Fatty liver causes premature death worldwide and requires long‐term health care. We examined relationships of liver disease markers, including patatin‐like phospholipase domain‐containing protein 3 (PNPLA3) I148M, with mortality in the U.S. National Health and Nutrition Examination Survey, 1988‐1994, with 27 years of linked mortality data.

We studied 13,298 viral hepatitis negative adults who fasted at least 4 hours using the nonalcoholic fatty liver disease (NAFLD) liver fat score and NAFLD fibrosis score. PNPLA3 I148M was genotyped in a subgroup of participants from 1991 to 1994 (n = 5,640). Participants were passively followed for mortality, identified by death certificate underlying or contributing causes, by linkage to the National Death Index through 2015. During follow‐up (median, 23.2 years), cumulative mortality was 33.2% overall and 1.1% with liver disease, including primary liver cancer. Increased liver disease mortality was associated with PNPLA3 I148M (hazard ratio [HR], 2.9; 95% confidence interval [CI], 0.9‐9.8) and 148M genotypes (HR, 18.2; 95% CI, 3.5‐93.8), an intermediate (HR, 3.8; 95% CI, 1.3‐10.7) or high (HR, 12.6; 95% CI, 4.3‐36.3) NAFLD liver fat score, and a high NAFLD fibrosis score (HR, 12.2; 95% CI, 1.9‐80.6) adjusted for risk factors. Survival curves suggest that increased mortality risk with two 148M alleles was greatest beginning in the second decade of follow‐up. Overall, but not cardiovascular disease, mortality was associated with the PNPLA3 148M allele, and both mortality outcomes were associated with higher fat and fibrosis scores.

In the U.S. population, PNPLA3 I148M and higher NAFLD liver fat and fibrosis scores were associated with increased liver disease mortality. Genetic variant PNPLA3 I148M may complement other liver disease markers for NAFLD surveillance.