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Context A recent meta-analysis of genome-wide association studies data from East Asians identified aldehyde dehydrogenase 2 (ALDH2) rs671 as a susceptibility variant for type 2 diabetes in males. Objective To investigate the association between ALDH2 rs671 and metabolic characteristics. Methods We studied 94 nonobese, nondiabetic, Japanese men. Using a 2-step hyperinsulinemic-euglycemic clamp, we evaluated insulin sensitivity in muscle and liver. Intrahepatic lipid and fat distribution were measured using 1H-magnetic resonance spectroscopy and magnetic resonance imaging, respectively. We divided participants into a risk-carrying group with ALDH2 rs671 G/G (n = 53) and a nonrisk-carrying group with ALDH2 rs671 G/A or A/A (n = 41). Results The risk-carrying group had significantly higher levels of alcohol consumption (18.4 [interquartile range, IQR, 10.4-48.9]) vs 12.1 (IQR, 1.3-29.0) g/day; P = .003), elevated fasting plasma glucose (FPG) (97.5 ± 7.9 vs 93.5 ± 6.2 mg/dL; P = .010), lower hepatic insulin sensitivity (61.7 ± 20.5% vs 73.1 ± 15.9%; P = .003), and lower fasting glucose clearance (0.84 ± 0.8 dL·m–2·min–1 vs 0.87 ± 0.09 dL·m–2·min–1; P = .047) than the nonrisk-carrying group, while insulin resistance in muscle and body fat distribution were similar. The single linear correlation analysis revealed significant correlations between alcohol consumption and hepatic insulin sensitivity (r = –0.262, P = .011), fasting glucose clearance (r = –0.370, P &amp;lt; .001), or FPG (r = 0.489, P &amp;lt; .001). The multiple regression analysis revealed that both ALDH2 rs671 G/G genotype and alcohol consumption were significant independent correlates for hepatic insulin sensitivity, whereas only alcohol consumption was a significant independent correlate for fasting glucose clearance. Conclusion Our data suggest that high-alcohol intake–dependent and independent hepatic insulin resistance and reduced fasting glucose clearance due to high alcohol intake could be a relatively upstream metabolic abnormality in ALDH2 rs671 G/G carriers.

ALDH2 rs671 Is Associated With Elevated FPG, Reduced Glucose Clearance and Hepatic Insulin Resistance in Japanese Men