Genetics of Inflammatory Bowel Diseases

Abstract

In this Review, we provide an update on genome-wide association studies (GWAS) in inflammatory bowel disease (IBD). In addition, we summarize progress in defining the functional consequences of associated alleles for coding and non-coding genetic variation. In the small minority of loci where major association signals correspond to non-synonymous variation, we summarize studies defining their functional effects and implications for therapeutic targeting. Importantly, the large majority of GWAS-associated loci involve non-coding variation, many of which modulate levels of gene expression. Recent expression quantitative trait loci (eQTL) studies have established that expression of the large majority of human genes is regulated by non-coding genetic variation. Significant advances in defining the epigenetic landscape have demonstrated that IBD GWAS signals are highly enriched within cell-specific active enhancer marks. Studies in European ancestry populations have dominated the landscape of IBD genetics studies, but increasingly, studies in Asian and African-American populations are being reported. Common variation accounts for only a modest fraction of the predicted heritability and the role of rare genetic variation of higher effects (i.e. odds ratios markedly deviating from one) is increasingly being identified through sequencing efforts. These sequencing studies have been particularly productive in very-early onset, more severe cases. A major challenge in IBD genetics will be harnessing the vast array of genetic discovery for clinical utility, through emerging precision medicine initiatives. We discuss the rapidly evolving area of direct to consumer genetic testing, as well as the current utility of clinical exome sequencing, especially in very early onset, severe IBD cases. We summarize recent progress in the pharmacogenetics of IBD with respect of partitioning patient responses to anti-TNF and thiopurine therapies. Highly collaborative studies across research centers and across subspecialties and disciplines will be required to fully realize the promise of genetic discovery in IBD.

Paneth cell defects in Crohn’s disease patients promote dysbiosis

“…While it is possible that the sample size was too small to detect a correlation, it is also possible that additional genes involved in the development of CD in these patients also affect the development of Type I Paneth cell phenotype. Compared to adult CD, genetics plays a more important pathogenic role in pediatric CD, in particular those with very early onset disease (42)(43)(44), although in mouse models the Paneth cell antimicrobial function is independent of Nod2 (45). Thus, it is possible that additional CD susceptibility genes may cause the Paneth cell defect.…”

Evaluation of tumor necrosis factor (TNF)-α mRNA expression level and the rs1799964 polymorphism of the TNF-α gene in peripheral mononuclear cells of patients with inflammatory bowel diseases

“…The exact causes of this disease remains unknown, but studies have proposed that it may be the result of complex interactions between multiple factors, such as genetic, environmental and immunological factors (8,9). There is direct evidence for the role of genetics in IBD, associated with the family history of patients, as well as increased rates of IBD in monozygotic twins (10,11). The predominant genetic association in IBD is divided into genes that contribute to innate and adaptive immune responses (12).…”

The gut microbiota of siblings offers insights into microbial pathogenesis of inflammatory bowel disease

“…Genotype contributes to CD pathogenesis 35 and in addition the composition of the gut microbiota is partly determined by genotype. 36 In our study we demonstrated that genotype relative risk (a composite score of genotypic risk across 72 loci associated with CD) was the most significant factor in explaining variance between the 3 cohorts, (patients, healthy siblings and healthy, unrelated controls) and also within each cohort.…”