Genetic variation in both innate and adaptive immune systems is associated with Crohn's disease (CD) susceptibility, but much of the heritability to CD remains unknown. We performed a genome-wide association study (GWAS) in 896 CD cases and 3204 healthy controls all of Caucasian origin as defined by multidimensional scaling. We found supportive evidence for 21 out of 40 CD loci identified in a recent CD GWAS meta-analysis, including two loci which had only nominally achieved replication (rs4807569, 19p13; rs991804, CCL2/CCL7). In addition, we identified associations with genes involved in tight junctions/epithelial integrity (ASHL, ARPC1A), innate immunity (EXOC2), dendritic cell biology [CADM1 (IGSF4)], macrophage development (MMD2), TGF-beta signaling (MAP3K7IP1) and FUT2 (a physiological trait that regulates gastrointestinal mucosal expression of blood group A and B antigens) (rs602662, P=3.4x10(-5)). Twenty percent of Caucasians are 'non-secretors' who do not express ABO antigens in saliva as a result of the FUT2 W134X allele. We demonstrated replication in an independent cohort of 1174 CD cases and 357 controls between the four primary FUT2 single nucleotide polymorphisms (SNPs) and CD (rs602662, combined P-value 4.90x10(-8)) and also association with FUT2 W143X (P=2.6x10(-5)). Further evidence of the relevance of this locus to CD pathogenesis was demonstrated by the association of the original four SNPs and CD in the recently published CD GWAS meta-analysis (rs602662, P=0.001). These findings strongly implicate this locus in CD susceptibility and highlight the role of the mucus layer in the development of CD.
BackgroundThe recently identified member of the TNF superfamily TL1A (TNFSF15) increases IFN-γ production by T cells in peripheral and mucosal CCR9+ T cells. TL1A and its receptor DR3 are up-regulated during chronic intestinal inflammation in ulcerative colitis and Crohn's disease (CD). TL1A gene haplotypes increase CD susceptibility in Japanese, European, and US cohorts.Methodology and Principal FindingsHere we report that the presence of TL1A gene haplotype B increases risk in Jewish CD patients with antibody titers for the E. coli outer membrane porin C (OmpC+) (Haplotype B frequency in Jewish CD patients: 24.9% for OmpC negative and 41.9% for OmpC positive patients, respectively, P≤0.001). CD14+ monocytes isolated from Jewish OmpC+ patients homozygous for TL1A gene haplotype B express higher levels of TL1A in response to FcγR stimulation, a known inducing pathway of TL1A, as measured by ELISA. Furthermore, the membrane expression of TL1A is increased on peripheral monocytes from Jewish but not non-Jewish CD patients with the risk haplotype.Conclusions and SignificanceThese findings suggest that TL1A gene variation exacerbates induction of TL1A in response to FcγR stimulation in Jewish CD patients and this may lead to chronic intestinal inflammation via overwhelming T cell responses. Thus, TL1A may provide an important target for therapeutic intervention in this subgroup of IBD patients.
The IL23/IL17 pathway is pivotal in the development of chronic mucosal inflammation seen in Crohn's disease (CD). Genetic variants in the IL23R and IL12B have been associated with CD susceptibility. We investigated ten genes within the IL23/IL17 pathway in a case-control study of 763 CD cases and 254 healthy controls. We identified novel association in haplotypes in IL17A (empirical p value = 0.02), IL17RA (p = 0.001), IL17RD (p = 0.001), IL12RB1 (p = 0.003) and IL12RB2 (p = 0.001) as well as confirming the association with IL12B variants (p = 0.003). The cumulative risk for carrying increased number of CD risk haplotypes from genes in this pathway rises to an odds ratio of 4.3 for carrying 5 risk haplotypes. We have previously demonstrated an association between this cohort and IL23R haplotypes. Pairwise analyses suggest that there is statistical interaction between variants in IL17A and IL23R (p = 0.047) and between variants in IL17RA and IL23R (p = 0.036). Furthermore, a significant association between CD and the widely replicated IL23R variants is only seen in the presence of IL17A or IL17RA variants. These data support the investigation of pathways implicated in CD pathogenesis in order to identify further susceptibility genes and also suggest that important gene-gene interaction is present in CD susceptibility.
CBir1 is a dominant antigen with a role in innate and adaptive immunity in mouse models of colitis and antibodies to CBir1 are associated with severe human Crohn’s disease. Our aim was to determine whether CBir1 stimulates innate and antigen-specific T-cell responses in Crohn’s disease. We demonstrate that CBir1 enhanced IL-6 and IL-1β production by peripheral blood (PB) monocytes. IL-6 was significantly increased in monocytes from Crohn’s disease compared to controls and ulcerative colitis. Anti-CBir1+ patients and IL-6 was inversely correlated. A significant increase in CBir1 specific peripheral T cell proliferation was more evident in cells from Crohn’s disease than controls and ulcerative colitis. CBir1 induced increased numbers of IFN-gamma+ cells in lamina propria mononuclear cells (LPMC) from Crohn’s disease compared to ulcerative colitis and controls. CBir1 induces enhanced peripheral innate, and peripheral and mucosal antigen-specific T-cell responses in Crohn’s disease. Consistent with results from the mouse, CBir1 immune activation could play a role in Crohn’s disease.
Despite recent advances the majority of IBD susceptibility 'genes' remain undiscovered. Recent data suggest that autoimmune conditions may 'share' susceptibility loci. Epidemiological evidence indicate an association between celiac disease and IBD and both conditions demonstrate increased gut permeability. MAGI2, recently implicated in UC and celiac disease, encodes a scaffolding protein involved in epithelial integrity. Our aim was to test MAGI2 variants for association with IBD and also their role in determining intermediate hereditary phenotypes defined by antibody production to microbial antigens. We genotyped 113 MAGI2 SNPs in 681 cases of Crohn's disease (CD), 259 ulcerative colitis (UC) cases and 195 controls. The most significant IBD association was in intron 6 (rs2160322, p=0.009)) and both UC (p=0.006) and CD (p=0.03) contributed to this association. The most significant CD association was with an intron 2 haplotype (rs7785088/rs323149/rs13246026, p=0.002). We observed highly significant associations with UC in intron 6 (rs7803276/rs7803705, p=0.002) and also significant associations in introns 2, 6 and 20. Significant associations were seen with: IgG ASCA positive CD in intron 3 (p=0.003), intron 6 (p=0.003), and intron 20 (p=0.001); anti-CBir1 positive CD in intron 3 (p=0.0001) and intron 6 (p=0.008); and anti-OMPc positive CD in intron 3 (p=0.0009), and intron 9 (p=0.007). Quantitative antibody levels were also associated with variants in intron 4 (anti-IgA ASCA, p=0.0003 and anti-IgG ASCA, p=0.0002). These findings support the significance of the epithelial barrier in IBD pathogenesis.
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