Abstract P111: A Mendelian Randomization Study of Alcohol Intake and Ischemic Stroke in a Han Chinese Population

Introduction: Observational studies have reported inconsistent relationships between alcohol intake and ischemic stroke risk. The ALDH2 gene encodes an enzyme critical for alcohol metabolism and can serve as an unconfounded proxy for alcohol intake. The current study examined the association between the ALDH2 gene and ischemic stroke among 11,753 Chinese participants. Hypothesis: This study hypothesized that carriers of the ALDH2 variant tend to drink less alcohol and thus have lower risk for ischemic stroke. Methods: The discovery stage included 999 ischemic stroke cases and 1,001 controls with no history of atherosclerotic disease. The ALDH2 gene was sequenced using the SOLiD 4hq platform. Variants with minor allele count (MAC) >10 were each tested for association with stroke using logistic regression models. Interactions between alcohol intake and ALDH2 variants were also tested. Aggregate analysis of rare variants (MAC <20) used the sequence kernel association test. Variants with P<1х10 -4 were replicated among 4,724 ischemic stroke cases and 5,029 controls from the China Stroke Project. Results: An interaction of alcohol drinking with the ALDH2 rs671 variant, which encodes an inactive aldehyde dehydrogenase isozyme that limits tolerability to alcohol, on ischemic stroke risk was identified using the 2 degree of freedom test (P=2.77х10 -5 , 3.66х10 -11 , and 1.01х10 -15 in discovery, replication and joint analyses, respectively). Among drinkers, each copy of the variant allele conferred decreased odds of ischemic stroke, with odds ratios (95% CI) of 0.38 (0.25, 0.60), 0.79 (0.69, 0.91), and 0.74 (0.65, 0.85) in discovery, replication and joint analyses, respectively. While no association between the variant allele and stroke was observed among non-drinkers in the discovery stage [odds ratio (95% CI): 1.00 (0.82, 1.23)], the protective relation persisted among non-drinkers in the replication and joint analyses [odds ratios (95% confidence interval): 0.77 (0.71, 0.84) and 0.80 (0.74, 0.87), respectively]. This inconsistency may have resulted from disparate frequencies of former drinkers included in the non-drinking groups. No additional variants were identified. Conclusions: This large-scale genomic study implicates increased alcohol intake as an etiologically relevant risk factor for ischemic stroke.