NAFLD‐related gene polymorphisms and all‐cause and cause‐specific mortality in an Asian population: the Shanghai Changfeng Study

Summary Background The PNPLA3 and TM6SF2 gene variants have been found to cause NAFLD with a favourable cardiovascular risk profile. Aims To investigate the effects of the NAFLD risk alleles on the all‐cause and cause‐specific mortality in 5581 Chinese adults. Methods The genome‐wide genotypes were detected using a genotyping array and serum lipoprotein profiles were examined using 1H NMR platform. Liver fat content (LFC) was measured using a quantitative ultrasound method. The vital status was determined using official registration data. Results Genome‐wide association analysis showed that a series of variants in PNPLA3 were associated with LFC, including rs738409 C>G variant (P = 8.6 × 10−7). Further analyses validated the associations of TM6SF2 rs58542926 C>T and MBOAT7 rs641738 C>T variants with NAFLD. During 29 425.1 person‐years of follow‐up, the overall mortality was 816 per 100 000 person‐years, where 299 deaths were attributable to cardiovascular disease and 85 to liver disease. The PNPLA3 rs738409 C>G variant was independently associated with increased liver‐specific mortality (P for trend = 0.034) but reduced cardiovascular mortality (P for trend = 0.047). A composite genetic‐predisposition score of PNPLA3, TM6SF2, and MBOAT7 risk alleles presented similar opposite effects on liver‐specific and cardiovascular mortality. Moreover, interactions of the NAFLD risk alleles with adiposity for liver‐specific mortality were found (Pinteraction G variant and its combination with TM6SF2 rs58542926 C>T and MBOAT7 rs641738 C>T variants increase liver‐specific mortality but reduce cardiovascular mortality in overweight/obese Chinese. Several gene variants, such as the PNPLA3 and TM6SF2 gene variants, have been found to cause NAFLD with a favorable cardiovascular risk profile. In the current study, the PNPLA3 rs738409 C>G variant and a composite effect of the major NAFLD‐related gene variants (PNPLA3, TM6SF2 and MBOAT7 variants) increased liver‐specific mortality but reduced cardiovascular mortality in Chinese adults. The presence of adiposity interacted with the major NAFLD‐related gene variants and might be a prerequisite for their effect on liver‐specific mortality. 1H‐NMR‐based lipoprotein examination indicated that the reduced serum VLDL1 concentration and its subsequent relative deficie