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Progress in Genomic Research in Inflammatory Bowel Disease

Dermot P. B. McGovern, MD, PhD; Gil Y. Melmed, MD

The academic world of genetic research has been dominated by genome-wide association studies (GWAS), and genetic research in inflammatory bowel disease (IBD) has been no exception -- the publication of individual and meta-analyses of GWAS have led to significant advances in our understanding of the pathogenesis of IBD.
The Power of GWAS

Two recently published GWAS meta-analyses[1,2] have identified more than 30 genetic regions that increase susceptibility to both ulcerative colitis (UC) and Crohn's disease (CD). Furthermore, the UC study[2] demonstrated that more than 50% of genes for UC were already known to be associated with CD.

At Digestive Disease Week (DDW) 2010, The International IBD Genetics Consortium presented 2 studies[3,4] that continue the recent trend of combining individual genetic studies, thereby increasing statistical power and strengthening the gene-disease association.

The first study[3] presented a meta-analysis of CD GWAS of more than 6000 CD cases and 15,000 controls, as well as a replication cohort of nearly 15,000 CD cases and more than 14,000 controls from centers in North America, Europe, and Australasia. All of the individuals studied were of Northern European descent.

Of the nearly 1 million single nucleotide polymorphisms (SNPs) examined in this study, 52 new loci were associated with CD at a P value of < 1 x 10-5 in the index cohort. Thirty-three of these were confirmed to be associated with CD when tested in the independent replication cohort, achieving a combined P value of < 5.0 x 10-8, which is widely recognized by statisticians as the mark for achieving "genome-wide significance" -- ie, accounting for the multiple statistical comparisons involved in looking at the whole genome.

These newly identified genetic regions, when taken together with those previously identified, bring the known CD susceptibility loci to a total of 65. Remarkably, initial analyses suggest that these loci account for less than 25% of the genetic contribution to CD in this population -- a calculation that is likely to be an underestimate.

A number of interesting new genes were implicated in this study, including genes associated with other autoimmune conditions such as celiac disease (TAGAP), type 1 diabetes (IL2RA, TAGAP), ankylosing spondylitis (ERAP1), multiple sclerosis (IL2RA), asthma (DENND1B), and rheumatoid arthritis (TAGAP), suggesting a common shared biological pathway across inflammatory diseases. Pathways (such as the IL23/IL17 pathway, which had been previously identified as important in IBD) were further implicated, with associations seen between CD susceptibility and SMAD3 and TYK2, which are known to influence regulation of this pathway.

The same consortium presented data on a similarly designed study in UC consisting of over 50,000 cases and controls.[4] Preliminary analysis identified 21 new loci for UC and suggested that approximately half of the UC loci were shared with CD and one quarter were shared with other inflammatory conditions. These new loci implicated epithelial tight junctions (GA12) and further implicated the IL23/Th17 pathway (EST1) as important processes in UC pathogenesis.
Moving Beyond GWAS

It is widely accepted that GWAS are the first step in identifying genes in complex diseases and that, once a locus has been identified, studies including fine-mapping (a more intensive genetic analysis of the implicated region), as well as expression and functional studies are a natural extension of the research.

One study presented at DDW 2010[5] focused on fine-mapping one of the previously identified CD GWAS loci at 10q21, implicating a nonsynonymous SNP in the ZNF365 as the likely CD susceptibility polymorphism at this locus. The implicated SNP is located in an isoform of the protein that the authors demonstrated is expressed in both inflamed and noninflamed small bowel and colonic tissue. ZNF365 is a likely transcription factor, but very little is so far known about its function, highlighting the considerable amount of work required to follow up on GWAS-implicated loci.

A very well-conducted candidate gene study that identified RAC1 as a likely CD susceptibility gene[6] highlights the increased understanding of the pathogenesis of this disease. Recent work suggested that RAC1 may be involved in reactive oxygen species-associated microbicidal functions, and that it may also be an important mediator in the therapeutic pathways of thiopurines.[7] The data presented at DDW 2010 fit neatly with previous findings implicating defects in the innate immune system in the pathogenesis of CD. They also suggest that a susceptibility locus may also have a pharmacogenetic role in IBD, although this remains to be investigated.

These studies underscore the rapid pace of genetic discovery in IBD, but the actual clinical benefits that these discoveries might yield, as yet, remain elusive.

1. Barrett JC, Hansoul S, Nicolae DL, et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet. 2008;40:955-962.
2. McGovern DP, Gardet A, Törkvist L, et al. Genome-wide association identifies multiple ulcerative colitis susceptibility loci. Nat Genet. 2010;42:332-337.
3. Parkes M, McGovern DP, Franke A, et al. 18 new Crohn's disease susceptibility genes and loci identified by the International IBD Genetics Consortium. Digestive Disease Week 2010; May 1-5, 2010; New Orleans, Louisiana. Abstract 847v.
4. Rioux JD. International IBD Genetics Consortium identifies over 50 genetic risk factors for ulcerative colitis. Digestive Disease Week 2010; May 1-5, 2010; New Orleans, Louisiana. Abstract 847f.
5. Haritunians T, Jones MR, McGovern DP, et al. Variants in Znf365 on 10q21 are associated with Crohn's disease. Digestive Disease Week 2010; May 1-5, 2010; New Orleans, Louisiana. Abstract 30.
6. Muise AM, Walters TD, Xu W, et al. The GTPase RAC1 is associated with inflammatory bowel disease. Digestive Disease Week 2010; May 1-5, 2010; New Orleans, Louisiana. Abstract 33.
7. Wu W, Hsu YM, Bi L, Songyang Z, Lin X. CARD9 facilitates microbe-elicited production of reactive oxygen species by regulating the LyGDI-Rac1 complex. Nat Immunol. 2009;10:1208-1214.


To save time...Ask Dusty!
David, I'm certain you will continue to follow this research. If they find a practical application for any new knowledge gained from it....would you paraphrase the results for those of us (me) who are just too stupid to know wth they are talking about?:)

I'm glad you continue your research...it's good to have brains between me and the medical world!!! Thanks David!!