Contributions of IBD5, IL23R, ATG16L1, and NOD2 to Crohn's disease risk in a population-based case-control study: Evidence of gene–gene interactions

Authors

  • Toshihiko Okazaki MD, PhD,

    1. Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
    Search for more papers by this author
    • M.H. Wang and T. Okazaki contributed equally to this work

  • Ming-Hsi Wang MD, PhD,

    1. Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
    2. Department of Epidemiology and the Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland
    Search for more papers by this author
    • M.H. Wang and T. Okazaki contributed equally to this work

  • Patricia Rawsthorne RN,

    1. Section of Gastroenterology, University of Manitoba Inflammatory Bowel Disease Clinical and Research Centre, Winnipeg, Manitoba, Canada
    Search for more papers by this author
  • Michael Sargent,

    1. Section of Gastroenterology, University of Manitoba Inflammatory Bowel Disease Clinical and Research Centre, Winnipeg, Manitoba, Canada
    Search for more papers by this author
  • Lisa Wu Datta MSc,

    1. Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
    Search for more papers by this author
  • Yin Yao Shugart PhD,

    1. Department of Epidemiology and the Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland
    Search for more papers by this author
  • Charles N. Bernstein MD,

    1. Section of Gastroenterology, University of Manitoba Inflammatory Bowel Disease Clinical and Research Centre, Winnipeg, Manitoba, Canada
    Search for more papers by this author
    • C.N. Bernstein and S.R. Brant contributed equally to this work.

  • Steven R. Brant MD

    Corresponding author
    1. Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
    2. Department of Epidemiology and the Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland
    • Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, 1503 E. Jefferson St., Rm. B136, Baltimore, MD 21231
    Search for more papers by this author
    • C.N. Bernstein and S.R. Brant contributed equally to this work.

Errata

This article is corrected by:

  1. Errata: Erratum: Contributions of IBD5, IL23R, ATG16L1, and NOD2 to Crohn's disease risk in a population-based case-control study: Evidence of gene-gene interactions Volume 18, Issue 8, 1591, Article first published online: 16 July 2012

Abstract

Background: IBD5, IL23R, and ATG16L1 genetic variations are established Crohn's disease (CD) risks alleles. We evaluated these in a population-based case-control study within a cohort to determine their penetrance, population attributable risk, independence, and relationship to other established CD risk factors, including NOD2.

Methods: DNA from 213 CD, 117 ulcerative colitis, and 310 healthy control subjects from the population-based University of Manitoba IBD Research Registry were genotyped for IBD5 and IL23R single-nucleotide polymorphisms (SNPs), and for the Thr300Ala ATG16L1 SNP. Univariate and multivariate analyses were performed for these and nongenetic risk factors. We introduce multidimensionality reduction (MDR) to explore gene–gene interactions.

Results: ATG16L1, IBD5, and IL23R SNPs were significantly associated with CD. Multivariate analysis showed independent CD association for carriers of ATG16L1 (odds ratio [OR] = 1.8, 95% confidence interval [CI] 1.09–3.24), IBD5-IGR2230 (OR = 2.16, 95% CI 1.30–3.59), and IL23R-rs10889677 (OR = 2.13, 95% CI 1.39–3.28) while retaining association for NOD2 mutation carriers (OR = 4.45, 95% CI 2.68–7.38), IBD family history (OR = 2.75, 95% CI 1.42–5.31), tobacco (OR = 2.06, 95% CI 1.35–3.14), and Jewish ethnicity (OR = 20.1, 95% CI 2.16–186.8). IL23R minor variants for Arg381Gln and Intron 6 rs7517848 showed independent, CD protection and 3′ untranslated variant rs108896778 showed risk. MDR analysis suggested an interaction between IBD5, ATG16L1, and IL23R risk alleles. Penetrance values for ATG16L1 and IBD5 were 0.27% for heterozygotes, and 0.35% and 0.44%, respectively, for homozygotes. IL23R rs108896778 penetrance was 0.37%.

Conclusions: A population-based analysis of CD risk factors is useful for characterizing the epidemiology of multiple CD genetic and nongenetic risk factors. Gene–gene interactions are likely, but require further evaluation in large population-based cohorts.

(Inflamm Bowel Dis 2008)

Ancillary