ausblenden:
Schlagwörter:
primary sclerosing cholangitis; genome-wide association study; single nucleotide polymorphism; immunogenetics.
Zusammenfassung:
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 influence 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 of microbiota on biliary
pathology in PSC.
