Dissecting the contribution of single nucleotide polymorphisms in CCR9 and CCL25 genomic regions to the celiac disease phenotype

Purpose and objectives: Given their role in homing immune cells to the intestine, CC motif chemokine receptor 9 (CCR9) and its specific ligand CC motif chemokine ligand 25 (CCL25) are interesting candidate genes for celiac disease. These genes are located in regions previously shown to be associated with or linked to celiac disease, but no investigations on their association with various celiac disease phenotypes have so far been conducted. Here we studied such associations of both genotyped and imputed single nucleotide polymorphisms (SNPs) with either regulatory function or exonic location of the CCR9 and CCL25 loci. Results: Exploiting a carefully phenotyped cohort of 625 celiac disease patients and 1817 non-celiac controls, we identified that multiple SNPs with predicted regulatory function (RegulomeDB score 0.05). Conclusions: We conclude that SNPs in the region of CCR9 and CCL25 with predicted functional effect or exonic localization likely contribute only modestly to various celiac disease phenotypes.Peer reviewe

Independent and cumulative coeliac disease-susceptibility loci are associated with distinct disease phenotypes

The phenotype of coeliac disease varies considerably for incompletely understood reasons. We investigated whether established coeliac disease susceptibility variants (SNPs) are individually or cumulatively associated with distinct phenotypes. We also tested whether a polygenic risk score (PRS) based on genome-wide associated (GWA) data could explain the phenotypic variation. The phenotypic association of 39 non-HLA coeliac disease SNPs was tested in 625 thoroughly phenotyped coeliac disease patients and 1817 controls. To assess their cumulative effects a weighted genetic risk score (wGRS39) was built, and stratified by tertiles. In our PRS model in cases, we took the summary statistics from the largest GWA study in coeliac disease and tested their association at eight P value thresholds (P-T) with phenotypes. Altogether ten SNPs were associated with distinct phenotypes after correction for multiple testing (P-EMP2 1.62 for having coeliac disease-related symptoms during childhood, a more severe small bowel mucosal damage, malabsorption and anaemia. PRS was associated only with dermatitis herpetiformis (P-T = 0.2, P-EMP2 = 0.02). Independent coeliac disease-susceptibility loci are associated with distinct phenotypes, suggesting that genetic factors play a role in determining the disease presentation. Moreover, the increased number of coeliac disease susceptibility SNPs might predispose to a more severe disease course.Peer reviewe