Prescott Natalie J, Fisher Sheila A, Franke Andre, Hampe Jochen, Onnie Clive M, Soars Dianne, Bagnall Richard, Mirza Muddassar M, Sanderson Jeremy, Forbes Alastair, Mansfield John C, Lewis Cathryn M, Schreiber Stefan, Mathew Christopher G
Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London, UK.
Gastroenterology. 2007 May;132(5):1665-71. doi: 10.1053/j.gastro.2007.03.034. Epub 2007 Mar 24.
BACKGROUND & AIMS: A genome-wide association scan of nonsynonymous DNA polymorphisms identified association of a threonine-to-alanine substitution (T300A) in the autophagy-related 16-like gene ATG16L1 with Crohn's disease. We investigated this association in independent U.K. cohorts of Crohn's disease and ulcerative colitis.
The T300A variant (rs2241880) was genotyped in an independent sample of 727 Crohn's disease and 877 ulcerative colitis cases, and in 579 controls. We then performed an extension analysis combining these data with the U.K. data from the initial study to give a total of 1236 U.K. Crohn's disease cases and 1235 controls to estimate disease risk and test for interaction with the CARD15 and IBD5 risk loci and for association with disease subtypes.
The association of T300A was replicated in the independent sample of 727 Crohn's disease cases (P = .001), and was strongly associated in the extended analysis of 1236 Crohn's cases (P = 2.4 x 10(-6)). The 300A/A genotype conferred a 1.65-fold risk of Crohn's disease, with a 2.2-fold risk of ileal disease. Analysis of the interaction of ATG16L1 with CARD15 and IBD5 indicated that all 3 loci contribute independently to disease risk. Homozygosity for the risk allele at all 3 loci conferred a combined risk of 20.4 (95% confidence interval: 8.71, 47.7) for Crohn's disease. The ATG16L1 risk genotype showed a modest but significant association with ulcerative colitis (P = .026).
The association of ATG16L1 with Crohn's disease and possibly with ulcerative colitis supports a role for autophagy in the pathogenesis of inflammatory bowel disease.
一项针对非同义DNA多态性的全基因组关联扫描发现，自噬相关16样基因ATG16L1中的苏氨酸到丙氨酸替换（T300A）与克罗恩病相关。我们在英国独立的克罗恩病和溃疡性结肠炎队列中对这种关联进行了研究。
在727例克罗恩病患者、877例溃疡性结肠炎患者以及579例对照的独立样本中对T300A变异（rs2241880）进行基因分型。然后我们进行了一项扩展分析，将这些数据与初始研究中的英国数据相结合，共计1236例英国克罗恩病患者和1235例对照，以评估疾病风险，并检测与CARD15和IBD5风险位点的相互作用以及与疾病亚型的关联。
T300A的关联在727例克罗恩病患者的独立样本中得到重复验证（P = 0.001），并且在对1236例克罗恩病患者的扩展分析中显示出强关联（P = 2.4×10⁻⁶）。300A/A基因型使患克罗恩病的风险增加1.65倍，患回肠疾病的风险增加2.2倍。对ATG16L1与CARD15和IBD5相互作用的分析表明，这三个位点均独立影响疾病风险。在所有三个位点上风险等位基因均为纯合子的情况使患克罗恩病风险的综合值达到20.4（95%置信区间：8.71，47.7）。ATG16L1风险基因型与溃疡性结肠炎存在适度但显著的关联（P = 0.026）。
ATG16L1与克罗恩病以及可能与溃疡性结肠炎的关联支持自噬在炎症性肠病发病机制中发挥作用。
