Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci

Abstract

Background & Aims A limited number of genetic risk factors have been reported in primary sclerosing cholangitis (PSC). To discover further genetic susceptibility factors for PSC, we followed up on a second tier of single nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS). Methods We analyzed 45 SNPs in 1221 PSC cases and 3508 controls. The association results from the replication analysis and the original GWAS (715 PSC cases and 2962 controls) were combined in a meta-analysis comprising 1936 PSC cases and 6470 controls. We performed an analysis of bile microbial community composition in 39 PSC patients by 16S rRNA sequencing. Results Seventeen SNPs representing 12 distinct genetic loci achieved nominal significance (Preplication<0.05) in the replication. The most robust novel association was detected at chromosome 1p36 (rs3748816; Pcombined=2.1×10−8) where the MMEL1 and TNFRSF14 genes represent potential disease genes. Eight additional novel loci showed suggestive evidence of association (Prepl<0.05). FUT2 at chromosome 19q13 (rs602662; Pcomb=1.9×10−6, rs281377; Pcomb = 2.1×10−6 and rs601338; Pcomb=2.7×10−6) is notable due to its implication in altered susceptibility to infectious agents. We found that FUT2 secretor status and genotype defined by rs601338 significantly influences biliary microbial community composition in PSC patients. Conclusions We identify multiple new PSC risk loci by extended analysis of a PSC GWAS. FUT2 genotype needs to be taken into account when assessing the influence from microbiota on biliary pathology in PSC.

FUT 2 polymorphism and outcome in very-low-birth-weight infants

“…The polymorphism confers a nonsense mutation which results in a stop codon and subsequently leads to a nonfunctioning protein. The distribution of the polymorphism in our cohort is in concordance with existing literature (7,8). Mothers of 6.2% of enrolled infants had Asian, African, or unknown ethnicity and the infants were excluded from analysis.…”

“…As ethnic differences for FUT 2 genotype distribution have been previously noted, we decided to exclude infants with Asian (n = 48), African (n = 75), and unknown background (n = 37). The genotype frequencies in the remaining cohort of 2,406 infants were in the expected range for Caucasian populations (6)(7)(8) and appropriate to allele frequencies, as determined by Hardy-Weinberg equilibrium (FUT2 428 GG: n = 744, 30.9%; FUT2 428 GA: n = 1,193, 49.6%; FUT2 428 AA: n = 469, 19.5%). The power of this study to detect a difference in mortality rates between AA and AG/GG genotype groups was 99.9885% at the two-sided 5% test-level.…”

Genetically dictated change in host mucus carbohydrate landscape exerts a diet-dependent effect on the gut microbiota

“…Recent genome-wide association studies have implicated FUT2 in the pathogenesis of Crohn's disease, primary sclerosing cholangitis, celiac disease, and type-1 diabetes (13,14,33,34). Furthermore, nonsecretors at higher risk of Crohn's disease and primary sclerosing cholangitis have altered gut and biliary microbial communities compared with secretors: These nonsecretors exhibit changes in alpha diversity, increases in Firmicutes and decreases in Proteobacteria, as well as differences in Bacteroidetes, Actinobacteria, and Tenericutes in both the colonic and biliary microbiota (14,20).…”

“…The importance of this residue in host-pathogen interaction is suggested by the observation that susceptibility to infection with Norwalk (8) and respiratory viruses (9), Vibrio cholerae (10), Campylobacter jejuni (11), and Helicobacter pylori (12) is affected by secretor status. Recently, genome-wide association studies have found nonsecretors have increased susceptibility to chronic inflammatory conditions linked to the gut microbiota, such as Crohn's disease (13) and primary sclerosing cholangitis (14).…”

Microbial, metabolomic, and immunologic dynamics in a relapsing genetic mouse model of colitis induced by T-synthase deficiency

“…18,19 In humans, deficiency of FUT2 -which occurs in around 20% of individuals, termed "nonsecretors" -is associated with shifts in microbial composition in the colonic mucosa, feces, and bile. [20][21][22][23] Tsyn deficiency could similarly affect microbial composition by altering nutrient sources and disrupting attachment sites for the intestinal microbiota.…”