointestinal symptoms in the substantial HLA-risk group, there were no significant differences in clinical characteristics or degree of severity of the small-bowel histological findings between the children in the different HLA-risk groups. CONCLUSION No correlation was found between disease severity and a double HLA-DQ2 gene dose.
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Affiliation(s)
- Beatrijs A N Vermeulen
- Department of Paediatric Gastroenterology, Leiden University Medical Centre, Leiden, The Netherlands
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Cassinotti A, Birindelli S, Clerici M, Trabattoni D, Lazzaroni M, Ardizzone S, Colombo R, Rossi E, Porro GB. HLA and autoimmune digestive disease: a clinically oriented review for gastroenterologists. Am J Gastroenterol 2009; 104:195-217; quiz 194, 218. [PMID: 19098870 DOI: 10.1038/ajg.2008.10] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES The human leukocyte antigen (HLA) system includes genes involved in graft-vs-host rejection and in immune response. The discovery that HLAs are associated with several diseases led to appealing developments both in basic biomedical research and in clinical medicine, and offered the opportunity to improve the understanding of pathogenesis and classification of diseases, as well as to provide diagnostic and prognostic indicators. The aim of this article is to review the association between HLA alleles and autoimmune digestive disease and its current relationship with modern HLA nomenclature and clinical practice. METHODS Articles dealing with the association between HLAs and autoimmune digestive disease (including celiac disease, inflammatory bowel disease, autoimmune hepatitis, sclerosing cholangitis and primary biliary cirrhosis) were searched for using Pubmed and SCOPUS databases from earliest records to January 2008. RESULTS The review has provided two sections. In the first, we explain the basic principles of HLA structure, function, and nomenclature, as an introduction to the second section, which describes current associations between HLA alleles and digestive diseases. The clinical implications of each HLA association are critically discussed. Actually, a clinical role for HLA typing is suggested for only a few conditions, e.g., celiac disease. CONCLUSIONS The knowledge of current HLA nomenclature and of its association with some digestive diseases such as celiac disease can be useful in clinical practice for diagnostic and prognostic purposes. This can avoid improper HLA typing as well as stressing the need for further studies on other possible clinical applications.
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Affiliation(s)
- Andrea Cassinotti
- Department of Clinical Science, Division of Gastroenterology, L. Sacco University Hospital, via G.B.Grassi 74, Milan, Italy.
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HLA-DQB1*02 dose effect on RIA anti-tissue transglutaminase autoantibody levels and clinicopathological expressivity of celiac disease. J Pediatr Gastroenterol Nutr 2008; 47:288-92. [PMID: 18728523 DOI: 10.1097/mpg.0b013e3181615ca7] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVES Celiac disease is an autoimmune enteropathy caused by gluten ingestion in genetically susceptible individuals. Anti-transglutaminase autoantibody (tTGAb) assay is useful to detect candidates undergoing intestinal biopsy. Our aim was to investigate whether the DQB1*02 allele could influence tTGAb titers and the clinicopathological expressivity of the disease. METHODS A total of 124 patients with celiac disease, tested for RIA tTGAb at diagnosis, were typed for HLA-DRB1, -DQA1, and -DQB1 genes and divided according to the number of DQB1*02 alleles: group 1, homozygous; group 2, heterozygous; group 3, negative. RESULTS The mean of tTGAb indexes was significantly higher in group 1 patients than in group 2 (P < 0.02) and group 3 patients (P < 0.01). Patients with at least 1 DQB1*02 allele showed more often a typical CD and diffuse histological lesions than did patients in the other groups. CONCLUSIONS The study demonstrates that tTGAb titers are HLA-DQB1*02 dose dependent, with significantly higher levels in homozygous individuals. Moreover, individuals with at least 1 HLA-DQB1*02 allele tend to have a more expressed clinical and histological form of celiac disease.
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Santin I, Castellanos-Rubio A, Aransay AM, Castaño L, Vitoria JC, Bilbao JR. The functional R620W variant of the PTPN22 gene is associated with celiac disease. ACTA ACUST UNITED AC 2008; 71:247-9. [PMID: 18194365 DOI: 10.1111/j.1399-0039.2007.01002.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
The functional (R620W) variant of human PTPN22 (protein tyrosine phosphatase non-receptor 22) gene has been implicated in the risk to several autoimmune disorders, including type 1 diabetes, Graves' disease, rheumatoid arthritis and systemic lupus erythematosus. In an association study of this single nucleotide polymorphism with celiac disease (CD), comparison of 262 young diagnosis patients and 214 adult controls from Spain showed a higher frequency of the minor allele in the CD group (9.7% vs 5.6% in controls; P = 0.018), suggestive of an increased genetic risk to the disease (odds ratio = 1.82; 95% confidence interval 1.1-3.0). These results support the role of PTPN22 as a general autoimmunity locus involved in tolerance induction in the thymus.
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Affiliation(s)
- I Santin
- Immunogenetics Laboratory, Endocrinology and Diabetes Research Group, Hospital de Cruces, Barakaldo, Bizkaia, Spain
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Abstract
The concept of pharmacogenomics, the study of how variation in the human genome affects response to drugs, attracts attention from clinicians and the pharmaceutical industry alike. The aim is to distinguish, using appropriate genetic tests, individuals who may be harmed by certain drugs from those who may benefit from them. Adverse drug reactions cause significant morbidity and mortality and incur a large cost to healthcare systems. Pharmacogenomics may help in the prediction and prevention of adverse reactions to drugs. While some recent studies (e.g., abacavir hypersensitivity) have shown strong associations with single genetic factors, whether these represent the exceptions rather than the rule is unclear. Further studies on adverse drug reaction pharmacogenetics are needed – these should be adequately powered and utilize the most appropriate study design that allows for an evaluation of both genetic and environmental factors. For pharmacogenetic testing to become acceptable in clinical practice, it is important that such studies are also able to provide evidence of clinical validity and clinical utility.
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Affiliation(s)
- Ana Alfirevic
- The University of Liverpool, Department of Pharmacology & Therapeutics, Sherrington Building, Ashton Street, Liverpool, Merseyside, L69 3GE, UK
| | - Munir Pirmohamed
- The University of Liverpool, Department of Pharmacology & Therapeutics, Sherrington Building, Ashton Street, Liverpool, Merseyside, L69 3GE, UK
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Murray JA, Moore SB, Van Dyke CT, Lahr BD, Dierkhising RA, Zinsmeister AR, Melton LJ, Kroning CM, El-Yousseff M, Czaja AJ. HLA DQ gene dosage and risk and severity of celiac disease. Clin Gastroenterol Hepatol 2007; 5:1406-12. [PMID: 17919990 PMCID: PMC2175211 DOI: 10.1016/j.cgh.2007.08.013] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Celiac disease (CD) is a chronic inflammatory disorder of the small intestine that is strongly associated with certain HLA molecules encoded by DQA and DQB genes. The aim of this study was to examine the role of DQA and DQB alleles in determining the risk for and the age of onset and severity of CD in an American population. METHODS High-resolution class 2 HLA genotyping was performed in a population-based sample (n = 84) of southeastern Minnesota residents with CD and a comparable control group (n = 102) to determine the contribution of DQA and DQB alleles to disease risk. Logistic regression modeling was used to examine the relative and absolute risks of CD. RESULTS Ninety-seven percent of CD patients carried both of the HLA alleles, DQA1*05 and DQB1*02. Those who carried a second allele of DQB1*02 were 5 times more likely to have CD than those with just one (95% confidence interval, 1.4-18.1). The carriage of 2 copies of DQB1*02 did not predict either an earlier age of onset or severity of disease. CONCLUSIONS Both HLA alleles DQA1*05 and DQB1*02 are associated with a greatly increased risk of CD, although the latter has the greater effect. Carrying 2 copies of DQB1*02 was associated with an even greater risk for disease but did not predict an earlier age of onset and diagnosis or disease severity. Assessing the copy number of the DQB1*02 allele might allow for the stratification of disease risk.
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Affiliation(s)
- Joseph A Murray
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
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Wolters VM, Verbeek WHM, Zhernakova A, Onland-Moret C, Schreurs MWJ, Monsuur AJ, Verduijn W, Wijmenga C, Mulder CJJ. The MYO9B gene is a strong risk factor for developing refractory celiac disease. Clin Gastroenterol Hepatol 2007; 5:1399-405, 1405.e1-2. [PMID: 17967566 DOI: 10.1016/j.cgh.2007.08.018] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Celiac disease (CD) is associated with HLA-DQ2 and HLA-DQ8 and has been linked to genetic variants in the MYO9B gene on chromosome 19. HLA-DQ2 homozygosity is associated with complications of CD such as refractory celiac disease type II (RCD II) and enteropathy-associated T-cell lymphoma (EATL). We investigated whether MYO9B also predisposes to RCD II and EATL. METHODS Genotyping of MYO9B and molecular HLA-DQ2 typing were performed on 62 RCD II and EATL patients, 421 uncomplicated CD patients, and 1624 controls. RESULTS One single nucleotide polymorphism in MYO9B showed a significantly different allele distribution in RCD II and EATL patients compared with controls (P = .00002). The rs7259292 T allele was significantly more frequent in RCD II and EATL patients compared with CD patients (P = .0003; odds ratio [OR], 3.61; 95% confidence interval [CI], 1.78-7.31). The frequency of the haplotype carrying the T allele of this single nucleotide polymorphism was significantly increased in RCD II and EATL patients (11%), compared with controls (2%) and CD patients (3%) (OR, 6.76; 95% CI, 3.40-13.46; P = 2.27E-09 and OR, 4.22; 95% CI, 1.95-9.11; P = .0001, respectively). Both MYO9B rs7259292 and HLA-DQ2 homozygosity increase the risk for RCD II and EATL to a similar extent when compared with uncomplicated CD patients (OR, 4.3; 95% CI, 1.9-9.8 and OR, 5.4; 95% CI, 3.0-9.6, respectively), but there was no evidence for any interaction between these 2 risk factors. CONCLUSIONS We show that both MYO9B and HLA-DQ2 homozygosity might be involved in the prognosis of CD and the chance of developing RCD II and EATL.
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Affiliation(s)
- Victorien M Wolters
- Department of Pediatric Gastroenterology, University Medical Centre Utrecht, Utrecht, The Netherlands
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Jores RD, Frau F, Cucca F, Grazia Clemente M, Orrù S, Rais M, De Virgiliis S, Congia M. HLA-DQB1*0201 homozygosis predisposes to severe intestinal damage in celiac disease. Scand J Gastroenterol 2007; 42:48-53. [PMID: 17190762 DOI: 10.1080/00365520600789859] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
OBJECTIVE Celiac disease (CD) is a T-lymphocyte-mediated small intestinal enteropathy triggered and maintained by dietary gluten, with a strong genetic component mapping to the HLA genes encoding for the class II DQ(alpha1*0501, beta1*02) molecule. Damage of the small intestine may cause a variety of clinical signs ranging from isolated long-standing iron-deficiency anemia refractory to iron supplementation to forms of severe malnutrition that may become life threatening. However, patients carrying the typical intestinal lesions of CD and presenting no symptoms at all (silent CD) are also a common clinical observation. Since it is commonly assumed that clinical signs and symptoms tend to correlate with the severity of the intestinal damage, the purpose of this study was to investigate whether particular HLA class II genotypes might also influence the extent of intestinal damage and consequently the clinical presentation of the disease. MATERIAL AND METHODS We retrospectively compared histological grading of celiac disease intestinal biopsies with HLA haplotype, age at onset of disease and clinical signs and symptoms. RESULTS Our findings showed that homozygosis for the DQB1*0201 allele is associated with a higher severity of the histological score (p<0.008). Of note for the clinician, this work also suggests that the same type 3c of intestinal damage causes a different clinical syndrome, depending on the patient's age. CONCLUSIONS The genetic predisposition at the HLA-DQB1 locus influences the severity of the mucosal damage in a dose-dependent manner, but not the clinical presentation, of celiac disease.
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Affiliation(s)
- Rita-Désirée Jores
- Department of Biological Science and Biotechnology, University of Cagliari, Cagliari, Italy.
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Voorter CEM, van den Berg-Loonen EM. Sequence-based typing of the complete coding sequence of DQA1 and phenotype frequencies in the Dutch Caucasian population. Hum Immunol 2006; 67:756-63. [PMID: 17002907 DOI: 10.1016/j.humimm.2006.01.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2006] [Accepted: 01/31/2006] [Indexed: 11/27/2022]
Abstract
Typing of DQA1 by sequencing has been a challenge because of a 3-nucleotide deletion in exon 2 in half of the alleles. Furthermore, 19 of the 28 alleles cannot be identified on basis of exon 2 alone, but need additional exon information. With the sequencing strategy presented here the complete exons 1-4 are sequenced heterozygously, enabling identification of all DQA1 alleles by sequence-based typing (SBT). Exons 1-4 were amplified and sequenced separately, the combined sequences were used for automated allele assignment. The method was validated by typing 21 individuals with all possible different allele group combinations. In addition 26 quality control samples were correctly typed by this method. To determine the phenotype frequencies 155 unrelated Dutch Caucasian individuals were DQA1 typed. In total 15 known and two new DQA1 alleles were identified. DQA1*0103 and *0505 were the most frequent alleles with phenotype frequencies of 30% and 29%, respectively. The SBT method presented here is an improvement compared to already existing protocols in that the complete exon sequence is obtained for all coding exons, using identical polymerase chain reaction conditions. Furthermore, all exons are sequenced heterozygously, facilitating allele assignment and reducing the number of amplification reactions.
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Affiliation(s)
- Christina E M Voorter
- Tissue Typing Laboratory, University Hospital Maastricht, Maastricht, The Netherlands
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Uibo O, Teesalu K, Metskula K, Reimand T, Saat R, Sillat T, Reimand K, Talvik T, Uibo R. Screening for celiac disease in Down’s syndrome patients revealed cases of subtotal villous atrophy without typical for celiFac disease HLA-DQ and tissue transglutaminase antibodies. World J Gastroenterol 2006; 12:1430-4. [PMID: 16552815 PMCID: PMC4124324 DOI: 10.3748/wjg.v12.i9.1430] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the prevalence of celiac disease (CD) as well as CD marker antibodies and susceptibility HLA-DQ haplotypes in 134 karyotyped Down’s syndrome (DS) patients.
METHODS: Immunoglobulin A (IgA) and G (IgG) type anti-gliadin antibodies (AGA), IgA type anti-tissue transglutaminase (tTG) antibodies (anti-tTG) with antigen of guinea pig and human source were determined by enzyme-linked immunosorbent assay and endomysium antibodies (EMA) by indirect immunofluoresence test. HLA-DQA1*0501/DQB1*0201 (DQ2) was revealed by polymerase chain reaction. Celiac disease was diagnosed by revised ESPGHAN criteria.
RESULTS: 41 % of DS patients had AGA, 6.0 % IgA anti-tTG with guinea pig antigen, and 3.0 % IgA EMA (all positive for anti-tTG with human tTG). Subtotal villous atrophy was found in 5 out of 9 DS patients who had agreed to small bowel biopsy. One of them had DQA1*0501/DQB1*0201 and anti-tTG and EMA i.e. typical for CD markers (this case also fulfilled the ESPGHAN diagnostic criteria), but other four lacked these markers. Three non-biopsied DS patients had also most probably CD because DQA1*0501/DQB1*0201 and IgA anti-tTG (EMA) were detected. Thus, the prevalence of CD among our DS patients population is 3.0 % (95 % of confidence interval [CI]: 0.1-5.9 %).
CONCLUSION: We confirm the increased frequency of CD among DS patients. In addition, we have revealed a subgroup of patients with subtotal villous atrophy but without characteristic for CD immunological and genetic markers. Whether these cases represent CD (with atypical immunopathogenesis) or some other immune enteropathy, requires further investigations.
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Affiliation(s)
- Oivi Uibo
- Department of Paediatrics, University of Tartu, 6 Lunini Street, Tartu 51014, Estonia.
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Al-Toma A, Goerres MS, Meijer JWR, Peña AS, Crusius JBA, Mulder CJJ. Human leukocyte antigen-DQ2 homozygosity and the development of refractory celiac disease and enteropathy-associated T-cell lymphoma. Clin Gastroenterol Hepatol 2006; 4:315-9. [PMID: 16527694 DOI: 10.1016/j.cgh.2005.12.011] [Citation(s) in RCA: 138] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Celiac disease (CD) is a common gluten-sensitive enteropathy associated with human leukocyte antigen (HLA)-DQ2 and HLA-DQ8. The aim of this study was to determine if a particular HLA-DQ subtype predisposes to complications such as refractory CD with (RCD II) or without aberrant T cells (RCD I), and enteropathy-associated T-cell lymphomas (EATL). METHODS Molecular HLA-DQ typing was performed on 43 RCD I, 43 RCD II, and 30 EATL patients, and compared with age-matched groups of 121 patients with histologically defined uncomplicated CD and 183 healthy controls. All individuals were Dutch Caucasians and were at least 21 years of age. RESULTS HLA-DQ2 was present in 79% of RCD I, 97.7% of RCD II, and 96.6% of EATL patients. The differences were significant when compared with 28.9% in controls but not with 91.7% in uncomplicated CD. Homozygosity for HLA-DQ2 was observed in 25.5% of RCD I, 44.1% of RCD II, and 53.3% of EATL patients vs 20.7% of uncomplicated CD patients and 2.1% of controls. HLA-DQ8 was present in 10.7% of CD, 16.2% of RCD I, 9.3% of RCD II, and 6.6% of EATL patients vs 20.2% of controls. CONCLUSIONS Homozygosity for HLA-DQ2 is associated with RCD II and EATL. Early identification of HLA-DQ2 homozygous CD patients may help to recognize CD patients at risk for developing these severe complications.
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Affiliation(s)
- Abdulbaqi Al-Toma
- Department of Gastroenterology, VU University Medical Center, Amsterdam, The Netherlands
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