NRF2 Genetic Polymorphism Modifies the Association of Plasma Selenium Levels With Incident Coronary Heart Disease Among Individuals With Type 2 Diabetes

Plasma selenium and NRF2 promoter variants (e.g., rs6721961) are associated with cardiovascular disease risk in the general population. However, epidemiological evidence on the interaction between plasma selenium and NRF2 genetic susceptibility in relation to incident coronary heart disease (CHD) risk remains scarce, especially among individuals with type 2 diabetes (T2D). Thus, we examined whether rs6721961 in the NRF2 gene might modify the association between plasma selenium levels and incident CHD risk among people with T2D. During a mean (SD) follow-up period of 6.90 (2.96) years, 798 incident CHD cases were identified among 2,251 T2D cases. Risk-allele carriers of rs6721961 had a higher risk of incident CHD among people with T2D (adjusted hazard ratio [HR] 1.17; 95% CI 1.02-1.35) versus nonrisk-allele carriers. Each 22.8-μg/L increase in plasma selenium levels was associated with a reduced risk of incident CHD among risk-allele carriers with T2D (HR 0.80; 95% CI 0.71-0.89), whereas no association was found in those without risk alleles (P for interaction = 0.004), indicating that the NRF2 promoter polymorphism might modify the association between plasma selenium levels and incident CHD risk among people with T2D. Our study findings suggest redox-related genetic variants should be considered to identify populations that might benefit most from selenium supplementation. More mechanistic studies are warranted.