Genetic determinants of pediatric inflammatory bowel disease: is age of onset genetically determined?

Abstract

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.