Scherr Rebecca, Essers Jonah, Hakonarson Hakon, Kugathasan Subra
Department of Pediatrics, Emory University School of Medicine and Children's Health Care of Atlanta, Atlanta, GA 30322, USA.
Dig Dis. 2009;27(3):236-9. doi: 10.1159/000228555. Epub 2009 Sep 24.
Inflammatory bowel disease (IBD) is thought to develop as a result of dysregulation of the immune response to normal gut flora in a genetically susceptible host. Approximately 25% of incident cases of IBD occur during childhood and the rest occur throughout adulthood, peaking in the second and third decades of life. What determines the age of onset remains unexplained currently. Studying early-onset presentation of complex diseases such as IBD is appealing to geneticists and scientists alike because of the expectation that these efforts will increase the probability of finding novel risk variants. Genome-wide association studies (GWAS) have yielded more susceptible loci in IBD than in any other complex common disease studied. Using 35 confirmed Crohn's disease risk alleles from adult studies, a recent pediatric replication study detected no significant association between risk score and age of onset through age 30, indicating age of onset does not have any impact on increased disease development in IBD. The first GWAS study using an exclusively pediatric IBD cohort found 2 novel risk variants that were not previously reported in predominately adult GWAS studies. However, during the data-mining of adult GWAS, these 2 novel loci (TNFRSF6 and PSMG1) were found with nominal significance suggesting that these risk loci are not restricted to early-onset CD cases. These analyses illustrate that the genetic effects of established CD risk variants is similar in early- and late-onset CD. However, the quest to find early-onset IBD risk variants is continuing. As such, GWAS studies involving large pediatric-onset CD cohorts and early-onset ulcerative colitis presentations are presently underway. A future joint analysis of genome-wide association data of early- and late-onset cohorts will likely reveal more IBD risk variants since the power to detect small effects of genes increases.
炎症性肠病（IBD）被认为是在遗传易感宿主中，对正常肠道菌群的免疫反应失调所致。约25%的IBD新发病例发生在儿童期，其余病例则在成年期发病，发病高峰在20至30岁。目前尚不清楚发病年龄的决定因素。研究IBD等复杂疾病的早发表现对遗传学家和科学家都很有吸引力，因为人们期望这些研究将增加发现新风险变异的可能性。全基因组关联研究（GWAS）在IBD中发现的易感基因座比其他任何复杂常见疾病都多。一项近期的儿科重复研究使用了来自成人研究的35个已确认的克罗恩病风险等位基因，结果发现风险评分与30岁之前的发病年龄之间无显著关联，这表明发病年龄对IBD疾病进展增加没有任何影响。第一项仅使用儿科IBD队列的GWAS研究发现了2个新的风险变异，这些变异在主要针对成人的GWAS研究中未曾报道。然而，在对成人GWAS数据进行挖掘时，发现这2个新基因座（TNFRSF6和PSMG1）具有名义显著性，这表明这些风险基因座并不局限于早发性克罗恩病病例。这些分析表明，已确定的克罗恩病风险变异在早发性和晚发性克罗恩病中的遗传效应相似。然而，寻找早发性IBD风险变异的工作仍在继续。因此，目前正在进行涉及大量儿童期发病的克罗恩病队列和早发性溃疡性结肠炎病例的GWAS研究。由于检测基因微小效应的能力增强，未来对早发性和晚发性队列的全基因组关联数据进行联合分析可能会发现更多IBD风险变异。
