PNPLA3 rs738409, environmental factors and liver-related mortality in the US population

Background & aims: Little is known about the interplay between patatin-like phospholipase domain-containing protein 3 (PNPLA3 rs738409 C>G), environmental factors, and the risk of liver-related death (LRD).

Methods: A total of 4,361 adults were selected from NHANES III, 1991-1994. All participants were linked to the National Death Index until 2019 (mean follow-up: 23.2 years). LRD was the study outcome. Associations of PNPLA3, diet, light alcohol intake, smoking, and BMI (kg/m²) with LRD were examined using competing risk regression models.

Results: PNPLA3 G-allele was significantly associated with LRD (adjusted subhazard ratio [adj.sHR] 2.9, 95% CI 1.4-5.8). Light alcohol intake (adj.sHR 2.2, 95% CI 1.1-4.5), top quartiles of monounsaturated fat (adj.sHR 0.43, 95% CI 0.12-0.99), and cholesterol (adj.sHR 2.6, 95% CI 1.00-8.8) and coffee intake ≥3 cups/day (adj.sHR 0.05, 95% CI 0.06-0.10), former/current smoking (adj.sHR 1.8, 95% CI 1.2-2.6), BMI (adj.sHR 1.1, 95% CI 1.03-1.2), and healthy eating index (adj.sHR 0.96, 95% CI 0.93-0.98) were associated with LRD. Joint effects between PNPLA3 and environmental factors showed that the risk of LRD was significantly increased in carriers of the G-allele with light alcohol intake (adj.sHR 3.7), higher consumption (top quartile) of cholesterol (adj.sHR 4.1), former (adj.sHR 4.3) or current (adj.sHR 3.5) smoking, or BMI ≥30 (adj.sHR 4.0) kg/m². The effects of the G-allele on the risk of LRD were significantly attenuated in those with top quartile consumption of monounsaturated fat (adj.sHR 0.5) or ≥3 cups/day of coffee (adj.sHR 0.09). Healthy eating index was inversely associated with LRD across all PNPLA3 genotypes (adj.sHR 0.94, 0.96, and 0.97 for CC, CG, and GG, respectively).

Conclusions: PNPLA3 is associated with LRD and this relationship is significantly modified by anthropometric and environmental factors.

Impact and implications: Light alcohol intake, dietary factors (healthy eating index, monounsaturated fat, cholesterol), coffee intake, smoking status, and BMI are independently associated with the risk of liver-related death. The inherited increased risk of PNPLA3 rs738409 on the risk of liver-related death appears to be attenuated by healthy eating index, monounsaturated fat, and coffee intake, and exacerbated by light alcohol intake, smoking, and BMI. Reducing harmful environmental exposures and increasing healthy eating habits may help mitigate the risk of liver-specific mortality even in those with high genetic risk.