Cutler David J, Zwick Michael E, Okou David T, Prahalad Sampath, Walters Thomas, Guthery Stephen L, Dubinsky Marla, Baldassano Robert, Crandall Wallace V, Rosh Joel, Markowitz James, Stephens Michael, Kellermayer Richard, Pfefferkorn Marian, Heyman Melvin B, LeLeiko Neal, Mack David, Moulton Dedrick, Kappelman Michael D, Kumar Archana, Prince Jarod, Bose Promita, Mondal Kajari, Ramachandran Dhanya, Bohnsack John F, Griffiths Anne M, Haberman Yael, Essers Jonah, Thompson Susan D, Aronow Bruce, Keljo David J, Hyams Jeffrey S, Denson Lee A, Kugathasan Subra
Department of Human Genetics, Emory University, Atlanta, Georgia, United States of America.
Department of Pediatrics, Emory University, Atlanta, Georgia, United States of America.
PLoS One. 2015 Jun 22;10(6):e0128074. doi: 10.1371/journal.pone.0128074. eCollection 2015.
The inflammatory bowel diseases (IBD) are common, complex disorders in which genetic and environmental factors are believed to interact leading to chronic inflammatory responses against the gut microbiota. Earlier genetic studies performed in mostly adult population of European descent identified 163 loci affecting IBD risk, but most have relatively modest effect sizes, and altogether explain only ~20% of the genetic susceptibility. Pediatric onset represents about 25% of overall incident cases in IBD, characterized by distinct disease physiology, course and risks. The goal of this study is to compare the allelic architecture of early onset IBD with adult onset in population of European descent.
We performed a fine mapping association study of early onset IBD using high-density Immunochip genotyping on 1008 pediatric-onset IBD cases (801 Crohn's disease; 121 ulcerative colitis and 86 IBD undetermined) and 1633 healthy controls. Of the 158 SNP genotypes obtained (out of the 163 identified in adult onset), this study replicated 4% (5 SNPs out of 136) of the SNPs identified in the Crohn's disease (CD) cases and 0.8% (1 SNP out of 128) in the ulcerative colitis (UC) cases. Replicated SNPs implicated the well known NOD2 and IL23R. The point estimate for the odds ratio (ORs) for NOD2 was above and outside the confidence intervals reported in adult onset. A polygenic liability score weakly predicted the age of onset for a larger collection of CD cases (p< 0.03, R2= 0.007), but not for the smaller number of UC cases.
The allelic architecture of common susceptibility variants for early onset IBD is similar to that of adult onset. This immunochip genotyping study failed to identify additional common variants that may explain the distinct phenotype that characterize early onset IBD. A comprehensive dissection of genetic loci is necessary to further characterize the genetic architecture of early onset IBD.
炎症性肠病（IBD）是常见的复杂疾病，其中遗传和环境因素被认为相互作用，导致针对肠道微生物群的慢性炎症反应。早期的遗传学研究主要在欧洲血统的成年人群中进行，确定了163个影响IBD风险的基因座，但大多数效应大小相对较小，总共仅解释了约20%的遗传易感性。儿童期发病约占IBD总体发病病例的25%，具有独特的疾病生理、病程和风险特征。本研究的目的是比较欧洲血统人群中早发性IBD与成年发病IBD的等位基因结构。
我们对1008例儿童期发病的IBD病例（801例克罗恩病；121例溃疡性结肠炎和86例未定型IBD）和1633例健康对照进行了高密度免疫芯片基因分型，以进行早发性IBD的精细定位关联研究。在获得的158个单核苷酸多态性（SNP）基因型中（在成年发病中鉴定出的163个中），本研究在克罗恩病（CD）病例中重复了4%（136个中的5个SNP），在溃疡性结肠炎（UC）病例中重复了0.8%（128个中的1个SNP）。重复的SNP涉及著名的NOD2和IL23R。NOD2比值比（OR）的点估计值高于成年发病报告的置信区间且不在该区间内。多基因风险评分对更大一组CD病例的发病年龄有较弱的预测作用（p<0.03，R2 = 0.007），但对较少数量的UC病例则没有预测作用。
早发性IBD常见易感变异的等位基因结构与成年发病相似。这项免疫芯片基因分型研究未能识别出可能解释早发性IBD独特表型的其他常见变异。有必要对基因座进行全面剖析，以进一步表征早发性IBD的遗传结构。
