Interactive effects of smoking and glutathione S-transferase polymorphisms on the development of non-alcoholic fatty liver disease

• High-risk GST genotypes with no/low enzyme activities influenced the risk for NAFLD.
• Never-smokers with high-risk GST genotypes were at high risk for NAFLD.
• The risk was further increased among current-smokers with high-risk GST genotypes.
• Current-smoking and high-risk GST genotypes were interactively associated the risk.
• Current-smoking status alone was not an independent risk factor for NAFLD.

Glutathione S-transferases (GSTs) protect cells against exogenous and endogenous oxidative stress. GST polymorphisms are associated with the development of cardiovascular disease (CVD) and diabetes mellitus (DM), especially in current-smokers. Non-alcoholic fatty liver disease (NAFLD) is a predictor of future CVD or DM, because oxidative stress contributes to their pathogenesis. This study investigated whether the combination of smoking status and GST genotypes could affect the risk for NAFLD. A cross-sectional analysis was conducted among 713 Japanese participants (458 males and 255 females) during a health screening program. The GSTM1 null, GSTT1 null, GSTP1 *A/*B or *B/*B and GSTA1 *A/*B or *B/*B genotypes were determined and deemed to be high-risk genotypes. The prevalence of NAFLD was 18.7%. Among never-smokers, carriers of one, and those of two or more high-risk GSTM1, GSTP1 or GSTA1 genotypes were at a higher risk for NAFLD than those who were not carriers [odds ratio (95% confidence interval): 2.6 (1.1–5.9) and 3.3 (1.3–8.1), respectively], and the risk was further increased among current-smokers [4.6 (1.6–13.0) and 5.4 (1.2–23.7), respectively]. This is the first report to show that the combination of current-smoking and harboring high-risk GSTM1, GSTP1 and/or GSTA1 genotypes is interactively associated with the risk of NAFLD.