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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 < 0.05). The reduced serum VLDL1 concentration was responsible for the increased liver‐specific mortality related to NAFLD risk alleles. Conclusion: The PNPLA3 rs738409 C>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. [ABSTRACT FROM AUTHOR]

LINKED CONTENT: This article is linked to Xia et al papers. To view these articles, visit https://doi.org/10.1111/apt.16772 and https://doi.org/10.1111/apt.16818 [ABSTRACT FROM AUTHOR]