COMMENTARY

Genetic Underpinnings of IBD: Immunity, Infection, and More

Dermot P.B. McGovern, MD, PhD

Disclosures

January 10, 2013

Host–Microbe Interactions Have Shaped the Genetic Architecture of Inflammatory Bowel Disease

Jostins L, Ripke S, Weersma RK, et al
Nature. 2012;491:119-124

Summary

The study by the International IBD Genetics Consortium published in Nature continues the trail-blazing efforts in inflammatory bowel disease (IBD) genetics within the field of complex disease genetics by extending the number of known IBD susceptibility loci to more than 160. Yet, while this number is truly staggering, achieving this number is not the most thought-provoking finding from this study.

The consortium performed a meta-analysis of previously published IBD genome-wide association scans and used the recently developed Immunochip platform as a vehicle for replicating the initial findings.

The Immunochip genotyping chip (Illumina; San Diego, California) was originally developed when it became increasingly obvious that many immune-related diseases "shared" genetic susceptibility loci. The groups studying these conditions combined their knowledge to produce a custom chip of approximately 200,000 single nucleotide polymorphisms (SNPs) that had previously been shown to be important in at least one of the following immune-related conditions: type 1 diabetes, autoimmune thyroid disease, ankylosing spondylitis, Crohn disease (CD), celiac disease, immunoglobulin A deficiency, multiple sclerosis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and ulcerative colitis (UC). Of most importance, not only was this chip enriched for immune-related genetic variants, it was marketed for approximately $40, allowing many thousands of samples to be included in a very cost-effective manner. Accordingly, the 2-tiered study by the IBD Genetics Consortium included samples from more than 75,000 subjects, which provided enough statistical power to expand to 163 loci.

One of the most striking findings was the significant overlap in loci shared between UC and CD: 110 of the 163 loci were shared between UC and CD, with only 30 loci CD-specific and 23 UC-specific. These findings support the epidemiologic evidence that a family history of CD also leads to an increased risk for UC and vice versa. At the same time, however, the amount of variance, which is an estimate of the amount of disease explained by the findings, increased from 8.2% to 13.6% in CD and from 4.1% to 7.5% in UC, suggesting that a very significant amount of work is still needed to explain the "missing heritability."

Overall, these 163 loci contain more than 600 genes. Although analyses of existing expression and genetic databases reduced the number of candidate genes to about 300, it is clear that significant amounts of genetic fine-mapping, expression, functional, and other studies are still needed to unravel their role in IBD pathogenesis.

Another striking finding of this study was that approximately 70% of the IBD loci show association with other diseases. There was the expected overlap with other immune-related conditions including type 1 diabetes, ankylosing spondylitis, and psoriasis but there was also overlap with primary immune deficiencies as well as a very striking overlap with mycobacterial disease loci. Indeed, 6 of the 8 known loci for the mendelian susceptibility to mycobacterial disease and 7 of the 8 known susceptibility loci for leprosy overlap with IBD loci -- and in 6 of the loci shared by leprosy and IBD, the exact same SNPs have been implicated.

However, before we assume that this implicates mycobacteria directly in the pathogenesis of IBD, it is important to note that the SNP disease associations do not necessarily occur in the same direction (ie, whereas NOD2 and STAT3 SNPs increase susceptibility for both IBD and leprosy, IFNGR2 decreases susceptibility for IBD but increases susceptibility for leprosy).

Viewpoint

This seminal paper, as is often the case, raises as many questions as it answers. However, it has provided researchers with a rich framework on which to lay their future studies into the pathogenesis of IBD. Furthermore, it has provided some unique insights into overlaps between IBD and other immune conditions and also suggested novel processes/pathways that are involved in the development of chronic, recurring gastrointestinal inflammation.

Perhaps the most intriguing finding is the overlap with mycobacterial disease. This is likely to reinvigorate the debate of the role of these organisms in IBD, although the data in this paper (and elsewhere) suggest that this relationship is likely to be much more complicated than simply causative. Nevertheless, these data clearly highlight the importance of studying the microbiome and its role in IBD in conjunction with an understanding of the host's genetic profile.

Finally, it is worth noting that this paper is a testament to the benefits of large-scale and collegiate collaboration from groups across the globe. The authors should be commended for their approach to these complex diseases.

Abstract

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