Gastroenterology

Gastroenterology

Volume 148, Issue 4, April 2015, Pages 794-805
Gastroenterology

Original Research
Full Report: Basic and Translational—Alimentary Tract
Identification of Risk Loci for Crohn’s Disease Phenotypes Using a Genome-Wide Association Study

https://doi.org/10.1053/j.gastro.2014.12.030Get rights and content

Background & Aims

Crohn’s disease is a highly heterogeneous inflammatory bowel disease comprising multiple clinical phenotypes. Genome-wide association studies (GWASs) have associated a large number of loci with disease risk but have not associated any specific genetic variants with clinical phenotypes. We performed a GWAS of clinical phenotypes in Crohn’s disease.

Methods

We genotyped 576,818 single-nucleotide polymorphisms in a well-characterized cohort of 1090 Crohn’s disease patients of European ancestry. We assessed their association with 17 phenotypes of Crohn’s disease (based on disease location, disease behavior, disease course, age at onset, and extraintestinal manifestations). A total of 57 markers with strong associations to Crohn’s disease phenotypes (P < 2 × 10-4) were subsequently analyzed in an independent replication cohort of 1296 patients of European ancestry.

Results

We replicated the association of 4 loci with different Crohn’s disease phenotypes. Variants in MAGI1, CLCA2, 2q24.1, and LY75 loci were associated with a complicated stricturing disease course (Pcombined = 2.01 × 10-8), disease location (Pcombined = 1.3 × 10-6), mild disease course (Pcombined = 5.94 × 10-7), and erythema nodosum (Pcombined = 2.27 × 10-6), respectively.

Conclusions

In a GWAS, we associated 4 loci with clinical phenotypes of Crohn’s disease. These findings indicate a genetic basis for the clinical heterogeneity observed for this inflammatory bowel disease.

Section snippets

Patients

A total of 1338 patients fulfilling Lennard-Jones16 diagnostic criteria for CD were enrolled in the discovery phase (GWAS) of this study. Patient recruitment was performed between June 2007 and December 2010 at 15 Gastroenterology Departments from different Spanish University Hospitals belonging to the Immune-Mediated Inflammatory Disease Consortium (IMIDC).15 The IMIDC is a Spanish network of researchers investigating the genomic basis of immune-mediated inflammatory diseases. A cohort of 1493

Phenotypic Characterization of the Studied Cohorts

The clinical and epidemiologic characteristics of the discovery and replication patient cohorts are shown in Table 1. The GWAS cohort was characterized by a markedly longer follow-up time than the replication cohort (median, 15.48 y; interquartile range, 11.80–20.54 y vs median, 10.65 y; interquartile range, 6.09–16.56 y; P = 4 × 10-43). Consequently, there was also a statistically significantly higher percentage of patients with severe clinical phenotypes such as B2, B3, and perianal disease

Discussion

In the present study, we report the results of a GWAS on clinically relevant phenotypes in CD. A total of 17 CD phenotypes of clinical importance were analyzed, including disease behavior, disease location, complicated disease course, age at onset, and other complications such as perianal disease and extraintestinal manifestations. By using an independent cohort of patients, we have validated the strong GWAS association of MAGI1 with stricturing behavior and a complicated stricturing disease

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      NOD2 variants have been consistently linked to a stricturing behavior and need for surgery [30], but this is likely to be a secondary phenomenon driven by the most frequent ileal localization in these patients. Many other variants have also been associated with some specific sub-phenotypes, but data are not always consistent and prediction value not strong enough to drive decision making [31–36]. It is unfortunate that the largest international study evaluating genotype/phenotype in roughly 35,000 IBD patients, found only a few genome-wide significant associations, namely NOD2, MST1, and MHC with most clear cut association only with disease localization [37].

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    Conflicts of interest The authors disclose no conflicts.

    Funding Supported by the Spanish Ministry of Economy and Competitiveness grants (PSE-010000-2006-6 and IPT-010000-2010-36). The study sponsor had no role in the collection, analysis, or interpretation of the data.

    Author names in bold designate shared co-first authors.

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