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Abstract
Primary biliary cirrhosis (PBC), a chronic autoimmune liver disease, has been associated with increased incidence of osteoporosis. Intriguingly, two PBC susceptibility loci identified through genome-wide association studies are also involved in bone mineral density (BMD). These observations led us to investigate the genetic variants shared between PBC and BMD. We evaluated 72 genome-wide significant BMD SNPs for association with PBC using two European GWAS data sets (n = 8392), with replication of significant findings in a Chinese cohort (685 cases, 1152 controls). Our analysis identified a novel variant in the intron of the CLDN14 gene (rs170183, Pfdr = 0.015) after multiple testing correction. The three associated variants were followed-up in the Chinese cohort; one SNP rs170183 demonstrated consistent evidence of association in diverse ethnic populations (Pcombined = 2.43 × 10−5). Notably, expression quantitative trait loci (eQTL) data revealed that rs170183 was correlated with a decline in CLDN14 expression in both lymphoblastoid cell lines and T cells (Padj = 0.003 and 0.016, respectively). In conclusion, our study identified a novel PBC susceptibility variant that has been shown to be strongly associated with BMD, highlighting the potential of pleiotropy to improve gene discovery.
Highlights
Primary biliary cirrhosis (PBC) is the most common autoimmune liver disease that approximately affects 1 in 1000 women over the age of 401,2
We examine whether the genetic variants previously shown to be associated with bone mineral density (BMD) at genome-wide significance level predispose to PBC
Using two European PBC Genome-wide association studies (GWAS) data sets and a Chinese Han PBC cohort, we identified a novel variant in CLDN14 that is likely to have pleiotropic effect on PBC and BMD
Summary
Primary biliary cirrhosis (PBC) is the most common autoimmune liver disease that approximately affects 1 in 1000 women over the age of 401,2. Genome-wide association studies (GWAS) and fine-mapping studies have identified multiple PBC risk loci outside HLA8–12. Despite these advances, the majority of the genetic factors underlying susceptibility to PBC remain unknown[13]. MAPT, another gene associated with BMD confers risk of PBC12,18 This coincides with the observation from numerous GWAS studies that many genetic variants appear to have pleotropic effects[22]. We examine whether the genetic variants previously shown to be associated with BMD at genome-wide significance level predispose to PBC.
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