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Rouvroye MD, Roos A, Bergkamp F, Haagen IA, van der Pol P, Neefjes-Borst EA, Bouma G, Bontkes HJ. The frequency of HLA-DQ7 in patients at risk of coeliac disease: A haplotype to be reckoned with for screening? Hum Immunol 2024; 85:111158. [PMID: 39423728 DOI: 10.1016/j.humimm.2024.111158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 10/05/2024] [Accepted: 10/10/2024] [Indexed: 10/21/2024]
Abstract
HLA-DQ2 and -DQ8 carriers are genetically predisposed to develop coeliac disease (CD). Testing negative for HLA-DQ2/DQ8 has a high negative predictive value. Full HLA-DQ genotyping as well as tests only typing for HLA-DQ2/DQ8 are therefore used for screening at-risk populations. However, HLA-DQ7 positive and HLA-DQ2/DQ8 negative CD patients have been described in various populations. In this study we examine the relevance for HLA-DQ7 typing in a large at-risk CD population. The HLA-DQ status of all paediatric and adult patients at-risk of CD that were typed in a tertiary medical centre laboratory between 2012 and 2016 (n = 3983) was obtained. HLA-DQ7 (HLA-DQB1*03:01) positive and HLA-DQ2/DQ8 negative patients were selected. We gathered information on serology, histology and dietary status, and CD diagnosis. In total, 489/3983 patients were HLA-DQ7-positive and HLA-DQ2/DQ8 negative, and after exclusion (missing data on diet or serology/histology), 325 were included. Only one adult patient was diagnosed with CD, based on a duodenal biopsy and a clinical response to a gluten-free diet. Homozygosity was observed in 14.8 %. Based on the current cohort additional typing of HLA-DQ7 does not seem relevant for screening at-risk populations for CD in the Netherlands. It should be considered in patients with a high suspicion of CD.
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Affiliation(s)
- M D Rouvroye
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Location VU Medical Center, AGEM Research Institute, Amsterdam, The Netherlands; Department of Gastroenterology and Hepatology, Spaarne Gasthuis, Boerhavelaan 22, 2035 RC Haarlem, The Netherlands.
| | - A Roos
- Department of Medical Microbiology and Immunology, St. Antonius Hospital, Nieuwegein, The Netherlands
| | - F Bergkamp
- Department of Clinical Chemistry, Atalmedial, Louwesweg 6, 1066 EC Amsterdam, The Netherlands
| | - I A Haagen
- Department of Clinical Chemistry, OLVG Lab, Amsterdam, The Netherlands
| | - P van der Pol
- Reinier Haga MDC, Delft, Medical Laboratories, Department of Immunology, The Netherlands
| | - E A Neefjes-Borst
- Amsterdam UMC, Vrije Universiteit Amsterdam, Pathology, Amsterdam, The Netherlands
| | - G Bouma
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Location VU Medical Center, AGEM Research Institute, Amsterdam, The Netherlands
| | - H J Bontkes
- Amsterdam UMC, Vrije Universiteit Amsterdam, Medical Immunology Laboratory, Department of Clinical Chemistry, Amsterdam Infection and Immunity Institute, Amsterdam, The Netherlands
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Celi A, Trelis M, Ponce L, Ortiz V, Garrigues V, Soriano JM, Merino-Torres JF. Food-Intolerance Genetic Testing: A Useful Tool for the Dietary Management of Chronic Gastrointestinal Disorders. Nutrients 2024; 16:2741. [PMID: 39203877 PMCID: PMC11357470 DOI: 10.3390/nu16162741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 08/07/2024] [Accepted: 08/13/2024] [Indexed: 09/03/2024] Open
Abstract
The rise in food intolerances and celiac disease, along with advanced diagnostic techniques, has prompted health professionals to seek effective and economical testing methods. This study evaluates combining genetic tests with routine carbohydrate-absorption breath tests to classify patients with chronic gastrointestinal disorders into therapeutic groups, enhancing dietary management and improving gut health and quality of life. Forty-nine patients with suspected carbohydrate intolerance underwent genetic testing for lactase non-persistence, hereditary fructose intolerance, and celiac disease risk. Simultaneously, breath tests assessed lactose and fructose absorption. The lactase non-persistence genotype appeared in 36.7% of cases, with one hereditary fructose-intolerance case in a heterozygous condition. Celiac disease risk markers (HLA-DQ2/8 haplotypes) were found in 49.0% of the population. Secondary lactose and/or fructose malabsorption was present in 67.3% of patients, with 66.1% of lactase non-persistence individuals showing secondary lactose malabsorption. Fructose malabsorption was prevalent in 45.8% of patients at risk for celiac disease. Two main treatment groups were defined based on genetic results, indicating primary and irreversible gastrointestinal disorder causes, followed by a sub-classification using breath test results. Genetic testing is a valuable tool for designing dietary management plans, avoiding unnecessary diet restrictions, and reducing recovery times.
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Affiliation(s)
- Alexandra Celi
- Joint Research Unit on Endocrinology, Nutrition and Clinical Dietetics, Health Research Institute La Fe, 46026 Valencia, Spain; (A.C.); (J.M.S.); (J.F.M.-T.)
| | - María Trelis
- Joint Research Unit on Endocrinology, Nutrition and Clinical Dietetics, Health Research Institute La Fe, 46026 Valencia, Spain; (A.C.); (J.M.S.); (J.F.M.-T.)
- Parasite & Health Research Group, Area of Parasitology, Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, 46010 Valencia, Spain
| | - Lorena Ponce
- Department of Bioinformatics, Overgenes S.L., 46980 Valencia, Spain;
| | - Vicente Ortiz
- Digestive Functional Disorders Unit, Department of Gastroenterology, University and Polytechnic Hospital La Fe, 46026 Valencia, Spain; (V.O.); (V.G.)
| | - Vicente Garrigues
- Digestive Functional Disorders Unit, Department of Gastroenterology, University and Polytechnic Hospital La Fe, 46026 Valencia, Spain; (V.O.); (V.G.)
- Department of Medicine, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain
| | - José M. Soriano
- Joint Research Unit on Endocrinology, Nutrition and Clinical Dietetics, Health Research Institute La Fe, 46026 Valencia, Spain; (A.C.); (J.M.S.); (J.F.M.-T.)
- Food & Health Lab, Institute of Materials Science, University of Valencia, 46980 Valencia, Spain
| | - Juan F. Merino-Torres
- Joint Research Unit on Endocrinology, Nutrition and Clinical Dietetics, Health Research Institute La Fe, 46026 Valencia, Spain; (A.C.); (J.M.S.); (J.F.M.-T.)
- Department of Medicine, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain
- Department of Endocrinology and Nutrition, University and Polytechnic Hospital La Fe, 46026 Valencia, Spain
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Hyöty H, Kääriäinen S, Laiho JE, Comer GM, Tian W, Härkönen T, Lehtonen JP, Oikarinen S, Puustinen L, Snyder M, León F, Scheinin M, Knip M, Sanjuan M. Safety, tolerability and immunogenicity of PRV-101, a multivalent vaccine targeting coxsackie B viruses (CVBs) associated with type 1 diabetes: a double-blind randomised placebo-controlled Phase I trial. Diabetologia 2024; 67:811-821. [PMID: 38369573 PMCID: PMC10954874 DOI: 10.1007/s00125-024-06092-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 11/21/2023] [Indexed: 02/20/2024]
Abstract
AIMS/HYPOTHESIS Infection with coxsackie B viruses (CVBs) can cause diseases ranging from mild common cold-type symptoms to severe life-threatening conditions. CVB infections are considered to be prime candidates for environmental triggers of type 1 diabetes. This, together with the significant disease burden of acute CVB infections and their association with chronic diseases other than diabetes, has prompted the development of human CVB vaccines. The current study evaluated the safety and immunogenicity of the first human vaccine designed against CVBs associated with type 1 diabetes in a double-blind randomised placebo-controlled Phase I trial. METHODS The main eligibility criteria for participants were good general health, age between 18 and 45 years, provision of written informed consent and willingness to comply with all trial procedures. Treatment allocation (PRV-101 or placebo) was based on a computer-generated randomisation schedule and people assessing the outcomes were masked to group assignment. In total, 32 participants (17 men, 15 women) aged 18-44 years were randomised to receive a low (n=12) or high (n=12) dose of a multivalent, formalin-inactivated vaccine including CVB serotypes 1-5 (PRV-101), or placebo (n=8), given by intramuscular injections at weeks 0, 4 and 8 at a single study site in Finland. The participants were followed for another 24 weeks. Safety and tolerability were the primary endpoints. Anti-CVB IgG and virus-neutralising titres were analysed using an ELISA and neutralising plaque reduction assays, respectively. RESULTS Among the 32 participants (low dose, n=12; high dose, n=12; placebo, n=8) no serious adverse events or adverse events leading to study treatment discontinuation were observed. Treatment-emergent adverse events considered to be related to the study drug occurred in 37.5% of the participants in the placebo group and 62.5% in the PRV-101 group (injection site pain, headache, injection site discomfort and injection site pruritus being most common). PRV-101 induced dose-dependent neutralising antibody responses against all five CVB serotypes included in the vaccine in both the high- and low-dose groups. Protective titres ≥8 against all five serotypes were seen in >90% of participants over the entire follow-up period. CONCLUSIONS/INTERPRETATION The results indicate that the tested multivalent CVB vaccine is well tolerated and immunogenic, supporting its further clinical development. TRIAL REGISTRATION ClinicalTrials.gov NCT04690426. FUNDING This trial was funded by Provention Bio, a Sanofi company.
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Affiliation(s)
- Heikki Hyöty
- Department of Virology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
- Fimlab Laboratories, Tampere, Finland.
- Department of Pediatrics, Tampere University Hospital, Tampere, Finland.
| | | | - Jutta E Laiho
- Department of Virology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Gail M Comer
- Provention Bio, Inc., a Sanofi Company, Bridgewater, NJ, USA
| | - Wei Tian
- Provention Bio, Inc., a Sanofi Company, Bridgewater, NJ, USA
| | - Taina Härkönen
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Jussi P Lehtonen
- Department of Virology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Sami Oikarinen
- Department of Virology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Leena Puustinen
- Department of Virology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Michele Snyder
- Provention Bio, Inc., a Sanofi Company, Bridgewater, NJ, USA
| | - Francisco León
- Provention Bio, Inc., a Sanofi Company, Bridgewater, NJ, USA
| | - Mika Scheinin
- Clinical Research Services Turku - CRST Oy, Turku, Finland
- Institute of Biomedicine, University of Turku, Turku, Finland
| | - Mikael Knip
- Department of Pediatrics, Tampere University Hospital, Tampere, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Miguel Sanjuan
- Provention Bio, Inc., a Sanofi Company, Bridgewater, NJ, USA
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Penizzotto A, Vespa F, López Grove R, Rendón O, Tsai R, Ocantos JA. CT and MR Enterography in the Evaluation of Celiac Disease. Radiographics 2024; 44:e230122. [PMID: 38483832 DOI: 10.1148/rg.230122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/19/2024]
Abstract
Celiac disease is a common inflammatory disease of the small bowel that induces mucosal intestinal lesions. The disease is mediated by an immune response and triggered by the ingestion of gluten in genetically predisposed individuals. Gluten contains gliadin, a component found mostly in wheat, barley, and rye. This process leads to gastrointestinal malabsorption with symptoms such as diarrhea, constipation, abdominal pain, and distention. It has a prevalence of 1%-2% in the general adult population, who present with symptoms at any age, but is more frequently found in adult women in the 3rd or 4th decade of life. Recognition of the disease has increased, but it remains a challenge to diagnose. CT and MR enterography are noninvasive studies used for evaluation of small bowel neoplasms and inflammatory small bowel pathologic conditions such as celiac disease. The authors review the spectrum of intestinal and extraintestinal findings of celiac disease at CT and MR enterography, as well as its complications, and the importance of recognizing certain imaging features that help in the diagnosis of celiac disease. More common and specific findings of celiac disease such as inversion of the jejunoileal fold pattern and mesenteric lymphadenopathy are reviewed. More uncommon entities that are more frequently associated with refractory or untreated celiac disease, such as ulcerative jejunoileitis, cavitary mesenteric lymph node syndrome, and malignancies including small bowel adenocarcinoma and lymphoma, are described. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material. The slide presentation from the RSNA Annual Meeting is available for this article.
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Affiliation(s)
- Andrea Penizzotto
- From the Department of Radiology, Hospital Italiano de Buenos Aires, Teniente General Juan Domingo Perón 4190, Buenos Aires, Argentina C1199ABB (A.P., F.V., L.P.G., O.R., J.A.O.); and Mallinckrodt Institute of Radiology, Washington University St. Louis, St. Louis, Mo (R.T.)
| | - Florencia Vespa
- From the Department of Radiology, Hospital Italiano de Buenos Aires, Teniente General Juan Domingo Perón 4190, Buenos Aires, Argentina C1199ABB (A.P., F.V., L.P.G., O.R., J.A.O.); and Mallinckrodt Institute of Radiology, Washington University St. Louis, St. Louis, Mo (R.T.)
| | - Roy López Grove
- From the Department of Radiology, Hospital Italiano de Buenos Aires, Teniente General Juan Domingo Perón 4190, Buenos Aires, Argentina C1199ABB (A.P., F.V., L.P.G., O.R., J.A.O.); and Mallinckrodt Institute of Radiology, Washington University St. Louis, St. Louis, Mo (R.T.)
| | - Omar Rendón
- From the Department of Radiology, Hospital Italiano de Buenos Aires, Teniente General Juan Domingo Perón 4190, Buenos Aires, Argentina C1199ABB (A.P., F.V., L.P.G., O.R., J.A.O.); and Mallinckrodt Institute of Radiology, Washington University St. Louis, St. Louis, Mo (R.T.)
| | - Richard Tsai
- From the Department of Radiology, Hospital Italiano de Buenos Aires, Teniente General Juan Domingo Perón 4190, Buenos Aires, Argentina C1199ABB (A.P., F.V., L.P.G., O.R., J.A.O.); and Mallinckrodt Institute of Radiology, Washington University St. Louis, St. Louis, Mo (R.T.)
| | - Jorge Alberto Ocantos
- From the Department of Radiology, Hospital Italiano de Buenos Aires, Teniente General Juan Domingo Perón 4190, Buenos Aires, Argentina C1199ABB (A.P., F.V., L.P.G., O.R., J.A.O.); and Mallinckrodt Institute of Radiology, Washington University St. Louis, St. Louis, Mo (R.T.)
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Andres MP, Peloggia A, Abrao HM, Magalhaes TF, Neto JS, Abrão MS. Evaluation of HLA-DQ2 and HLA-DQ8 haplotypes in patients with endometriosis, A case-control study. Clinics (Sao Paulo) 2024; 79:100317. [PMID: 38432123 PMCID: PMC10914556 DOI: 10.1016/j.clinsp.2023.100317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 10/31/2023] [Accepted: 11/27/2023] [Indexed: 03/05/2024] Open
Abstract
OBJECTIVE To evaluate the relationship between genetic haplotypes associated with celiac disease (Human Leucocyte Antigen [HLA] DQ2 and DQ8) with the diagnosis, clinical presentation, and location of endometriosis in Brazilian women. METHOD A retrospective cross-sectional study, was conducted in a Tertiary hospital. PATIENTS Women aged 18-50 years who underwent HLA-DQ2 and HLA-DQ8 haplotype analysis. INTERVENTION The patients were divided into endometriosis and control groups and evaluated for symptoms; endometriosis location, American Society for Reproductive Medicine (ASRM) stage, and the presence of anti-tissue transglutaminase IgA (anti-TgA), HLA-DQ2, and HLA-DQ8 markers. RESULTS A total of 434 consecutive patients with (n = 315) and without (n = 119) endometriosis were included. Pain and infertility were more frequent in the endometriosis group than in the control group. The presence of HLA-DQ2, HLA-DQ8, and anti-TgA was similar between both groups. The presence of HLA-DQ2 and HLA-DQ8 markers did not differ based on age, pain symptoms, ASRM stage, or endometriosis location. CONCLUSION Although there are similarities in inflammatory markers and pathophysiology between celiac disease and endometriosis, this study found no significant associations in the presence of HLA-DQ2 or HLA-DQ8 haplotypes and endometriosis.
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Affiliation(s)
- Marina P. Andres
- Divisão de Clínica Ginecológica, Departamento de Obstetrícia e Ginecologia, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil
- Divisão de Clínica Ginecológica, BP ‒ A Beneficência Portuguesa de São Paulo, São Paulo, SP, Brazil
| | - Alessandra Peloggia
- Centro de Pesquisa em Saúde Reprodutiva de Campinas (CEMICAMP), Campinas, SP, Brazil
| | - Henrique M. Abrao
- Divisão de Clínica Ginecológica, BP ‒ A Beneficência Portuguesa de São Paulo, São Paulo, SP, Brazil
| | - Thais F. Magalhaes
- Divisão de Clínica Ginecológica, Departamento de Obstetrícia e Ginecologia, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil
| | - João Siufi Neto
- Divisão de Clínica Ginecológica, BP ‒ A Beneficência Portuguesa de São Paulo, São Paulo, SP, Brazil
| | - Mauricio Simões Abrão
- Divisão de Clínica Ginecológica, Departamento de Obstetrícia e Ginecologia, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil
- Divisão de Clínica Ginecológica, BP ‒ A Beneficência Portuguesa de São Paulo, São Paulo, SP, Brazil
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Pritchard D, Anand A, De'Ath A, Lee H, Rees MT. UK NEQAS and BSHI guideline: Laboratory testing and clinical interpretation of HLA genotyping results supporting the diagnosis of coeliac disease. Int J Immunogenet 2024; 51 Suppl 1:3-20. [PMID: 38153308 DOI: 10.1111/iji.12649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Accepted: 12/08/2023] [Indexed: 12/29/2023]
Abstract
Coeliac disease is a common immune-mediated inflammatory disorder caused by dietary gluten in genetically susceptible individuals. While the diagnosis of coeliac disease is based on serological and histological criteria, HLA-DQ genotyping can be useful, especially in excluding the diagnosis in patients who do not carry the relevant DQ heterodimers: DQA1*05 DQB1*02, DQB1*03:02 or DQA1*02 DQB1*02 (commonly referred to as DQ2.5, DQ8 and DQ2.2, respectively). External quality assessment results for HLA genotyping in coeliac disease have revealed concerning errors in HLA genotyping, reporting and clinical interpretation. In response, these guidelines have been developed as an evidence-based approach to guide laboratories undertaking HLA genotyping for coeliac disease and provide recommendations for reports to standardise and improve the communication of results.
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Affiliation(s)
| | - Arthi Anand
- H&I Laboratory, North West London Pathology, Imperial College Healthcare NHS Trust, London, UK
| | - Amy De'Ath
- UK NEQAS for H&I, Velindre University NHS Trust, Cardiff, UK
| | - Helena Lee
- Transplantation Laboratory, Manchester Royal Infirmary, Manchester University NHS Foundation Trust, Manchester, UK
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Harisinghani A, Raffaele G, Zawatsky CB, Santoro SL. Beyond chromosome analysis: Additional genetic testing practice in a Down syndrome clinic. AMERICAN JOURNAL OF MEDICAL GENETICS. PART C, SEMINARS IN MEDICAL GENETICS 2023; 193:e32063. [PMID: 37774106 DOI: 10.1002/ajmg.c.32063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 08/29/2023] [Accepted: 09/09/2023] [Indexed: 10/01/2023]
Abstract
Down syndrome (DS) and other genetic conditions have been reported to co-occur in the same person. This study sought to examine the genetic evaluation beyond chromosome analysis of individuals with DS at one DS specialty clinic. Retrospective chart review of genetic testing performed beyond chromosome analysis, the indication for the genetic testing, and the result of the genetic testing from the electronic health record was performed. Demographic information was collected and summary statistics, including mean and frequency, were calculated. The charts of 637 individuals with DS were reviewed. Overall, 146 genetic tests in addition to routine chromosome analysis were performed on 92 individuals with DS. Tests included chromosomal microarray, gene panels, and whole exome sequencing. Tests were performed for the indication of: autism spectrum disorder, celiac disease, dementia, hematologic diseases, and others. Eleven individuals with DS were found to have a second genetic diagnosis. Individuals with DS in one multidisciplinary clinic for DS had a variety of genetic tests beyond chromosomes completed, for varied indications, and with some abnormal results leading to additional diagnoses. Additional genetic testing beyond chromosome analysis is a reasonable consideration for patients with DS who have features suggestive of a secondary diagnosis.
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Affiliation(s)
- Ayesha Harisinghani
- Down Syndrome Program, Division of Medical Genetics and Metabolism, Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USA
| | | | - Carrie Blout Zawatsky
- Institute of Health Professions, MGH, Boston, Massachusetts, USA
- Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Stephanie L Santoro
- Down Syndrome Program, Division of Medical Genetics and Metabolism, Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USA
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
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Hitawala AA, Almomani A, Onwuzo S, Boustany A, Kumar P, Asaad I. Prevalence of autoimmune, cholestatic and nonalcoholic fatty liver disease in celiac disease. Eur J Gastroenterol Hepatol 2023; 35:1030-1036. [PMID: 37395201 DOI: 10.1097/meg.0000000000002599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
BACKGROUND While there is higher prevalence of autoimmune, cholestatic and fatty liver disease in celiac disease (CeD), most data is from small-scale studies. We evaluated the prevalence and risk factors of the same using large cohort data. METHODS A population-based cross-sectional study was conducted using Explorys, a multi-institutional database. Prevalence and risk factors of autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and nonalcoholic fatty liver disease (NAFLD) in CeD were assessed. RESULTS Out of 70 352 325 subjects, 136 735 had CeD (0.19%). The prevalence of AIH (0.32%), PBC (0.15%), PSC (0.004%) and NAFLD (0.7%) were high in CeD. After adjusting for age, gender, Caucasian race and anti-tissue transglutaminase antibody (anti-TTG), CeD subjects had higher odds of AIH [adjusted odds ratio (aOR) 7.06, 95% confidence interval (CI) 6.32-7.89] and PBC (aOR 4.16, 95% CI 3.46-5.0). Even after adjusting for CeD, anti-TTG positivity concurred with higher odds of AIH (aOR 4.79, 95% CI 3.88-5.92) and PBC (aOR 9.22, 95% CI 7.03-12.1). After adjusting for age, gender, Caucasian race, diabetes mellitus (DM), obesity, hypothyroidism and metabolic syndrome, there was higher prevalence of NAFLD in CeD, with the aOR in the presence of DM type 1 being 2.1 (95% CI 1.96-2.25), and in the presence of DM type 2 being 2.92 (95% CI 2.72-3.14). CONCLUSION Subjects with CeD are more likely to have AIH, PBC, PSC and NAFLD. AIH and PBC have higher odds in the presence of anti-TTG. The odds of NAFLD in CeD are high regardless of type of DM.
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Affiliation(s)
- Asif Ali Hitawala
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Ashraf Almomani
- Department of Gastroenterology and Digestive Diseases, Cleveland Clinic Foundation, Weston, Florida
| | - Somtochukwu Onwuzo
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Antoine Boustany
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Prabhat Kumar
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Imad Asaad
- Department of Gastroenterology and Digestive Diseases, Cleveland Clinic Foundation, Cleveland, Ohio, USA
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Stahl M, Li Q, Lynch K, Koletzko S, Mehta P, Gragert L, Norris JM, Andrén Aronsson C, Lindfors K, Kurppa K, Ilonen J, Krischer J, Alkolkar B, Ziegler AG, Toppari J, Rewers M, Agardh D, Hagopian W, Liu E. Incidence of Pediatric Celiac Disease Varies by Region. Am J Gastroenterol 2023; 118:539-545. [PMID: 36219178 PMCID: PMC9991947 DOI: 10.14309/ajg.0000000000002056] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 09/16/2022] [Indexed: 11/05/2022]
Abstract
INTRODUCTION The Environmental Determinants of Diabetes in the Young study follows an HLA risk selected birth cohort for celiac disease (CD) development using a uniform protocol. Children under investigation come from 6 different regions within Europe and the United States. Our aim was to identify regional differences in CD autoimmunity and CD cumulative incidence for children born between 2004 and 2010. METHODS Children (n = 6,628) with DQ2.5 and/or DQ8.1 were enrolled prospectively from birth in Georgia, Washington, Colorado, Finland, Germany, and Sweden. Children underwent periodic study screening for tissue transglutaminase antibodies and then CD evaluation per clinical care. Population-specific estimates were calculated by weighting the study-specific cumulative incidence with the population-specific haplogenotype frequencies obtained from large stem cell registries from each site. RESULTS Individual haplogenotype risks for CD autoimmunity and CD varied by region and affected the cumulative incidence within that region. The CD incidence by age 10 years was highest in Swedish children at 3%. Within the United States, the incidence by age 10 years in Colorado was 2.4%. In the model adjusted for HLA, sex, and family history, Colorado children had a 2.5-fold higher risk of CD compared to Washington. Likewise, Swedish children had a 1.4-fold and 1.8-fold higher risk of CD compared with those in Finland and Germany, respectively. DISCUSSION There is high regional variability in cumulative incidence of CD, which suggests differential environmental, genetic, and epigenetic influences even within the United States. The overall high incidence warrants a low threshold for screening and further research on region-specific CD triggers.
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Affiliation(s)
- Marisa Stahl
- Digestive Health Institute, Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Qian Li
- Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, United States
| | - Kristian Lynch
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
| | - Sibylle Koletzko
- Department of Pediatrics, Dr von Hauner Kinderspital, LMU Klinikum, Munich, Germany
- Department of Pediatrics, Gastroenterology and Nutrition, School of Medicine Collegium Medicum University of Warmia and Mazury, Olsztyn, Poland
| | - Pooja Mehta
- Digestive Health Institute, Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Loren Gragert
- Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, United States
| | - Jill M. Norris
- Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | | | - Katri Lindfors
- Celiac Disease Research Center, Tampere University and Tampere University Hospital
| | - Kalle Kurppa
- Celiac Disease Research Center, Tampere University and Tampere University Hospital
- Tampere Center for Child, Adolescent and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital
- University of Consortium of Seinäjoki
| | - Jorma Ilonen
- Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland
| | - Jeffrey Krischer
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
| | - Beena Alkolkar
- Department of Pediatrics, Turku University Hospital, Turku, Finland
- National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, United States
| | - Anette-G Ziegler
- Forschergruppe Diabetes e.V. and Institute of Diabetes Research, Helmholtz Zentrum, Munich, Germany
| | - Jorma Toppari
- Institute of Biomedicine, Centre for Integrative Physiology and Pharmacology, Univeristy of Turku, Turku, Finland
| | - Marian Rewers
- Barbara Davis Center for Diabetes, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Daniel Agardh
- Diabetes and Celiac Disease, Lund University, Malmo, Sweden
| | - William Hagopian
- Department of Diabetes, Pacific Northwest Research Institute, Seattle, WA, United States
| | - Edwin Liu
- Digestive Health Institute, Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
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10
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Tamai T, Ihara K. Celiac Disease Genetics, Pathogenesis, and Standard Therapy for Japanese Patients. Int J Mol Sci 2023; 24:ijms24032075. [PMID: 36768398 PMCID: PMC9916540 DOI: 10.3390/ijms24032075] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/14/2023] [Accepted: 01/17/2023] [Indexed: 01/21/2023] Open
Abstract
Celiac disease is an autoimmune disease primarily affecting the small intestine that is caused by the ingestion of gluten in genetically susceptible individuals. The development of celiac disease is based on a complex immune response to gluten proteins. The global average prevalence in the general population is about 1%. In recent years, it has become clear that celiac disease is not less common in Asian countries than in Western countries but often remains undiagnosed. Although the number of patients with celiac disease in Asia is expected to increase with improving disease recognition and advances in diagnostic techniques, there remain few reports of celiac disease in the Far East region of Asia, especially in Japan. In this paper, we outline the epidemiology, diagnosis, and treatment of celiac disease. In addition, we summarize the reported Japanese cases of celiac disease with an overview in Japan.
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11
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Meta-Analysis and Systematic Review of HLA DQ2/DQ8 in Adults with Celiac Disease. Int J Mol Sci 2023; 24:ijms24021188. [PMID: 36674702 PMCID: PMC9863503 DOI: 10.3390/ijms24021188] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 09/23/2022] [Accepted: 10/04/2022] [Indexed: 01/11/2023] Open
Abstract
Although people with human leukocyte antigens (HLA) DQ2 and/or DQ8 are more likely to develop celiac disease (CD), the condition cannot be fully explained by this genetic predisposition alone. Multiple, as yet unidentified, factors contribute to the genesis of CD, including genetics, the environment, and the immune system. In order to provide insight into a prospective possibility and an expanded screening technique, we aim to undertake a comprehensive and meta-analytical study of the assessment and distribution of HLA class II (HLA-DQ2/DQ8) in adult CD patients. A systematic review was conducted using an electronic search of databases (PubMed, Google Scholar, Embase, and Direct Science) from January 2004 to February 2022. DQ2/DQ2 homozygotes have the highest risk of developing CD. DQ2/DQ8 typing is an effective test to exclude CD from the differential diagnosis of a patient with CD symptoms. Although other non-HLA genes have been associated with CD, they are rarely considered at diagnosis because they account for only a small proportion of the heritability of CD. This finding, together with the information gathered previously, may be useful in considering widely available and economically feasible screening options for celiac disease in young people.
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12
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Is Celiac Disease (CD) Prevalent in Patients with Multiple Sclerosis (MS): A Systematic Review and Meta-Analysis. Mult Scler Int 2022; 2022:7091140. [DOI: 10.1155/2022/7091140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 11/10/2022] [Accepted: 11/14/2022] [Indexed: 12/14/2022] Open
Abstract
Background. Celiac disease (CD) is an autoimmune disease, and its prevalence reported variously in different studies. The goal of this study is to evaluate the pooled prevalence of CD in subjects with MS. Methods. PubMed, Scopus, EMBASE, Web of Science, and Google Scholar along with gray literature were systematically searched. The search included all relevant studies which were published up to October 2022. Two researchers independently searched all databases and also references of included studies. Results. We found 8211 articles by literature search, and after deleting duplicates, 5594 remained. Fifteen articles remained for meta-analysis. Totally, 31418 patients were evaluated, and the total number of possible/confirmed cases was 124. Studies were published between 2004 and 2020, and the most published studies were from Italy. Five studies provided information regarding controls. The total number of controls was 22394, of whom 22 had CD. Mean age ranged from 35 to 55 years. The pooled prevalence of CD in MS patients was 0 (
%,
). The pooled odds of CD in subjects with MS are 0.46 (95% CI: 0.19-1.1) (
,
). Conclusion. The pooled prevalence of this systematic review showed that CD is not prevalent in MS cases.
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13
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Carreras J. Artificial Intelligence Analysis of Celiac Disease Using an Autoimmune Discovery Transcriptomic Panel Highlighted Pathogenic Genes including BTLA. Healthcare (Basel) 2022; 10:1550. [PMID: 36011206 PMCID: PMC9408070 DOI: 10.3390/healthcare10081550] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 08/09/2022] [Accepted: 08/14/2022] [Indexed: 12/18/2022] Open
Abstract
Celiac disease is a common immune-related inflammatory disease of the small intestine caused by gluten in genetically predisposed individuals. This research is a proof-of-concept exercise focused on using Artificial Intelligence (AI) and an autoimmune discovery gene panel to predict and model celiac disease. Conventional bioinformatics, gene set enrichment analysis (GSEA), and several machine learning and neural network techniques were used on a publicly available dataset (GSE164883). Machine learning and deep learning included C5, logistic regression, Bayesian network, discriminant analysis, KNN algorithm, LSVM, random trees, SVM, Tree-AS, XGBoost linear, XGBoost tree, CHAID, Quest, C&R tree, random forest, and neural network (multilayer perceptron). As a result, the gene panel predicted celiac disease with high accuracy (95-100%). Several pathogenic genes were identified, some of the immune checkpoint and immuno-oncology pathways. They included CASP3, CD86, CTLA4, FASLG, GZMB, IFNG, IL15RA, ITGAX, LAG3, MMP3, MUC1, MYD88, PRDM1, RGS1, etc. Among them, B and T lymphocyte associated (BTLA, CD272) was highlighted and validated at the protein level by immunohistochemistry in an independent series of cases. Celiac disease was characterized by high BTLA, expressed by inflammatory cells of the lamina propria. In conclusion, artificial intelligence predicted celiac disease using an autoimmune discovery gene panel.
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Affiliation(s)
- Joaquim Carreras
- Department of Pathology, School of Medicine, Tokai University, 143 Shimokasuya, Isehara 259-1193, Japan
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14
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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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15
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The Role of HLA in the Association between IgA Deficiency and Celiac Disease. DISEASE MARKERS 2021; 2021:8632861. [PMID: 35186163 PMCID: PMC8856801 DOI: 10.1155/2021/8632861] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 10/17/2021] [Accepted: 11/10/2021] [Indexed: 01/18/2023]
Abstract
Selective IgA deficiency (SIgAD) is the most frequent primary immune defect. Since SIgAD is not characterized by relevant infectious issues in most cases, it is often diagnosed during the diagnostic work up of several and different autoimmune disorders, which are associated with this primary immune defect. The genetic background of SIgAD is complex and three HLA haplotypes resulted to be more frequently associated with it; in detail, two of them include HLA-DQB1∗02 allelic variants, which are essential predisposing factors to develop Celiac Disease (CD). Here, we discuss the evidence regarding the role of HLA in the etiopathogenesis of SIgAD and its association with CD. Actually, the HLA region seems to play a modest role in the genetic predisposition to SIgAD and we may speculate that the association with the HLA-DQB1∗02 alleles (or haplotypes including them) could derive from its link with CD. Indeed, SIgAD and some related immunological alterations are likely to predispose to several autoimmune diseases (with and despite different HLA backgrounds), including CD, which is relatively common and directly associated with the HLA-DQB1∗02 allelic variants coding the DQ2 heterodimer. Further and specific studies are needed to make final conclusions in this regard.
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16
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Airaksinen L, Cerqueira JXM, Huhtala H, Saavalainen P, Yohannes DA, Mäki M, Kurppa K, Kilpeläinen E, Shcherban A, Palotie A, Kaukinen K, Lindfors K. Dissecting the contribution of single nucleotide polymorphisms in CCR9 and CCL25 genomic regions to the celiac disease phenotype. J Transl Autoimmun 2021; 4:100128. [PMID: 34901814 PMCID: PMC8640869 DOI: 10.1016/j.jtauto.2021.100128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 10/02/2021] [Accepted: 10/13/2021] [Indexed: 11/30/2022] Open
Abstract
PURPOSE AND OBJECTIVES Given their role in homing immune cells to the intestine, CC motif chemokine receptor 9 (CCR9) and its specific ligand CC motif chemokine ligand 25 (CCL25) are interesting candidate genes for celiac disease. These genes are located in regions previously shown to be associated with or linked to celiac disease, but no investigations on their association with various celiac disease phenotypes have so far been conducted. Here we studied such associations of both genotyped and imputed single nucleotide polymorphisms (SNPs) with either regulatory function or exonic location of the CCR9 and CCL25 loci. RESULTS Exploiting a carefully phenotyped cohort of 625 celiac disease patients and 1817 non-celiac controls, we identified that multiple SNPs with predicted regulatory function (RegulomeDB score ≤3a and/or eQTL effect) located between 100 kB upstream and downstream of CCR9 and CCL25 are associated with celiac disease and/or selected phenotypes. Of the genotyped SNPs in the CCR9 loci, rs213360 with an eQTL effect on CCR9 expression in blood was associated with celiac disease and all investigated phenotypes except high HLA risk. Rs1545985 with an eQTL on CCR9 expression and rs7652331 and rs12493471, both with RegulomeDB score ≤3a, were all associated with gastrointestinal symptoms and malabsorption and the latter additionally with anemia. The genotyped CCL25 SNPs rs952444 and rs882951, with RegulomeDB scores 1d and 1f respectively and eQTL effect on CCL25 expression in small intestine, were associated with gastrointestinal symptoms and malabsorption. The CCL25 SNP rs2303165 identified in sequencing followed by imputation was associated with partial villous atrophy. However, the association did not pass the permutation based multiple testing correction (PEMP2 > 0.05). CONCLUSIONS We conclude that SNPs in the region of CCR9 and CCL25 with predicted functional effect or exonic localization likely contribute only modestly to various celiac disease phenotypes.
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Key Words
- CCL25, CC motif chemokine ligand 25
- CCR9, CC motif chemokine receptor 9
- CI, confidence interval
- Celiac disease
- Chemokine receptor
- Clinical picture
- FUMA, Functional Mapping and Annotation of GWAS
- GWAS, genome-wide association study
- Genetic association
- Genetic variation
- HLA, human leukocyte antigen
- HWE, Hardy-Weinberg equilibrium
- MAF, minor allele frequency
- OR, odds ratio
- PBMC, peripheral blood mononuclear cell
- QC, quality control
- SNP, single nucleotide polymorphism
- TG2, transglutaminase 2
- eQTL, expression quantitative trait loci
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Affiliation(s)
- Laura Airaksinen
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Juliana XM. Cerqueira
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Faculty of Nutrition and Food Sciences, University of Porto, Porto, Portugal
| | - Heini Huhtala
- Faculty of Social Sciences, Tampere University, Tampere, Finland
| | - Päivi Saavalainen
- Translational Immunology Research Program, and Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
| | - Dawit A. Yohannes
- Translational Immunology Research Program, and Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
| | - Markku Mäki
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Tampere Center for Child, Adolescent, and Maternal Health Research, Tampere University, and Department of Pediatrics, Tampere University Hospital, Tampere, Finland
| | - Kalle Kurppa
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Tampere Center for Child, Adolescent, and Maternal Health Research, Tampere University, and Department of Pediatrics, Tampere University Hospital, Tampere, Finland
- University Consortium of Seinäjoki, Seinäjoki, Finland
| | - Elina Kilpeläinen
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Anastasia Shcherban
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Aarno Palotie
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
- Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Analytic and Translational Genetics Unit, Department of Medicine, and the Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
| | - Katri Kaukinen
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Internal Medicine, Tampere University Hospital, Tampere, Finland
| | - Katri Lindfors
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
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17
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Paavola S, Lindfors K, Kivelä L, Cerqueira J, Huhtala H, Saavalainen P, Tauschi R, Kaukinen K, Kurppa K. Presence of high-risk HLA genotype is the most important individual risk factor for coeliac disease among at-risk relatives. Aliment Pharmacol Ther 2021; 54:805-813. [PMID: 34278595 DOI: 10.1111/apt.16534] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/07/2021] [Accepted: 07/02/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND Family screening has been advocated as a means to reduce the major underdiagnosis of coeliac disease. However, the precise risk of the disease in relatives and the impact of patient- and relative-related individual factors remain obscure. AIMS To investigate the individual risk of coeliac disease among patients' relatives. METHODS Altogether 2943 relatives of 624 index patients were assessed for the presence of previous coeliac disease diagnosis, or were screened for the disease. Coeliac disease-associated human leucocyte antigen (HLA) genotype was determined from all participants. The association between individual factors and new screening positivity was assessed by logistic regression. RESULTS There were 229 previously diagnosed non-index relatives with coeliac disease and 2714 non-affected (2067 first-degree, 647 more distant) relatives. Of these 2714 relatives, 129 (4.8%) were screening-positive (first-degree 5.1%, second-degree 3.6%, more distant 3.5%). The combined prevalence of the previously diagnosed and now detected cases in relatives was 12.2% (6.3% clinically detected, 5.9% screen-detected). In univariate analysis, age <18 years at diagnosis (odds ratio 1.60, 95% CI 1.04-2.45) in index, and age 41-60 years (1.73, 1.10-2.73), being a sibling (1.65, 1.06-2.59) and having the high-risk genotype (3.22, 2.01-5.15 DQ2.5/2.5 or DQ2.5/2.2 vs other risk alleles) in relatives were associated with screening positivity. Only high-risk HLA remained significant (2.94, 1.80-4.78) in multivariable analysis. CONCLUSIONS Unrecognised coeliac disease was common among at-risk relatives even in a country with an active case-finding policy, and also in relatives more distant than first-degree. The presence of a high-risk genotype was the most important predictor for screening positivity. ClinicalTrials.gov identifier NCT03136731.
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Affiliation(s)
- Saana Paavola
- Faculty of Medicine and Health Technology, University of Tampere and Tampere University Hospital, Tampere, Finland
| | - Katri Lindfors
- Faculty of Medicine and Health Technology, University of Tampere and Tampere University Hospital, Tampere, Finland
| | - Laura Kivelä
- Faculty of Medicine and Health Technology, University of Tampere and Tampere University Hospital, Tampere, Finland
| | - Juliana Cerqueira
- Faculty of Medicine and Health Technology, University of Tampere and Tampere University Hospital, Tampere, Finland
| | - Heini Huhtala
- Faculty of Social Sciences, University of Tampere, Tampere, Finland
| | - Päivi Saavalainen
- Translational Immunology Research Program, and Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
| | - Riku Tauschi
- Faculty of Medicine and Health Technology, University of Tampere and Tampere University Hospital, Tampere, Finland
| | - Katri Kaukinen
- Faculty of Medicine and Health Technology, University of Tampere and Tampere University Hospital, Tampere, Finland
| | - Kalle Kurppa
- Faculty of Medicine and Health Technology, University of Tampere and Tampere University Hospital, Tampere, Finland.,The University Consortium of Seinäjoki, Seinäjoki, Finland
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18
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Levine J, Hauptman L, Moy L, Trachtman H. Effect of a gluten-free diet on albuminuria in children with newly diagnosed celiac disease. GLOMERULAR DISEASES 2021; 1:3-9. [PMID: 34368799 DOI: 10.1159/000514635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Background and objectives Altered gastrointestinal permeability in celiac disease (CD) is mediated by zonulin. The receptor for zonulin is expressed on podocytes. Therefore, we tested the effect of a gluten-free diet (GFD) on albuminuria in pediatric patients with newly diagnosed CD. Methods We performed a cohort study comparing urinary albumin (μg):creatinine (mg) ratio (ACR) in CD patients vs controls and in response to a GFD. Results Children with CD (n=46) had higher ACR compared to controls (n=21), 20.2±5.6 versus 8.4±1.1 μg/mg, P=0.16 and exceeded 30 μg/mg (microalbuminuria cut-off) in 7/46 cases. 17 patients had a follow-up assessment (interval 6.1±0.7 months) on a GFD. Baseline ACR was 20.7±5.2 that fell to 10.4±1.5 μg/mg, P=0.035. Conclusion Children and adolescents with newly diagnosed CD have low-grade albuminuria that is numerically higher than controls and that declined after implementation of a GFD. CD may be associated with reversible defects in the glomerular barrier.
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Affiliation(s)
- Jeremiah Levine
- NYU Langone Health, Department of Pediatrics, Divisions of Gastroenterology, New York, NY
| | - Leora Hauptman
- NYU Langone Health, Department of Pediatrics, Divisions of Gastroenterology, New York, NY
| | - Libia Moy
- NYU Langone Health, Department of Pediatrics, Divisions of Gastroenterology, New York, NY
| | - Howard Trachtman
- NYU Langone Health, Department of Pediatrics, Divisions Nephrology, New York, NY
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19
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Zammit SC, Elli L, Scaramella L, Sanders DS, Tontini GE, Sidhu R. Small bowel capsule endoscopy in refractory celiac disease: a luxury or a necessity? Ann Gastroenterol 2021; 34:188-195. [PMID: 33654358 PMCID: PMC7903573 DOI: 10.20524/aog.2021.0586] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Accepted: 10/27/2020] [Indexed: 12/11/2022] Open
Abstract
Background Small bowel capsule endoscopy (SBCE) has an established role in the management of refractory celiac disease (RCD) for the detection of complications. The aim of this study was to define the role of SBCE in the management of patients with RCD. Method Patients with histologically confirmed RCD who underwent successive SBCEs were recruited retrospectively from 2 tertiary centers. Results Sixty patients with RCD were included. The percentage extent of the affected small bowel (SB) mucosa improved on repeating a second SBCE in 26 patients (49.1%) (median 27.6% vs. 18.1%, P=0.007). Patients with RCD type II had more extensive disease than those with RCD type I on first (41.4% vs. 19.2%, P=0.004) and second (29.8% vs. 12.0%, P=0.016) SBCE. Patients with RCD type I tended to show a greater improvement in percentage of abnormal SB involved on repeat SBCE compared to those with RCD type II (P=0.049). Nine patients (15%) had RCD-related complications. Five patients developed ulcerative jejunoileitis, 3 patients developed enteropathy-associated T-cell lymphoma, and 1 patient developed cutaneous T-cell lymphoma. Conclusions SBCE can be a useful tool for monitoring the effects of treatment, primarily following its initiation. Patients with RCD type II have more extensive SB disease, equating to a more aggressive disease pattern.
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Affiliation(s)
- Stefania Chetcuti Zammit
- Gastroenterology Department, Sheffield Teaching Hospitals, United Kingdom (Stefania Chetcuti Zammit, David S. Sanders, Reena Sidhu)
| | - Luca Elli
- Centre for Prevention and Diagnosis of Coeliac Disease, Gastroenterology and Endoscopy Unit, Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Italy (Luca Elli, Lucia Scaramella, Gian Eugenio Tontini)
| | - Lucia Scaramella
- Centre for Prevention and Diagnosis of Coeliac Disease, Gastroenterology and Endoscopy Unit, Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Italy (Luca Elli, Lucia Scaramella, Gian Eugenio Tontini)
| | - David S Sanders
- Gastroenterology Department, Sheffield Teaching Hospitals, United Kingdom (Stefania Chetcuti Zammit, David S. Sanders, Reena Sidhu)
| | - Gian Eugenio Tontini
- Centre for Prevention and Diagnosis of Coeliac Disease, Gastroenterology and Endoscopy Unit, Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Italy (Luca Elli, Lucia Scaramella, Gian Eugenio Tontini)
| | - Reena Sidhu
- Gastroenterology Department, Sheffield Teaching Hospitals, United Kingdom (Stefania Chetcuti Zammit, David S. Sanders, Reena Sidhu)
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20
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Fujisawa M, Matsushima M, Ueda T, Kaneko M, Fujimoto R, Sano M, Teramura E, Monma M, Mizukami H, Nakahara F, Suzuki H, Suzuki T. Celiac Disease Complicated by Rhabdomyolysis. Intern Med 2021; 60:217-222. [PMID: 32921688 PMCID: PMC7872804 DOI: 10.2169/internalmedicine.5358-20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
At 37 years old, a patient developed chronic watery diarrhea, generalized pain, severe hypokalemia and elevated creatine kinase levels. She was thought to have rhabdomyolysis due to hypokalemia from chronic diarrhea. No organic cause was found. Her symptoms subsided with potassium correction, but hypokalemia persisted; she visited our hospital at 44 years old. Endoscopy detected prominent atrophy of the intestinal villi. Histology indicated Marsh-Oberhuber type-3b disease. Anti-gliadin and anti-tissue transglutaminase IgA antibody tests were positive. She was diagnosed with celiac disease and started on a gluten-free diet, which improved her symptoms. This report is only the tenth of its kind worldwide.
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Affiliation(s)
- Mia Fujisawa
- Divisions of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Japan
| | - Masashi Matsushima
- Divisions of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Japan
| | - Takashi Ueda
- Divisions of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Japan
| | - Motoki Kaneko
- Divisions of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Japan
| | - Ryutaro Fujimoto
- Divisions of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Japan
| | - Masaya Sano
- Divisions of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Japan
| | - Erika Teramura
- Divisions of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Japan
| | - Makiko Monma
- Divisions of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Japan
| | - Hajime Mizukami
- Divisions of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Japan
| | - Fumio Nakahara
- Divisions of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Japan
| | - Hidekazu Suzuki
- Divisions of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Japan
| | - Takayoshi Suzuki
- Divisions of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Japan
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21
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Bodkhe R, Marietta EV, Balakrishnan B, Luckey DH, Horwath IE, Shouche YS, Taneja V, Murray JA. Human gut-derived commensal suppresses generation of T-cell response to gliadin in humanized mice by modulating gut microbiota. Anaerobe 2020; 68:102237. [PMID: 32721554 DOI: 10.1016/j.anaerobe.2020.102237] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 06/20/2020] [Accepted: 06/25/2020] [Indexed: 12/14/2022]
Abstract
The human intestinal tract is colonized by a large number of diverse microorganisms that play various important physiologic functions. In inflammatory gut diseases including celiac disease (CeD), a dysbiotic state of microbiome has been observed. Interestingly, this perturbed microbiome is normalized towards eubiosis in patients showing recovery after treatment. The treatment has been observed to increase the abundance of beneficial microbes in comparison to non-treated patients. In this study, we investigated the effect of Prevotella histicola or Prevotella melaninogenica, isolated from the duodenum of a treated CeD patient, on the induction and maintenance of oral tolerance to gliadin, a CeD associated subgroup of gluten proteins, in NOD.DQ8.ABo transgenic mice. Conventionally raised mice on a gluten free diet were orally gavaged with bacteria before and after injection with pepsin trypsin digested gliadin (PTD-gliadin). P. histicola suppressed the cellular response to gliadin, whereas P. melaninogenica failed to suppress an immune response against gliadin. Interestingly, tolerance to gliadin in NOD.DQ8.ABo mice may be associated with gut microbiota as mice gavaged with P melaninogenica harbored a different microbial diversity as compared to P. histicola treated mice. This study provides experimental evidence that gut microbes like P. histicola from treated patients can suppress the immune response against gliadin epitopes.
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Affiliation(s)
- Rahul Bodkhe
- Department of Immunology, Mayo Clinic, Rochester, MN, USA; The YSS Lab, National Centre for Microbial Resource, National Centre for Cell Science, Pune, India
| | - Eric V Marietta
- Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | | | - David H Luckey
- Department of Immunology, Mayo Clinic, Rochester, MN, USA
| | - Irina E Horwath
- Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Yogesh S Shouche
- The YSS Lab, National Centre for Microbial Resource, National Centre for Cell Science, Pune, India
| | - Veena Taneja
- Department of Immunology, Mayo Clinic, Rochester, MN, USA.
| | - Joseph A Murray
- Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA.
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22
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Profaizer T, Pole A, Monds C, Delgado JC, Lázár-Molnár E. Clinical utility of next generation sequencing based HLA typing for disease association and pharmacogenetic testing. Hum Immunol 2020; 81:354-360. [PMID: 32499099 DOI: 10.1016/j.humimm.2020.05.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Revised: 04/22/2020] [Accepted: 05/02/2020] [Indexed: 12/17/2022]
Abstract
HLA associations have been linked to many diseases and are important for risk assessment of drug hypersensitivity reactions. The increasing number of HLA alleles discovered generated a list of ambiguities that cannot be resolved with the current clinical assays, which commonly include sequence-specific oligonucleotide probe (SSOP) genotyping, and real-time PCR with melting curve analysis. HLA typing by next-generation sequencing (NGS) has recently been adopted by clinical laboratories for transplantation testing, as it provides unambiguous and cost-effective HLA typing. The goal of this study was to evaluate the feasibility of using NGS-based HLA-B and DQ genotyping for clinical HLA disease association testing, and provide direct comparison with the currently used clinical tests, including SSOP genotyping, and real-time PCR with melting curve analysis. While the real-time PCR method is easy and inexpensive to perform, ambiguities are rapidly increasing as more and more HLA alleles are discovered. SSOP genotyping identifies the alleles present but limitations include ambiguities and underreporting less common alleles. Our data show that HLA typing by NGS is superior to the existing clinical methods for identifying HLA alleles associated with disease or drug hypersensitivity, and offers a viable approach for high volume clinical diagnostic laboratories.
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Affiliation(s)
- Tracie Profaizer
- ARUP Institute for Clinical and Experimental Pathology, United States.
| | - Ann Pole
- Histocompatibility & Immunogenetics Laboratory, University of Utah Health, Salt Lake City, UT 84108, United States.
| | - Cassandra Monds
- ARUP Institute for Clinical and Experimental Pathology, United States.
| | - Julio C Delgado
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84108, United States.
| | - Eszter Lázár-Molnár
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84108, United States.
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Celiac disease risk stratification based on HLA-DQ heterodimer (HLA-DQA1 ~ DQB1) typing in a large cohort of adults with suspected celiac disease. Hum Immunol 2020; 81:59-64. [PMID: 32005535 DOI: 10.1016/j.humimm.2020.01.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 12/18/2019] [Accepted: 01/19/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUNDS Patients with celiac disease (CeD) carry the major histocompatibility complex class II, HLA-DQ2 or DQ8 haplotype; the absence of these haplotypes excludes a diagnosis of CeD. While the most common and highest risk HLA haplotypes in CeD have been established, the risk profiles of the less common and equivocal HLA haplotypes need further refinement. The aim of this study was to use a large national patient cohort to further stratify the risk gradient of HLA-DQ haplotypes. METHODS The study cohort included 24,339 adult patients with suspected CeD and immunoglobulin (Ig)A sufficiency (total IgA ≥ 70 mg/dL) whose samples were assessed at Mayo Clinic Laboratories for HLA-DQ genotyping, total IgA, and tissue transglutaminase (tTG)-IgA. Data from a subset of the patients who had duodenal biopsies were analyzed to determine the risk gradient of CeD. Logistic regression models were used to evaluate the risk gradient and to calculate odds ratios (ORs) for being positive to CeD serology according to different HLA-DQ2 and DQ8 heterodimers. RESULTS Of the 24,339 patients, 55% (n = 13,456) expressed HLA-DQ2 or DQ8 heterodimers. Compared with patients who had non-permissive HLA-DQ heterodimers, patients who had HLA-DQ2 homozygosity (HLA-DQ2.5/DQ2.5, HLA-DQ2.5/DQ2.2, or HLA-DQ2.2/DQ2.2) showed increased odds for tTG-IgA positivity (OR = 96.9; 95% CI, 58.3-147.9). Interestingly, the odds for patients who were compound heterozygous for HLA-DQ2.5 and HLA-DQ8 were similar to those for HLA-DQ2.5 heterozygotes. However, a single HLA-DQ2.2 haplotype (without HLA-DQ8, DQ2.2 heterozygous) was not associated with tTG-IgA positivity. These findings were confirmed in a subset of patients (n = 738) who had duodenal biopsies performed in addition to CeD serologic testing. DISCUSSION This large national reference laboratory cohort study demonstrated that HLA-DQ2.2 heterozygous is not associated with positive tTG-IgA serology, suggesting the reclassification of this haplotype as non-permissive for CeD.
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24
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Abstract
Gluten-related disorders, including celiac disease, wheat allergy, and nonceliac gluten sensitivity (NCGS), are increasingly reported worldwide. Celiac disease is caused by an immune-mediated reaction to ingested gluten in genetically susceptible persons. NCGS is largely a diagnosis of exclusion when other causes of symptoms have been ruled out. All patients with celiac disease should be referred to a registered dietitian nutritionist with expertise in celiac disease and a gastroenterologist who specializes in celiac disease and malabsorptive disorders, and they should remain on a strict gluten-free diet indefinitely. This article provides an overview of gluten- and wheat-related disorders.
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Affiliation(s)
- Joshua Elliott Rubin
- University of California, San Diego School of Medicine, La Jolla, California (J.E.R., S.E.C.)
| | - Sheila E Crowe
- University of California, San Diego School of Medicine, La Jolla, California (J.E.R., S.E.C.)
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25
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Poddighe D, Turganbekova A, Baymukasheva D, Saduakas Z, Zhanzakova Z, Abdrakhmanova S. Genetic predisposition to celiac disease in Kazakhstan: Potential impact on the clinical practice in Central Asia. PLoS One 2020; 15:e0226546. [PMID: 31895924 PMCID: PMC6939901 DOI: 10.1371/journal.pone.0226546] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 11/24/2019] [Indexed: 02/08/2023] Open
Abstract
Background Celiac disease (CD) is a systemic immune-mediated disorder developing in HLA genetically predisposed individuals carrying HLA-DQ2 and/or HLA-DQ8 molecules. Recent evidences supported a predominant importance of HLA-DQB1 locus and, in particular, HLA-DQB1*02 alleles. This diagnosis is poorly considered in Kazakhstan, because of the assumption that CD is not prevalent in this population. Objective To demonstrate that the genetic predisposition to CD in Kazakhstan is not negligible and is actually comparable to Western populations. Methods Through the analysis of HLA-DQ genotypes of healthy bone marrow donors from Kazakhstan’s national registry, we estimated the HLA-related genetic predisposition to CD in the country. Results We demonstrated that the frequency of CD-related HLA-DQB1 alleles and, as a consequence, of predisposed individuals to CD in Kazakhstan is significant and comparable to countries with the highest disease prevalence. Conclusion Considering the dietary style in Kazakhstan, including wheat as a staple food, these results provided a preliminary background of knowledge to expect a significant CD prevalence in Kazakhstan and Central Asia by implementing appropriate and cost-effective diagnostic strategies.
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Affiliation(s)
- Dimitri Poddighe
- Department of Medicine, Nazarbayev University School of Medicine, Nur-Sultan City, Kazakhstan
- * E-mail:
| | - Aida Turganbekova
- RSE on REM «Research and Production Center of Transfusion», Ministry of Health of the Republic of Kazakhstan, Nur-Sultan City, Kazakhstan
| | - Dana Baymukasheva
- RSE on REM «Research and Production Center of Transfusion», Ministry of Health of the Republic of Kazakhstan, Nur-Sultan City, Kazakhstan
| | - Zhazira Saduakas
- RSE on REM «Research and Production Center of Transfusion», Ministry of Health of the Republic of Kazakhstan, Nur-Sultan City, Kazakhstan
| | - Zhuldyz Zhanzakova
- RSE on REM «Research and Production Center of Transfusion», Ministry of Health of the Republic of Kazakhstan, Nur-Sultan City, Kazakhstan
| | - Saniya Abdrakhmanova
- RSE on REM «Research and Production Center of Transfusion», Ministry of Health of the Republic of Kazakhstan, Nur-Sultan City, Kazakhstan
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26
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Al-Hussaini A, Eltayeb-Elsheikh N, Alharthi H, Osman A, Alshahrani M, Sandogji I, Alrashidi S, Bashir MS. HLA-DQ genotypes relative risks for celiac disease in Arabs: A case-control study. J Dig Dis 2019; 20:602-608. [PMID: 31496112 DOI: 10.1111/1751-2980.12817] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 08/30/2019] [Accepted: 09/04/2019] [Indexed: 12/11/2022]
Abstract
OBJECTIVES It remains unknown what degree of risk is conferred by celiac disease (CD)-predisposing human leukocyte antigen (HLA)-DQ genotypes in Saudi Arabia compared with in Western countries. In this study, we aimed to determine the CD risk gradient associated with the HLA-DQ genotypes and to compare HLA-DQ genotypes between symptomatic patients with CD and screening-identified asymptomatic CD patients. METHODS We enrolled three groups of subjects, including 46 CD children diagnosed consecutively over the past 10 years, 54 CD children diagnosed during a mass screening of schoolchildren, and 192 healthy controls. All the participants were typed for the HLA-DQA1 and HLA-DQB1 genes by polymerase chain reaction sequence-specific oligonucleotide probes. RESULTS Comparing the patients with CD to controls, we identified 5 groups in the CD risk gradient: (i) very high risk associated with the DQ2.5/DQ8 genotype (odds ratio [OR] 46.93); (ii) high risk (homozygous DQ2.5, DQ2.5/DQ2.2; OR 4.12-5.04); (iii) intermediate risk (heterozygous DQ2.5, DQ8/DQ2.2; OR 1.61 and 1.67); (iv) low risk (DQ8, DQ2.2); and (v) very low risk (DQ2.x, DQX.5, DQX.x). Heterozygous DQ8 was more common in screening-identified group compared to symptomatic patients (13.0% vs 2.2%); however, other genotypes were very similar between the two groups. CONCLUSION The highest risk of developing CD in our Saudi Arabia population is associated with the DQ2.5/DQ8 genotype.
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Affiliation(s)
- Abdulrahman Al-Hussaini
- Division of Pediatric Gastroenterology, Children's Specialized Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.,College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Nezar Eltayeb-Elsheikh
- Department of Pathology and Laboratory Medicine, Division of Immunology, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Hanan Alharthi
- Department of Pathology and Laboratory Medicine, Division of Immunology, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Awad Osman
- Department of Pathology and Laboratory Medicine, Division of Immunology, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Maram Alshahrani
- Division of Pediatric Gastroenterology, Children's Specialized Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Ibrahim Sandogji
- Division of Pediatric Gastroenterology, Children's Specialized Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Sami Alrashidi
- Division of Pediatric Gastroenterology, Children's Specialized Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Muhammed Salman Bashir
- Department of Biostatistics, Research Services Administration, Research Center at King Fahad Medical City, Riyadh, Saudi Arabia
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Abstract
Celiac disease is a common inflammatory disease triggered by dietary gluten in genetically susceptible individuals. The strongest and best-characterized genetic susceptibilities in celiac disease are class II human leukocyte antigen (HLA) genes known as HLA-DQ2 and DQ8. HLA genetic testing is available through a number of commercial and academic laboratories and is used in the evaluation of celiac disease and to identify at-risk family members. Importantly, HLA genetic testing has a high negative predictive value for celiac disease, but a low positive predictive value. Therefore, for a practicing clinician, it is important to understand when to order HLA genetic testing, what test to order, and how to interpret the result. This review provides a practical primer on HLA genetics in celiac disease.
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28
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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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29
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Stroud C, Almilaji O, Nicholas D, Kirkham S, Surgenor SL, Williams I, Snook J. Evolving patterns in the presentation of coeliac disease over the last 25 years. Frontline Gastroenterol 2019; 11:98-103. [PMID: 32134410 PMCID: PMC7043089 DOI: 10.1136/flgastro-2018-101170] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 04/11/2019] [Accepted: 05/18/2019] [Indexed: 02/04/2023] Open
Abstract
OBJECTIVE To document changes in the clinical features of coeliac disease (CD) at presentation over the last 25 years. DESIGN Observational study. PATIENTS 802 subjects diagnosed between 1993 and 2017 at a single general hospital. OUTCOME MEASURES Date of diagnosis, age, sex, postcode, symptoms, haematinic deficiency, smoking status, serology, family history and autoimmune phenomena. RESULTS The incidence of diagnosed CD rose threefold during the course of the study, with a rising prevalence of positive coeliac serology and positive family history of CD, and a falling prevalence of symptoms and haematinic deficiencies. There was little change in the female predominance, age at diagnosis or high prevalence of other autoimmune conditions over the 25 years, and a paucity throughout of cigarette smokers, particularly heavy smokers. A cohort of patients with seronegative CD was identified who shared many of the characteristics of seropositive CD, but with a significantly older age at diagnosis and a higher prevalence of cigarette smokers. CONCLUSION There have been major changes in the epidemiology of CD over the last 25 years, of relevance to both our understanding of the aetiopathogenesis of CD and the requirement for service provision. The implications are discussed.
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30
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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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31
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Abstract
Coeliac disease is an immune-mediated enteropathy against dietary gluten present in wheat, rye and barley and is one of the most common lifelong food-related disorders worldwide. Coeliac disease is also considered to be a systemic disorder characterized by a variable combination of gluten-related signs and symptoms and disease-specific antibodies in addition to enteropathy. The ingestion of gluten leads to the generation of harmful gluten peptides, which, in predisposed individuals, can induce adaptive and innate immune responses. The clinical presentation is extremely variable; patients may have severe gastrointestinal symptoms and malabsorption, extraintestinal symptoms or have no symptoms at all. Owing to the multifaceted clinical presentation, diagnosis remains a challenge and coeliac disease is heavily underdiagnosed. The diagnosis of coeliac disease is achieved by combining coeliac disease serology and small intestinal mucosal histology during a gluten-containing diet. Currently, the only effective treatment for coeliac disease is a lifelong strict gluten-free diet; however, the diet is restrictive and gluten is difficult to avoid. Optimizing diagnosis and care in coeliac disease requires continuous research and education of both patients and health-care professionals.
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Crespo Escobar P, Castillejo G, Martínez-Ojinaga E, Donat E, Polanco I, Mearin ML, Ribes-Koninckx C. Ten years of follow-up of the Spanish cohort of the European PreventCD study: the lessons learned. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2018; 110:493-499. [PMID: 29699403 DOI: 10.17235/reed.2018.5324/2017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
AIM to evaluate the influence of gluten consumption on celiac disease development and to describe its natural history in the Spanish cohort of the European PreventCD study. METHODS prospective multi-center double blind study of 225 children that were followed up from birth. All cases were HLA-DQ2/HLA-DQ8 positive with a 1st degree relative with celiac disease and were followed up in three centers from Madrid, Reus and Valencia. Gluten intake was determined between four and ten months according to the protocol. Gluten intake was ad libitum between eleven and 36 months and was prospectively quantified by means of dietary records. Clinical visits and specific antibody analysis for celiac disease were performed periodically. RESULTS twenty-six cases were diagnosed, all had a positive biopsy and serology; 21 had gastrointestinal symptoms and five were asymptomatic. In addition, 2,565 food records were analyzed and statistically significant differences (p < 0.001) were found with regard to gluten consumption among the three centers, although not between celiac and non-celiac children (p = 0.025). The HLA-DQ2.5/DQ2.5 and DQ2.5/DQ2.2 genotypes had a relative risk of 4.7 (95% CI: 0.80-27.55; p = 0.08), which was higher than for the rest of genotypes. Female gender also had a relative risk that was five times higher than that for males. CONCLUSIONS the amount of gluten intake between 11 and 36 months or the duration of breast feeding were not risk factors for the development of CD in the Spanish population. The HLA genotype and gender were the most relevant associated factors. In this at-risk group, the disease presented before two years of age in the majority of the cases with a weak clinical expression.
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Affiliation(s)
- Paula Crespo Escobar
- Unidad de Enfermedad Celiaca e Inmunopatología Dig, Instituto de Investigación Sanitaria la Fe, España
| | - Gemma Castillejo
- Hospital Universitari Sant Joan, Reus y Universitat Rovira i Virgili, España
| | | | - Ester Donat
- Gastroenterología y Hepatología Pediátrica,, Hospital Universitario y Politécnico La Fe,, España,
| | | | | | - Carmen Ribes-Koninckx
- Gastroenterología y Hepatología Pediátrica,, Hospital Universitario y Politécnico La Fe,
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Abstract
Celiac disease is an autoimmune disease affecting the small intestine, triggered by gluten sensitization in genetically susceptible individuals worldwide. Celiac disease development is strongly linked to the presence of HLA-DQ2 and/or DQ8, which present the immunogenic gluten peptides and trigger the immune response leading to pathogenesis. Because of the variability of clinical symptoms, the disease is often underdiagnosed. Intestinal biopsy and the presence of antibodies to deamidated gliadin and tissue transglutaminase are recommended diagnostic tools. Genetic testing for HLA DQ2 and DQ8 can be used to rule out disease in at-risk populations.
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Affiliation(s)
- Eszter Lázár-Molnár
- ARUP Laboratories, Department of Pathology, University of Utah School of Medicine, 500 Chipeta Way, MS 115, Salt Lake City, UT 84108, USA.
| | - Melissa Snyder
- Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA
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34
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Cabrera CM, Méndez-López IM, Caballero A. Risk variation in celiac disease in a population from Southern Spain: evaluating the influence of the DQB1*02:02 allele frequency. Scand J Gastroenterol 2018; 53:266-272. [PMID: 29361871 DOI: 10.1080/00365521.2018.1430253] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES To date, the greatest genetic risk factor known for celiac disease (CD) is the presence of HLA-DQ2 heterodimers, specifically DQ2.5 in state of homozygosis or heterozygosis. DQ2.2 variants are the second most important risk factor when carried trans to DQ2. This study aimed to determine the prevalence and risk genotypes of HLA-DR-DQ. MATERIAL AND METHODS A total of 196 patients with CD and 206 healthy controls from the Province of Málaga (southern Spain) were included. The corresponding risk gradient in our population was established in accordance with the odds ratios (ORs) found. RESULTS The heterozygous genotype for DR7-DQ2.2/DR3-DQ2.5 presented the highest risk (OR =6.404, p = .0001) followed by the DR3-DQ2.5 homozygous genotype (OR =4.721, p = .001). An intermediate risk was found for the DQ2.5 heterozygous genotype with no other DQ risk variant (DQ8 or DQ2.2). Similarly, these three genotypes had also an increase in the risk of associated-autoimmune diseases. The DQB1*02:01 allele was the most widely represented among patients with CD respect to the control group (f = 0.479, p = .0001), with the second most common being DQB1*02:02 (f = 0.209, p = .0001). CONCLUSIONS In addition to the gene dosage effect confirmed in our report, and in contrast with previous studies, we found a raised risk for those patients with DQ2.2 heterodimers in trans configuration to DQ2.5 compared to DQ2.5 homozygous individuals. Therefore, in our population of patients with CD the frequency of DQ2.2 acts as a factor that increases the genetic risk of developing CD.
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Affiliation(s)
- Carmen M Cabrera
- a Department of Hematology, Immunology Section , Carlos Haya Regional University Hospital , Málaga , Spain
| | - Isabel M Méndez-López
- a Department of Hematology, Immunology Section , Carlos Haya Regional University Hospital , Málaga , Spain
| | - Abelardo Caballero
- a Department of Hematology, Immunology Section , Carlos Haya Regional University Hospital , Málaga , Spain.,b Faculty of Medicine , University of Málaga , Málaga , Spain
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35
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Al-Hussaini A, Alharthi H, Osman A, Eltayeb-Elsheikh N, Chentoufi A. Genetic susceptibility for celiac disease is highly prevalent in the Saudi population. Saudi J Gastroenterol 2018; 24:268-273. [PMID: 29956690 PMCID: PMC6152002 DOI: 10.4103/sjg.sjg_551_17] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND/AIM To determine the frequency of celiac disease (CD)-predisposing human leukocyte antigen (HLA)-DQ genotypes in the Saudi population, where the prevalence of CD is 1.5% as recently reported in a mass screening study. PATIENTS AND METHODS In a cross-sectional population-based study, a total of 192 randomly selected healthy school children (97 females, mean age 10.5 ± 2.2 years, all negative for tissue transglutaminase-IgA) were typed for D QA1 and D QB1 genes by polymerase chain reaction sequence-specific oligonucleotide probes. RESULTS Of the 192 children, 52.7% carried the high-risk CD-associated HLA-DQ molecules: homozygous DQ2.5 ( 2.6%), DQ2.5/DQ2.2 ( 4.7%), heterozygous DQ2.5 ( 28.15%), homozygous DQ8 ( 4.2%), DQ8/DQ2.2 ( 3.6%), and double dose DQ2.2 ( 9.4%). Low-risk CD-associated HLA-DQ molecules (single dose DQ2.2 and heterozygous DQ8) constituted 3.6% and 9.4%, respectively. Among the very low-risk groups, individuals lacking alleles that contribute to DQ2/DQ8 variants (33.5%), 13.5% carried only one of the alleles of the high-risk HLA-DQ2.5 heterodimer called "half-heterodimer" (HLA-DQA1*05 in 12% and HLA-DQB1* 02 in 1.5%), and 20.8% lacked all the susceptible alleles (DQX.x). Gender distribution was not significantly different among the CD-risk groups. CONCLUSION We report one of the highest frequencies of CD-predisposing HLA-DQ genotypes among healthy general populations (52.7%) worldwide, which might partly explain the high prevalence of CD in the Saudi community.
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Affiliation(s)
- Abdulrahman Al-Hussaini
- Division of Pediatric Gastroenterology, Children's Specialized Hospital, King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia,College of Medicine, Alfaisal University, Riyadh, Kingdom of Saudi Arabia,Prince Abdullah bin Khalid Celiac Disease Research Chair, Department of Pediatrics, Faculty of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia,Address for correspondence: Dr. Abdulrahman Al-Hussaini, Division of Pediatric Gastroenterology, Children's Specialized Hospital, King Fahad Medical City, College of Medicine, Alfaisal University, Riyadh, Kingdom of Saudi Arabia. E-mail:
| | - Hanan Alharthi
- Department of Pathology and Laboratory Medicine, Division of Immunology, King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia
| | - Awad Osman
- Department of Pathology and Laboratory Medicine, Division of Immunology, King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia
| | - Nezar Eltayeb-Elsheikh
- Department of Pathology and Laboratory Medicine, Division of Immunology, King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia
| | - Aziz Chentoufi
- Department of Immunology, University of Mohammed VI for health sciences, Casablanca, Morocco
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Jamnik J, Villa CR, Dhir SB, Jenkins DJA, El-Sohemy A. Prevalence of positive coeliac disease serology and HLA risk genotypes in a multiethnic population of adults in Canada: a cross-sectional study. BMJ Open 2017; 7:e017678. [PMID: 39272232 PMCID: PMC5640059 DOI: 10.1136/bmjopen-2017-017678] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Accepted: 08/09/2017] [Indexed: 11/30/2022] Open
Abstract
OBJECTIVES Coeliac disease (CD) is a complex autoimmune disorder with known genetic risk factors. Approximately 1% of individuals of European ancestry have CD, but the prevalence among different ethnicities living in Canada remains unknown. The objective of the present study was to determine the prevalence of positive CD serology in a population of Canadian adults living in Toronto, and to determine whether the prevalence of CD seropositivity and predisposing human leucocyte antigen (HLA)-DQ2/DQ8 risk genotypes differ between major ethnocultural groups. DESIGN Cross-sectional screening study of participants from the Toronto Nutrigenomics and Health and the Toronto Healthy Diet studies. SETTING University campus and households across Toronto, Canada. PARTICIPANTS FREE-LIVING Adults (n=2832) of diverse ethnocultural backgrounds. MAIN OUTCOME MEASURES Prevalence of positive CD serology was determined by screening for antitissue transglutaminase antibodies in individuals with predisposing HLA-DQ2/DQ8 genotypes. HLA genotypes were determined using six single nucleotide polymorphisms in the HLA gene region. RESULTS Of the 2832 individuals screened, a total of 25 (0.88%; 95% CI 0.57% to 1.30%) were determined to have positive CD serology. The majority of seropositive CD cases were undiagnosed (87%). Prevalence was highest among Caucasians (1.48%; 95% CI 0.93% to 2.23%), and similar in those of 'Other' (0.74%; 95% CI 0.09% to 2.63%) or 'Unknown' (0.43; 95% CI 0.01% to 2.36%) ethnicity. No cases of positive CD serology were identified among East Asian or South Asian individuals. East Asians had a lower prevalence of HLA risk genotypes than Caucasians and South Asians (p<0.005). CONCLUSIONS The prevalence of positive CD serology among Canadian adults living in Toronto is likely ~1%, with 87% of cases being undiagnosed. These findings suggest the need for better screening in high genetic risk groups. TRIAL REGISTRATION NUMBER NCT00516620; Post-results.
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Affiliation(s)
- Joseph Jamnik
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Christopher R Villa
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Sirbarinder Bryn Dhir
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - David J A Jenkins
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Clinical Nutrition and Risk Factor Modification Centre, St Michael’s Hospital, Toronto, Ontario, Canada
| | - Ahmed El-Sohemy
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
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Lucchini V. Nutrigenetics in practice: little is better than nothing. Curr Opin Food Sci 2017. [DOI: 10.1016/j.cofs.2017.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Liu E, Dong F, Barón AE, Taki I, Norris JM, Frohnert BI, Hoffenberg EJ, Rewers M. High Incidence of Celiac Disease in a Long-term Study of Adolescents With Susceptibility Genotypes. Gastroenterology 2017; 152:1329-1336.e1. [PMID: 28188747 PMCID: PMC5533620 DOI: 10.1053/j.gastro.2017.02.002] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2016] [Revised: 01/27/2017] [Accepted: 02/01/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Little is known about the incidence of celiac disease in the general population of children in the United States. We aimed to estimate the cumulative incidence of celiac disease in adolescents born in the Denver metropolitan area. METHODS We collected data on HLA-DR, DQ genotypes of 31,766 infants, born from 1993 through 2004 at St. Joseph's Hospital in Denver, from the Diabetes Autoimmunity Study in the Young. Subjects with susceptibility genotypes for celiac disease and type 1 diabetes were followed up for up to 20 years for development of tissue transglutaminase autoantibodies (tTGA). Outcomes were the development of celiac disease autoimmunity (CDA) or celiac disease. CDA was defined as persistence of tTGA for at least 3 months or development of celiac disease. Celiac disease was defined based on detection of Marsh 2 or greater lesions in biopsy specimens or persistent high levels of tTGA. For each genotype, the cumulative incidence of CDA and celiac disease were determined. To estimate the cumulative incidence in the Denver general population, outcomes by each genotype were weighted according to the frequency of each of these genotypes in the general population. RESULTS Of 1339 subjects followed up, 66 developed CDA and met criteria for celiac disease and 46 developed only CDA. Seropositivity for tTGA resolved spontaneously, without treatment, in 21 of the 46 subjects with only CDA (46%). The estimated cumulative incidence for CDA in the Denver general population at 5, 10, and 15 years of age was 2.4%, 4.3%, and 5.1%, respectively, and incidence values for celiac disease were 1.6%, 2.8%, and 3.1%, respectively. CONCLUSIONS In a 20-year prospective study of 1339 children with genetic risk factors for celiac disease, we found the cumulative incidence of CDA and celiac disease to be high within the first 10 years. Although more than 5% of children may experience a period of CDA, not all children develop celiac disease or require gluten-free diets.
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Affiliation(s)
- Edwin Liu
- Digestive Health Institute and Colorado Center for Celiac Disease, Children's Hospital Colorado, University of Colorado Denver, Aurora, Colorado; Barbara Davis Center, University of Colorado Denver, Aurora, Colorado.
| | - Fran Dong
- Barbara Davis Center, University of Colorado Denver
| | - Anna E. Barón
- Biostatics and Informatics, Colorado School of Public Health, University of Colorado Denver
| | - Iman Taki
- Barbara Davis Center, University of Colorado Denver
| | - Jill M. Norris
- Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver
| | | | - Edward J Hoffenberg
- Digestive Health Institute and Colorado Center for Celiac Disease, Children’s Hospital Colorado, University of Colorado Denver
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Piancatelli D, Ben El Barhdadi I, Oumhani K, Sebastiani P, Colanardi A, Essaid A. HLA Typing and Celiac Disease in Moroccans. Med Sci (Basel) 2017; 5:medsci5010002. [PMID: 29099018 PMCID: PMC5635774 DOI: 10.3390/medsci5010002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 12/07/2016] [Accepted: 12/22/2016] [Indexed: 01/01/2023] Open
Abstract
Genetic and environmental factors are responsible for differences in the prevalence of some diseases across countries. Human leukocyte antigen (HLA) allele frequencies in North African populations show some differences in their distribution compared to Europeans, Mediterraneans, and sub-Saharans, and some specific alleles and haplotypes could be clinically relevant. Celiac disease (CD) has been fast increasing in prevalence in North Africa; but few immunogenetic data are available for this area, in which a high prevalence of the disease has been described. In this report, we assess and discuss results of HLA class II (HLA-DQA1/DQB1/DRB1) typing in Moroccan patients with CD and compare them with a control population from Morocco—genetically well characterized—and with other North African, Mediterranean, and European populations. The classical HLA-DQ associations were confirmed in Moroccans with CD. The high frequency of DQ2.5 homozygosity (45.2%) found in Moroccans with CD was noteworthy as compared with other populations (23%–32%). The genetic risk gradient for CD, identified by previous studies, has been confirmed in Moroccans with some differences, mainly concerning DQ8 genotypes. This study provides the immunogenetic framework of CD in Moroccans and confirms the need to learn more about associations with additional HLA and non-HLA genetic factors.
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Affiliation(s)
- Daniela Piancatelli
- National Research Council (CNR)-Institute of Translational Pharmacology, U.O.S. L'Aquila, Via Carducci 32, 67100 L'Aquila, Italy.
| | - Imane Ben El Barhdadi
- Mohammed V-Souissi University, 10000 Rabat, Morocco.
- Medicine C, Department of Gastroenterology, Ibn Sina Hospital, 10000 Rabat, Morocco.
| | | | - Pierluigi Sebastiani
- National Research Council (CNR)-Institute of Translational Pharmacology, U.O.S. L'Aquila, Via Carducci 32, 67100 L'Aquila, Italy.
| | - Alessia Colanardi
- National Research Council (CNR)-Institute of Translational Pharmacology, U.O.S. L'Aquila, Via Carducci 32, 67100 L'Aquila, Italy.
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Abstract
Celiac disease is an autoimmune disorder induced by gluten in genetically susceptible individuals. It can result in intraintestinal and extraintestinal manifestations of disease including diarrhea, weight loss, anemia, osteoporosis, or lymphoma. Diagnosis of celiac disease is made through initial serologic testing and then confirmed by histopathologic examination of duodenal biopsies. Generally celiac disease is a benign disorder with a good prognosis in those who adhere to a gluten-free diet. However, in refractory disease, complications may develop that warrant additional testing with more advanced radiologic and endoscopic methods. This article reviews the current strategy to diagnose celiac disease and the newer modalities to assess for associated complications.
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Affiliation(s)
- Sarah Shannahan
- Division of Internal Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Daniel A Leffler
- Division of Gastroenterology, The Celiac Center, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA.
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Abstract
AbstractThe aim of the paper is to show the various neurological and psychiatric symptoms in coeliac disease (CD). CD is a T cell-mediated, tissue-specific autoimmune disease which affects genetically susceptible individuals after dietary exposure to proline- and glutamine-rich proteins contained in certain cereal grains. Genetics, environmental factors and different immune systems, together with the presence of auto-antigens, are taken into account when identifying the pathogenesis of CD. CD pathogenesis is related to immune dysregulation, which involves the gastrointestinal system, and the extra-intestinal systems such as the nervous system, whose neurological symptoms are evidenced in CD patients. A gluten-free diet (GFD) could avoid cerebellar ataxia, epilepsy, neuropathies, migraine and mild cognitive impairment. Furthermore, untreated CD patients have more symptoms and psychiatric co-morbidities than those treated with a GFD. Common psychiatric symptoms in untreated CD adult patients include depression, apathy, anxiety, and irritability and schizophrenia is also common in untreated CD. Several studies show improvement in psychiatric symptoms after the start of a GFD. The present review discusses the state of the art regarding neurological and psychiatric complications in CD and highlights the evidence supporting a role for GFD in reducing neurological and psychiatric complications.
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Abstract
PURPOSE OF REVIEW The duodenal biopsy is the gold standard for the diagnosis of celiac disease. However, given improvements in the performance of serological testing, the possibility of accurately diagnosing celiac disease without the need of a biopsy has attracted interest. The European Society for Paediatric Gastroenterology, Hepatology and Nutrition has revised its recommendations to include a diagnostic algorithm that includes sequential serological testing and human leukocyte antigen genotyping for symptomatic children which would enable a diagnosis of celiac disease to be made in the absence of a confirmatory intestinal biopsy. RECENT FINDINGS Recent studies have evaluated the ESPGHAN guidelines and have mostly corroborated that celiac disease can be accurately diagnosed in specific pediatric patient populations without the need of a biopsy. However, two cautionary points have been raised that warrant further consideration - the success of this approach is highly dependent targeting a population with a high pretest probability of celiac disease, as well, the performance of serology assays must be established and the appropriate use of cutoffs is essential. SUMMARY The duodenal biopsy will remain the gold standard for diagnosing celiac disease in a majority of patients. However, as serology assays evolve and as a greater understanding of the genetic risk factors of celiac disease is achieved, more patients may be accurately diagnosed without the need for a biopsy.
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Jamnik J, García-Bailo B, Borchers CH, El-Sohemy A. Gluten Intake Is Positively Associated with Plasma α2-Macroglobulin in Young Adults. J Nutr 2015; 145:1256-62. [PMID: 25855121 DOI: 10.3945/jn.115.212829] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Accepted: 03/20/2015] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Gluten-free foods have increased in popularity over the past decade and are now being consumed by individuals without celiac disease. However, the physiologic effects of gluten intake in individuals without celiac disease remain unknown. High-abundance plasma proteins involved in inflammation, endothelial function, and other physiologic pathways may represent potential biomarkers of biological effects of gluten intake. OBJECTIVE The objective was to examine the association between gluten intake and plasma proteomic biomarkers in a population of adults without clinically diagnosed celiac disease. METHODS Subjects (n = 1095) were participants of the Toronto Nutrigenomics and Health Study, a cross-sectional examination of young adults aged 20-29 y. Dietary gluten intake was estimated by using a 1-mo, 196-item semiquantitative food-frequency questionnaire. The concentrations of 54 plasma proteins were measured simultaneously by liquid chromatography/multiple-reaction monitoring mass spectrometry. The association between gluten intake and each proteomic biomarker was examined by using general linear models. Analyses were then conducted in individuals who do not have the human leukocyte antigen (HLA)-DQ2 or DQ8 risk variants required for the development of celiac disease to determine whether any associations observed could have been due to undiagnosed cases of celiac disease. RESULTS Increased gluten intake was associated with increased concentrations of plasma α2-macroglobulin (P = 0.01), a marker of inflammation and cytokine release. The association remained after adjusting for age, sex, BMI, ethnicity, physical activity, energy intake, fiber intake, and hormonal contraceptive use among women. This relation was not modified by HLA risk variants. CONCLUSION Gluten consumption is associated with increased plasma α2-macroglobulin in young adults, which appears to be independent of celiac disease, suggesting possible effects of gluten on inflammation.
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Affiliation(s)
- Joseph Jamnik
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Canada; and
| | - Bibiana García-Bailo
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Canada; and
| | - Christoph H Borchers
- Genome British Columbia Proteomics Centre, University of Victoria, Victoria, Canada
| | - Ahmed El-Sohemy
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Canada; and
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Abstract
Wheat-related disorders have become a growing area of clinical and scientific interest and can be categorized broadly as: autoimmune-mediated; allergic; and non-autoimmune/non-allergic conditions. Non-celiac gluten sensitivity (NCGS) and non-celiac wheat sensitivity (NCWS) present on this spectrum as disorders associated with adverse gastrointestinal and extra-intestinal manifestations following exposure to gluten and/or other wheat-related constituents. NCGS/NCWS is increasingly considered in patients with unexplained symptoms after the exclusions of celiac disease and wheat allergy. As objective diagnostic data and specific biomarkers are lacking, response to a gluten-free/wheat-free diet can confirm the presence of NCGS/NCWS. An association with irritable bowel syndrome has been detected, and the effects of other food components, such as fermentable oligosaccharides, disaccharides, monosaccharides, and polyols, may contribute. Our organization and synthesis of extant knowledge pertaining to wheat-related disorders may advance current practice and research efforts toward an improved understanding of NCGS/NCWS as an evolving clinical entity.
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Affiliation(s)
- Renée M Marchioni Beery
- Division of Gastroenterology and Hepatology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-1845, USA
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Husby S, Murray JA. Diagnosing coeliac disease and the potential for serological markers. Nat Rev Gastroenterol Hepatol 2014; 11:655-63. [PMID: 25266110 DOI: 10.1038/nrgastro.2014.162] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The diagnosis of coeliac disease has advanced in the past decade owing to increased clinical awareness and improved tests. Coeliac disease is now regarded as a common disease presenting at any age with a broad spectrum of symptoms. Previous guidelines on diagnosis relied on the histological analysis of duodenal biopsy samples. However, contemporary antibody analysis is a diagnostic tool with a comparatively high accuracy that has reduced reliance on performing biopsies. Furthermore, determination of HLA-based genetic susceptibility to coeliac disease has become routine. European and North American guidelines utilize symptoms, coeliac antibodies (primarily tissue transglutaminase 2 IgA and endomysial IgA antibodies), HLA determination and histological analysis of biopsy tissue for diagnosis. Some guidelines conclude that the diagnostic accuracy of tissue transglutaminase 2 IgA antibodies is sufficient to omit duodenal biopsies in selected children with very high antibody levels, in the presence of clear symptom response as well as a positive endomysial antibody test and confirmation of genetic susceptibility. This Review discusses if such a strategy is appropriate for children and adults in all populations. The performance characteristics of antibody tests (particularly of the tissue transglutaminase 2 IgA test) including quality control and characterisation of the population in whom testing is performed are also discussed.
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Affiliation(s)
- Steffen Husby
- Hans Christian Andersen Children's Hospital, Odense University Hospital, 29 Southern Boulevard, DK-5000 Odense C, Denmark
| | - Joseph A Murray
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st Street South West, Rochester, MN 55905, USA
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Lemin AJ, Darke C. Prevalence of HLA-DQA1 alleles and haplotypes in blood donors resident in Wales. Int J Immunogenet 2014; 41:480-3. [DOI: 10.1111/iji.12154] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Revised: 09/08/2014] [Accepted: 09/25/2014] [Indexed: 11/30/2022]
Affiliation(s)
- A. J. Lemin
- Welsh Transplantation and Immunogenetics Laboratory; Welsh Blood Service; Pontyclun Wales UK
| | - C. Darke
- Welsh Transplantation and Immunogenetics Laboratory; Welsh Blood Service; Pontyclun Wales UK
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Barakauskas VE, Lam GY, Estey MP. Digesting all the options: Laboratory testing for celiac disease. Crit Rev Clin Lab Sci 2014; 51:358-78. [PMID: 25244521 DOI: 10.3109/10408363.2014.958813] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Pallav K, Kabbani T, Tariq S, Vanga R, Kelly CP, Leffler DA. Clinical utility of celiac disease-associated HLA testing. Dig Dis Sci 2014; 59:2199-206. [PMID: 24705698 PMCID: PMC4149591 DOI: 10.1007/s10620-014-3143-1] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2014] [Accepted: 03/26/2014] [Indexed: 12/30/2022]
Abstract
BACKGROUND Negative predictive value (NPV) of celiac disease (CD)-related human leukocyte antigens (HLA) DQ2 and DQ8 approaches 100 % in individual patients. However, studies evaluating its exclusionary utility in patient groups are lacking. AIM We aim to assess the performance of HLA testing when applied to patient groups with varying characteristics and propose evidence-based recommendations for its clinical use. METHODS Demographic and clinical information was recorded in patients undergoing HLA testing. Using predetermined criteria, patients were classified as CD, non-CD, or indeterminate. Diagnostic yield of HLA testing was defined as the percentage of patients in whom CD could be excluded based on negative HLA test. RESULTS Two hundred and fifty-six patients underwent testing for CD-related HLA DQ2 and DQ8. 102 (100 non-CD, 2 CD) patients tested HLA negative for a 98 % NPV and 39 % diagnostic yield. Diagnostic yield was highest (60 %) in patients with intraepithelial lymphocytosis plus normal IgA tissue transglutaminase antibody (IgA-tTG) and lowest in patients with positive IgA-tTG plus villous atrophy (0 %). CD was diagnosed in two HLA-negative patients, who carried half of DQ2.5 trans genotype. CONCLUSIONS Diagnostic yield of CD-related HLA testing varies widely depending on clinical indication. HLA testing is a practical and valuable test for most patients in whom initial evaluation for CD is inconclusive. A negative HLA result usually obviates the need for further celiac testing including endoscopy and gluten challenge. Rarely, in patients reported as HLA negative, half of HLA DQ2.5 (cis or trans) is sufficient for development of CD.
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Affiliation(s)
- Kumar Pallav
- The Celiac Center, Beth Israel Deaconess Medical Center, Harvard Medical School. 330 Brookline Avenue Boston, MA 02215
| | - Toufic Kabbani
- The Celiac Center, Beth Israel Deaconess Medical Center, Harvard Medical School. 330 Brookline Avenue Boston, MA 02215
| | - Sohaib Tariq
- The Celiac Center, Beth Israel Deaconess Medical Center, Harvard Medical School. 330 Brookline Avenue Boston, MA 02215
| | - Rohini Vanga
- The Celiac Center, Beth Israel Deaconess Medical Center, Harvard Medical School. 330 Brookline Avenue Boston, MA 02215
| | - Ciaran P. Kelly
- The Celiac Center, Beth Israel Deaconess Medical Center, Harvard Medical School. 330 Brookline Avenue Boston, MA 02215
| | - Daniel A. Leffler
- The Celiac Center, Beth Israel Deaconess Medical Center, Harvard Medical School. 330 Brookline Avenue Boston, MA 02215
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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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The winding road to understanding the neonatal origins of inflammatory gastrointestinal disorders. J Pediatr Gastroenterol Nutr 2013; 57:543-9. [PMID: 23857343 DOI: 10.1097/mpg.0b013e3182a321f1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Beginning with the observation that birth weight correlates with increased risk of cardiovascular disease, the concept of neonatal programming, that the environmental influence on fetal and neonatal development results in modification of the risk profile for adult disease, has begun to emerge as an important component to understanding the origin of chronic diseases of many different organ systems. Until recently, the gastrointestinal system has not been considered. Our understanding of the pathogenesis of many intestinal inflammatory disorders is still incomplete; however, a brief review of what is known reveals several opportunities for the early intraluminal environment to affect the development of the intestinal immune system. Early clinical observations such as the increased risk of celiac disease observed in those born by cesarean section and the protective effect of breast-feeding against inflammatory bowel disease and celiac disease support the role of neonatal programming in the development of chronic inflammatory gastrointestinal disease. Additional, more robust clinical studies are needed to confirm this role. Furthermore, examination of the possible mechanisms of immune phenotype modification is necessary.
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