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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.

Additive Effects of the Risk Alleles of PNPLA3 and TM6SF2 on Non-alcoholic Fatty Liver Disease (NAFLD) in a Chinese Population