From among the 40 IBD-associated SNPs that were investigated, only 16 demonstrated significantly different allele frequencies between UC/IBDU and CD. Most of the difference is found in genes related to the innate immunity, pattern recognition, or autophagy pathways and the HLA Class II locus. This adds to the mounting evidence that bacterial sensing mechanisms (NOD2) and the processing of bacterial components (autophagy) which leads to impaired bacterial clearance is likely more important in CD than in UC.6,10
In contrast, in our sample of CD and UC/IBDU patients, gene variants that were previously associated with IBD and putatively play a role in the immune response amplification and perpetuation, including the IL-23/Th17 pathways and genes involved in barrier function, were similar in their prevalence between UC/IBDU and CD. Fourteen out of the 18 SNPs (78%) related to these pathogenetic pathways were similar in their frequencies. Our findings support previous reports that implicated genetic variations in several inflammatory pathways in the pathogenesis of both UC and CD. For example, GWA studies in CD and UC have identified variants in the IL-23 pathway, which plays an important role in the promotion and synthesis of Th1 and Th17 cytokines and further extension of the local immune response and tissue damage in IBD25
. Specifically, the IL23 receptor gene, IL12B
gene, which encodes and p40 subunit of IL-12, and STAT3
and been associated with both UC and CD.26–28
Even more recently, a GWAS in a very large European UC cohort identified an association between another IL17 pathway gene (IL17REL
) and UC.29
This is further corroborated by functional studies wherein most of the Th17/IL-23 axis related cytokines were increased in both UC and CD compared to healthy controls.30
Other genes that have a role in the bridging between early innate immune response and late adaptive immune response such as TNFSF1531,32
and genes that may have a role in the orchestration and amplification of the inflammatory response33
have been associated in the past with both CD and UC—quite congruent with our findings in this IBD cohort.
Some prior genetic studies have described variations associated with both CD and UC. Franke et al34
investigated CD-associated loci in a German cohort of UC patients and found that gene variations in NKX2-3
that had been previously associated with CD35
also are associated with UC. Similarly, Fisher et al12
reported strong association of five previously CD-associated loci with UC (gene variations in the genes IL23R, MST1
, two SNPs within the IL12B
gene, and NKX2-3
). Another GWA study has also demonstrated association of other IL23 receptor gene associated loci in UC.13
Moreover, a recent meta-analysis demonstrated an association between UC and several previously associated CD SNPs in the autophagy genes ATG16L1
(rs2241880) and IRGM
These recent advances in the field of IBD genetics as well as in mucosal immunology have contributed significantly to our current understanding of the immunopathogenesis of IBD. While autophagy and bacterial sensing and processing mechanisms have been implicated in the pathogenesis of CD, the IL-23 pathway as well as the T-lymphocyte differentiation regulation through IL-17 producing T-helper regulatory cells have been associated with both CD and UC.31,33
In our CD patients with colonic involvement (Montreal L2) we were able to replicate the association of 11 of the 34 CD-associated SNPs, including one of the NOD2
variants. This is in contrast to previous reports that were not able to show an association between many of the CD-associated loci37
and, in particular, NOD2
and colon-only CD. This observation may be explained in part by our young patient population and the well-recognized phenomenon seen in early-onset CD where a colon predominant location precedes the evolution to ileal involvement.40
variants have been associated not only with ileal CD but also with ileocolonic CD.41
Moreover, we did not find an association of NOD2
SNP 13 with colon-only CD, and this is the SNP that was repeatedly shown to be associated with ileal-only CD.
CD-affected individuals with colon-only involvement (Montreal L2) showed almost complete overlap with UC of the genotypes that were investigated, with 6/6 of UC SNPs and 5/6 shared SNPs showing similar frequencies in our colonic IBD patients. It may be that the relatively smaller sample size of our colon-only CD contributed to the lack of ability to discern significant differences in allele frequencies between UC and L2 CD. However, common genetic loci for colon-only CD and UC have been reported in the past. Several studies showed that specific HLA loci were associated with both types of IBD.42,43
Our results suggest that at least for the SNPs investigated, colonic CD and UC have common genetic basis-a finding that may explain the location predisposition in both UC and CD of the colon.
In summary, studying the difference in allele frequencies of CD- and UC-associated SNPs in a large cohort of patients with IBD from Canada showed that UC and CD overlap significantly in their genetic associations. It is likely that factors outside of inherited DNA polymorphisms account for the clinical variability seen in IBD, Moreover, it may be difficult to develop a panel of genetic markers that will reliably distinguish CD from UC. Instead, other dynamic biomarkers such as gene expression or microbiome signatures may be more useful for understanding the clinical variability in IBD. The results of this study extend the hypothesis that CD and UC share common genetic variants that are related to impaired adaptive immune response and diverge genetically in mechanisms that concern early events in foreign antigen recognition and cellular processing. It should be emphasized that studying SNP frequencies provide only indirect evidence to the different and common pathogenesis of CD and UC and further functional as well as replication studies should be conducted to substantiate and understand the pathogenesis of CD and UC.