High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis

Goyette, Philippe; Boucher, Gabrielle; Mallon, Dermot; Ellinghaus, Eva; Jostins, Luke; Huang, Hailiang; Ripke, Stephan; Gusareva, Elena S.; Annese, Vito; Hauser, Stephen L.; Oksenberg, Jorge R.; Thomsen, Ingo; Leslie, Stephen; Daly, Mark J.; Steen, Kristel Van; Duerr, Richard H.; Barrett, Jeffrey C.; McGovern, Dermot P.; Schumm, L. Philip; Traherne, James A.; Carrington, Mary; Kosmoliaptsis, Vasilis; Karlsen, Tom H.; Franke, André; Rioux, John D.

doi:10.1038/ng.3176

Cited by 288 publications

(345 citation statements)

References 38 publications

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“…In this study, we have limited our participants to those who self-reported European ancestry and had both dietary assessment and genotype data for the rs12212067 polymorphism of the FOXO3 gene available. The rs12212067 polymorphism was genotyped using Immunochip, an Illumina iSelect HD custom genotyping array [30]. The study was conducted under ethical protocol MEC/04/12/011, authorised through the New Zealand Multi-Region Human Ethics Committee.…”

Section: Methodsmentioning

confidence: 99%

Food Intolerance: Associations with the rs12212067 Polymorphism of FOXO3 in Crohn's Disease Patients in New Zealand

et al. 2015

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Background: Diet is known to play a major role in Crohn's disease (CD). It has also been reported that the minor G allele from the rs12212067 polymorphism (T>G) in FOXO3 is associated with milder CD. The aim of this study was to investigate the association between the rs12212067 polymorphism and food intolerances for a total of 253 foods. Methods: Tolerances and intolerances were recorded on a self-reported dietary questionnaire. Each food was scored on a 5-point ordinal scale: beneficial effects as ‘+ +' or ‘+', adverse effects as ‘- -' or ‘-', and ‘makes no difference' as ‘='. Dietary and genotype data were available for a total of 283 CD patients. Results: We identified 17 foods with beneficial effects in our study which were significantly associated with the G allele of the FOXO3 rs12212067 polymorphism. Of these, sweet potatoes had the highest reported frequency of beneficial responses. We also identified 4 foods with detrimental effects in more than 25% of our study population. These were mustard, wasabi, and raw and cooked tomatoes, which again were significantly associated with the G allele in FOXO3. Conclusions: There was strong evidence that adverse effects of mustard, wasabi, and raw and cooked tomatoes were significantly associated with the G allele of FOXO3 and that these foods should be avoided by people carrying this allele.

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Section: Methodsmentioning

confidence: 99%

Food Intolerance: Associations with the rs12212067 Polymorphism of FOXO3 in Crohn's Disease Patients in New Zealand

et al. 2015

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“…In contrast to CD, however, a prognostic UC association, widely replicated, exists-namely the HLA DRB*0103 association with extensive and severe disease ( 43,44 ). Th e allele frequency of this variant in the background population is ~4% rising to just over 10% in acute severe UC, limiting its utility as a stand-alone prognostic marker.…”

Section: Genetic Markers In Ucmentioning

confidence: 99%

Using Markers in IBD to Predict Disease and Treatment Outcomes: Rationale and a Review of Current Status

Lichtenstein¹,

McGovern²

2016

Am J Gastroenterol Suppl

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Biomarkers, radiology fi ndings, and endoscopic studies, together with clinical assessment of patients with infl ammatory bowel disease, can be used to help determine prognosis, assess disease activity, and increasingly to inform treatment decision-making. This article reviews the current "state of the science" regarding the multitude of different tests that can be performed and how these can be used in the clinic to guide management. Initially, when patients present with symptoms suggestive of infl ammatory bowel disease (IBD), standard endoscopic studies and radiographic studies should be performed and the use of combinations of serologic and fecal markers may additionally be incorporated into patient assessment. Once the patient has a formal diagnosis, prognosis should be assessed and serologic evaluation may be used, but in conjunction with endoscopic and radiographic studies. Within the context of evaluating clinical predictors of disease (e.g., disease location, nutritional status, routine blood tests), early mucosal healing has been linked to better outcomes, and failure to heal the mucosa has been associated with poorer outcomes. Evaluation of response to therapy can be approximated with the use of biomarkers (e.g., C-reactive protein, fecal calprotectin, lactoferrin), and therapeutic drug monitoring has enabled us to assess levels of drug metabolites, drug levels, and antidrug antibodies to guide the ongoing management. Although there is not yet universal adoption of biomarkers to determine treatment choices (e.g., the use of anti-tumor necrosis factor therapy), biomarkers have enabled us to "fi ne tune" treatment of some patients with IBD. Establishing mechanisms of communicating these risks/benefi ts to patients will be a considerable challenge and remains a priority area of research.

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“…Genetic variations in the HLA-DQA and HLA-DQB may affect the function of the antigen peptide binding groove of the protein [38]. A high-density typing of MHC region found multiple HLA-DRB1 alleles have equivalent association with HLA-DQA1 and HLA-DQB1 [39]. HLA-DRB1*04 is a risk factor for rheumatoid arthritis and is caused by variations of the peptide-binding groove [40].…”

Section: Major Histocompatibility Complexmentioning

confidence: 99%

“…HLA-DRB1*01:03 is associated with colonic CD. The risk variations of HLA-DRB1*0103 also showed a different 3D structure of the peptide-binding groove [39]. …”

Section: Major Histocompatibility Complexmentioning

confidence: 99%

Risk Genes of Inflammatory Bowel Disease in Asia: What Are the Most Important Pathways Affected?

Guo

Wu²

2016

Dig Dis

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Genetic factors play an important role in the pathogenesis of inflammatory bowel disease (IBD), and IBD is now recognized as a complex disease that results from interplay between genetic and environment factors. To date, over 160 IBD-susceptible loci have been identified using genome-wide association studies (GWAS). The risk genes identified in these studies are involved in various pathways in innate and adaptive immune response such as innate bacterial sensing, autophagy and interleukin-23 receptor/T-helper cell 17 pathway. It was initially believed that the genetic backgrounds of Asian IBD patients differ from that of other populations. Recent GWAS and meta-analysis found that there is pervasive sharing of risk loci between the East and West. Overlapping risk genes between populations of different ancestries indicate that pathways underlying the etiology of IBD may be common between Asia and other areas. However, the importance of individual pathways may be different in Asia from the Western countries. Identifying the most important pathways affected in Asian IBD patients may provide a better understanding of pathogenesis of IBD in Asia and improve the clinical management of the patients.

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High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis

Cited by 288 publications

References 38 publications

Food Intolerance: Associations with the rs12212067 Polymorphism of FOXO3 in Crohn's Disease Patients in New Zealand

Food Intolerance: Associations with the rs12212067 Polymorphism of FOXO3 in Crohn's Disease Patients in New Zealand

Using Markers in IBD to Predict Disease and Treatment Outcomes: Rationale and a Review of Current Status

Risk Genes of Inflammatory Bowel Disease in Asia: What Are the Most Important Pathways Affected?

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