Abstract
Non-alcoholic fatty liver disease (NAFLD) is an increasingly common condition, strongly associated with the metabolic syndrome, that can lead to progressive hepatic fibrosis, cirrhosis and hepatic failure. Subtle inter-patient genetic variation and environmental factors combine to determine variation in disease progression. A common non-synonymous polymorphism in TM6SF2 (rs58542926 c.449 C>T, p.Glu167Lys) was recently associated with increased hepatic triglyceride content, but whether this variant promotes clinically relevant hepatic fibrosis is unknown. Here we confirm that TM6SF2 minor allele carriage is associated with NAFLD and is causally related to a previously reported chromosome 19 GWAS signal that was ascribed to the gene NCAN. Furthermore, using two histologically characterized cohorts encompassing steatosis, steatohepatitis, fibrosis and cirrhosis (combined n=1,074), we demonstrate a new association, independent of potential confounding factors (age, BMI, type 2 diabetes mellitus and PNPLA3 rs738409 genotype), with advanced hepatic fibrosis/cirrhosis. These findings establish new and important clinical relevance to TM6SF2 in NAFLD.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is an increasingly common condition, strongly associated with the metabolic syndrome, that can lead to progressive hepatic fibrosis, cirrhosis and hepatic failure
Consistent with our previously reported analysis[12], carriage of the PNPLA3 rs738409 minor allele was significantly associated with degree of steatosis in multivariate analysis adopting an additive model adjusted for gender, age at biopsy, BMI and presence of T2DM (b 1⁄4 0.192±0.056, 95% confidence interval (CI) 0.082–0.301; P 1⁄4 6.74 Â 10 À 4)
A variant within the NCAN gene that is in strong linkage disequilibrium (D0 1⁄4 0.926, r2 1⁄4 0.798) with TM6SF2 rs58542926 was reported to be associated with radiologically and histologically characterized NAFLD in both Genome-wide association studies (GWAS) and candidate-gene studies[9,21]
Summary
Non-alcoholic fatty liver disease (NAFLD) is an increasingly common condition, strongly associated with the metabolic syndrome, that can lead to progressive hepatic fibrosis, cirrhosis and hepatic failure. Using two histologically characterized cohorts encompassing steatosis, steatohepatitis, fibrosis and cirrhosis (combined n 1⁄4 1,074), we demonstrate a new association, independent of potential confounding factors (age, BMI, type 2 diabetes mellitus and PNPLA3 rs738409 genotype), with advanced hepatic fibrosis/cirrhosis. These findings establish new and important clinical relevance to TM6SF2 in NAFLD. C4G, p.Ile148Met), patatinlike phospholipase domain containing 3, has been validated across multiple patient cohorts[8,9,12,16] Carriage of this SNP has been robustly associated with steatosis and with clinically relevant factors, including severity of hepatic fibrosis/ cirrhosis and development of NAFLD-related HCC12,17,18
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
