Abstract
BackgroundThe recent genome-wide association studies (GWAS) in inflammatory bowel disease (IBD) suggest significant genetic overlap with complex mycobacterial diseases like tuberculosis or leprosy. TLR variants have previously been linked to susceptibility for mycobacterial diseases. Here we investigated the contribution to IBD risk of two TLR2 polymorphisms, the low-prevalence variant Arg753Gln and the GTn microsatellite repeat polymorphism in intron 2. We studied association with disease, possible correlations with phenotype and gene-gene interactions.Methodology/Principal findingsWe conducted a large study in 843 patients with Crohn’s disease, 426 patients with ulcerative colitis and 805 healthy, unrelated controls, all of European origin. Overall, the frequency for carriers of shorter GTn repeats in intron 2 of the TLR2 gene, which have previously been associated with low TLR2 expression and high IL-10 production, was slightly elevated in Crohn’s disease and ulcerative colitis compared to healthy controls (16.0% resp. 16.7% vs. 12.8%). The highest frequency of short GTn carriers was noted among IBD patients on anti TNF-alpha therapy. However, none of these differences was significant in the multivariate analysis. The Arg753Gln polymorphism showed no association with any clinical subtype of IBD, including extensive colitis, for which such an association was previously described. We found no association with specific phenotypic disease subgroups. Also, epistasis analysis revealed no significant interactions between the two TLR2 variants and confirmed IBD susceptibility genes.ConclusionsThe two functional relevant polymorphisms in TLR2, the GTn microsatellite repeat polymorphism in intron 2 and the Arg753Gln variant do not seem to play a role in the susceptibility to Crohn’s disease or ulcerative colitis.
Highlights
Among complex diseases some of the most notable progress has been made in the genetic characterisation of the inflammatory bowel diseases (IBD) Crohn’s disease (CD) and ulcerative colitis (UC)
Besides shared loci for IBD and other immune-mediated disorders such as psoriasis and ankylosing spondylitis, one of the key findings of the latest meta-analyses of the genome-wide association studies (GWAS) and ImmunoChip data is a considerable overlap between susceptibility for IBD and mycobacterial infection: six of the eight known autosomal genes linked to Mendelian susceptibility to mycobacterial disease are located within IBD loci; as regards complex mycobacterial disease, seven CD susceptibility genes overlap with leprosy susceptibility genes [1]
In the present study we examined in a large European population the contribution to susceptibility for IBD of two such variations of the TLR2 gene, the low-prevalence variant Arg753Gln and the GTn microsatellite repeat polymorphism in intron 2
Summary
Among complex diseases some of the most notable progress has been made in the genetic characterisation of the inflammatory bowel diseases (IBD) Crohn’s disease (CD) and ulcerative colitis (UC). Because of the ability of TLRs to recognise particular molecular patterns of diverse microorganisms, their contribution to disease susceptibility has been studied for various mycobacterial diseases as well as for IBD. Functional polymorphisms in TLR2, which result in impaired response to bacterial lipoproteins or influence promotor activity [6, 7], have been repeatedly associated with susceptibility to mycobacterial disease [8] and other infectious conditions [9] as well as common conditions such as atopic sensitization in the general population [10]. The recent genome-wide association studies (GWAS) in inflammatory bowel disease (IBD) suggest significant genetic overlap with complex mycobacterial diseases like tuberculosis or leprosy. We studied association with disease, possible correlations with phenotype and genegene interactions
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