FUT2: filling the gap between genes and environment in Behçet's disease?

Abstract

Background Behçet’s disease (BD) is a multisystemic immune and inflammatory disorder whose aetiology remains unclear. In order to identify novel susceptibility loci, we performed the first genome-wide association study (GWAS) for BD in the Iranian population using a DNA pooling strategy. Methods Two replicate pools of 292 BD cases and of 294 age- and sex-matched controls were allelotyped in quadruplicate on the Affymetrix Human SNP Array 6.0 arrays. The SNPs were ranked by relative allele score difference between cases and controls and 47 out of the 51 top markers were technically validated through individually genotyping. Replication of validated SNPs was performed in an independent Iranian dataset of 684 cases and 532 controls. Results In addition to the HLA-B locus, rs7528842 in a gene desert on chromosome 1p21.2, and rs632111 at the 3´UTR of FUT2 were associated in both the discovery and replication datasets (individually and in combination). However, only the FUT2 SNP has been associated in a previous GWAS for BD in Turkish [Remmers et al., 2010; Kirino et al., 2013]. Fine-mapping of FUT2 in the full Iranian dataset revealed additional associations in 5 coding SNPs (2.97E-06<P<1.34E-04), including the rs601338 non-sense (W143X) variant which, in Caucasians, determines the secretion of the H antigen (precursor of the ABO blood group antigens) in body fluids and on the intestinal mucosa. Meta-analysis with the Turkish GWAS data strengthened the FUT2 associations (4.78E-09<P<1.66E-07). Discussion The non-secretor phenotype affects mucosal glycosylation, which may explain its known association with dysbiosis and altered susceptibility to infections. This different antigenic stimulation in early life and consequent increased propensity for auto-immunity and inflammation may contribute to BD development. While confirming the well-established association of the HLA-B locus with BD, this study established for the first time a putative link between genes and environment in the etiopathogenesis of BD.