In this study, we demonstrated that a common ALDH2 genetic polymorphism was associated with progression to hypertension in a prospective Chinese cohort. The association was strongest in participants with heavy/moderate alcohol intake and was absent in participants who did not drink, indicating an interaction between ALDH2 genetic variation and alcohol consumption on hypertension risk. To our knowledge, this is the first prospective cohort study demonstrating that ALDH2 genetic polymorphism predicts development of hypertension in East Asian population.
Several cross-sectional studies and case–control association studies have consistently reported significant association between ALDH2 genetic polymorphisms and blood pressure and hypertension in East Asian population [10–16]. A recent meta-analysis including 7,658 subjects determined that the rs671 A allele was associated with a significantly lower odds ratio of hypertension and lower blood pressure. In our study, rs671 was associated with a significant increase of blood pressure and a trend of increased hypertension risk during follow-up. Another adjacent SNP rs2238152, which was in complete LD with rs671 (D' = 1), was associated with increased risk for incident hypertension but was not associated with significant changes in blood pressure. The discrepancy between association with hypertension risk and changes of blood pressure may be partly attributed to the confounding of antihypertensive medication. In a recent large GWAS meta-analysis for hypertension in east Asian, Kato, et al. reported a strong association signal ~ 0.5 Mb downstream the ALDH2 gene (P = 5.9 × 10-13). Daniel, et al. also reported strong association signal for diastolic blood pressure in the SH2B3 gene (P = 1.6 × 10-14) in a GWAS for hypertension in Caucasian. The SH2B3 gene is located in a large LD block spanning the ALDH2 gene . It is possible that the true causal variant is in LD with rs2238152 or rs671. Further fine mapping is needed to clarify the true causal variant.
We further explored the potential gene-environmental interaction between ALDH2 variants and environmental factors on hypertension risk. Alcohol intake modified the genetic effect of ALDH2 variant on hypertension risk. The mechanism underlying this interaction is currently unknown. Based on this observation, we propose that alcohol consumption level should be taken into account when ALDH2 genetic information is used to predict further hypertension risk. We further demonstrated that the risk allele was associated with lower ALDH2 gene expression in human adipose tissue. This suggested that the risk variant may influence the clinical phenotype though altered ALDH2 gene expression.
Our study has 3 unique strengths. First, population stratification is still a common concern of case–control association studies, which may lead to false positive results. The family-based design of SAPPHIRe essentially eliminates all potential population stratification. Second, case–control studies are often confounded by recall bias or ascertainment bias. This study is a prospective cohort study with comprehensive records of baseline exposures and thus is free of such bias. Third, the environmental exposures were comprehensively recorded in the SAPPHIRe study, making a thorough exploration for gene-environment interaction possible.
This study also has some limitations. First, this study is relatively small with limited incident case so that a chance finding is not unlikely. The power of this study to detect variants with small effect is also limited. Given the hypertension prevalence of 25% among the Chinese and a minor allele frequency of 0.25, the power to detect allelic odds ratios of 1.2, 1.5, and 2.0 for hypertension was 16.1%, 56.2%, and 95.1% respectively with type I error rate of 0.05. Second, the association between the rs2238152 genotype and progression to hypertension (P = 0.03) did not pass the significance threshold adjusted for multiple testing. For a type 1 error less than 5%, the study-wide significance threshold is estimated to be 0.02 after correction for the LD between each SNP . However, previous cross-sectional or case–control studies had demonstrated significant association between ALDH2 variants and hypertension. From a Bayesian point of view, the prior probability is already high and therefore stringent correction for multiple testing may not be necessary.