Abstract
Recent genome-wide association studies have identified that variants in or near PNPLA3, NCAN, GCKR, LYPLAL1, and TM6SF2 are significantly associated with non-alcoholic fatty liver disease (NAFLD) in multiple ethnic groups. Studies on their impact on NAFLD in Han Chinese are still limited. In this study, we examined the relevance of these variants to NAFLD in a community-based Han Chinese population and further explored their potential joint effect on NAFLD. Six single nucleotide polymorphisms (SNPs) (PNPLA3 rs738409, rs2294918, NCAN rs2228603, GCKR rs780094, LYPLAL1 rs12137855, and TM6SF2 rs58542926) previously identified in genome-wide analyses, to be associated with NAFLD were genotyped in 384 NAFLD patients and 384 age- and gender-matched healthy controls. We found two out of the six polymorphisms, PNPLA3 rs738409 (OR = 1.52, 95%CI: 1.19–1.96; P = 0.00087) and TM6SF2 rs58542926 (OR = 2.11, 95%CI: 1.34–3.39; P = 0.0016) are independently associated with NAFLD after adjustment for the effects of age, gender, and BMI. Our analysis further demonstrated the strong additive effects of the risk alleles of PNPLA3 and TM6SF2 with an overall significance between the number of risk alleles and NAFLD (OR = 1.64, 95%CI: 1.34–2.01; P = 1.4 × 10-6). The OR for NAFLD increased in an additive manner, with an average increase in OR of 1.52 per additional risk allele. Our results confirmed that the PNPLA3 and TM6SF2 variants were the most significant risk alleles for NAFLD in Chinese population. Therefore, genotyping these two genetic risk factors may help identify individuals with the highest risk of NAFLD.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder, whose prevalence is estimated to be 20–30% in Western industrialized countries (Bedogni et al, 2005)
Using a cohort of 384 nonalcoholic fatty liver disease (NAFLD) patients and 384 age- and gendermatched healthy controls, we confirmed that patatin-like phospholipase domain-containing3 (PNPLA3) rs738409 and transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 were independent risk factors conferred susceptibility to NAFLD in a Han Chinese population
To our best of knowledge, this is the first study to report the additive effect of PNPLA3 rs738409 and TM6SF2 rs58542926 polymorphisms on NAFLD in a Chinese population
Summary
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder, whose prevalence is estimated to be 20–30% in Western industrialized countries (Bedogni et al, 2005). The first genome-wide association study (GWAS) of NAFLD performed by Romeo et al (2008) identified that rs738409 G allele of the patatin-like phospholipase domain-containing (PNPLA3) is significantly associated with increased hepatic fat levels and susceptibility to NAFLD. A multiethnic study consisting of 957 obese children and adolescents showed that the allele frequency and effect size of TM6SF2 rs58542926 in conferring NAFLD risk varies in Caucasians, African Americans, and Hispanics (Goffredo et al, 2016). It is worthwhile examining the association of these variants with NAFLD in different ethnic settings. How these variants interact with each other and contribute together to the NAFLD susceptibility among each ethnic group remains to be explored
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