Alcohol intake and cardiovascular risk factors:A Mendelian randomisation study

Mendelian randomisation studies from Asia suggest detrimental influences of alcohol on cardiovascular risk factors, but such associations are observed mainly in men. The absence of associations of genetic variants (e.g. rs671 in ALDH2) with such risk factors in women – who drank little in these populations – provides evidence that the observations are not due to genetic pleiotropy. Here, we present a Mendelian randomisation study in a South Korean population (3,365 men and 3,787 women) that 1) provides robust evidence that alcohol consumption adversely affects several cardiovascular disease risk factors, including blood pressure, waist to hip ratio, fasting blood glucose and triglyceride levels. Alcohol also increases HDL cholesterol and lowers LDL cholesterol. Our study also 2) replicates sex differences in associations which suggests pleiotropy does not underlie the associations, 3) provides further evidence that association is not due to pleiotropy by showing null effects in male non-drinkers, and 4) illustrates a way to measure population-level association where alcohol intake is stratified by sex. In conclusion, population-level instrumental variable estimation (utilizing interaction of rs671 in ALDH2 and sex as an instrument) strengthens causal inference regarding the largely adverse influence of alcohol intake on cardiovascular health in an Asian population

Exploiting horizontal pleiotropy to search for causal pathways within a Mendelian randomization framework

In Mendelian randomization (MR) analysis, variants that exert horizontal pleiotropy are typically treated as a nuisance. However, they could be valuable in identifying alternative pathways to the traits under investigation. Here, we developed MR-TRYX, a framework that exploits horizontal pleiotropy to discover putative risk factors for disease. We begin by detecting outliers in a single exposure-outcome MR analysis, hypothesising they are due to horizontal pleiotropy. We search across hundreds of complete GWAS summary datasets to systematically identify other (candidate) traits that associate with the outliers. We developed a multi-trait pleiotropy model of the heterogeneity in the exposure-outcome analysis due to pathways through candidate traits. Through detailed investigation of several causal relationships, many pleiotropic pathways are uncovered with already established causal effects, validating the approach, but also alternative putative causal pathways. Adjustment for pleiotropic pathways reduces the heterogeneity across the analyses

Burdens of cardiometabolic diseases attributable to dietary and metabolic risks in Korean adults 2012–2013

PURPOSE: In line with epidemiological and sociocultural changes in Korea over the past decades, reliable estimation of diseases as a result of dietary and metabolic risks is required. In this study, we aimed to evaluate the contributions of dietary and metabolic factors to cardiometabolic diseases (CMDs) in Korean adults (25–64 years old) during 2012–2013. MATERIALS AND METHODS: Distribution of risk factors and cause-specific mortality by gender and age per year was obtained from the Korea National Health and Nutrition Examination Survey and Statistics Korea, respectively. The association between the two was obtained from published meta-analyses. The population-attributable fraction attributable to the risk factors was calculated across gender and age strata (male and female, age groups 25–34, 35–44, 45–54, and 55–64) in 2012 and 2013. RESULTS: The results showed that during the period studied, high body mass index [5628 deaths; uncertainty intervals (UIs): 5473–5781] and blood pressure (4202 deaths; UIs: 3992–4410) were major metabolic risks for CMD deaths, followed by dietary risks such as low intake of whole grain (4107 deaths; UIs: 3275–4870) and fruits (3886 deaths; UIs: 3227–4508), as well as high intake of sodium (2911 deaths, UIs: 2406–3425). Also, males and the younger population were seen more prone to be exposed to harmful dietary risk than their female and older counterparts. CONCLUSION: The findings provide the necessary information to develop targeted government interventions to improve cardiometabolic health at the population level

Genetic influences on alcohol flushing in East Asian populations

Background Although it is known that variation in the aldehyde dehydrogenase 2 (ALDH2) gene family influences the East Asian alcohol flushing response, knowledge about other genetic variants that affect flushing symptoms is limited. Methods We performed a genome-wide association study meta-analysis and heritability analysis of alcohol flushing in 15,105 males of East Asian ancestry (Koreans and Chinese) to identify genetic associations with alcohol flushing. We also evaluated whether self-reported flushing can be used as an instrumental variable for alcohol intake. Results We identified variants in the region of ALDH2 strongly associated with alcohol flushing, replicating previous studies conducted in East Asian populations. Additionally, we identified variants in the alcohol dehydrogenase 1B (ADH1B) gene region associated with alcohol flushing. Several novel variants were identified after adjustment for the lead variants (ALDH2-rs671 and ADH1B-rs1229984), which need to be confirmed in larger studies. The estimated SNP-heritability on the liability scale was 13% (S.E. = 4%) for flushing, but the heritability estimate decreased to 6% (S.E. = 4%) when the effects of the lead variants were controlled for. Genetic instrumentation of higher alcohol intake using these variants recapitulated known associations of alcohol intake with hypertension. Using self-reported alcohol flushing as an instrument gave a similar association pattern of higher alcohol intake and cardiovascular disease-related traits (e.g. stroke). Conclusion This study confirms that ALDH2-rs671 and ADH1B-rs1229984 are associated with alcohol flushing in East Asian populations. Our findings also suggest that self-reported alcohol flushing can be used as an instrumental variable in future studies of alcohol consumption. Trial registration This study only used secondary data

Proteome-wide Mendelian randomization in global biobank meta-analysis reveals multi-ancestry drug targets for common diseases

Proteome-wide Mendelian randomization (MR) shows value in prioritizing drug targets in Europeans but with limited evidence in other ancestries. Here, we present a multi-ancestry proteome-wide MR analysis based on cross-population data from the Global Biobank Meta-analysis Initiative (GBMI). We estimated the putative causal effects of 1,545 proteins on eight diseases in African (32,658) and European (1,219,993) ancestries and identified 45 and 7 protein-disease pairs with MR and genetic colocalization evidence in the two ancestries, respectively. A multi-ancestry MR comparison identified two protein-disease pairs with MR evidence in both ancestries and seven pairs with specific effects in the two ancestries separately. Integrating these MR signals with clinical trial evidence, we prioritized 16 pairs for investigation in future drug trials. Our results highlight the value of proteome-wide MR in informing the generalizability of drug targets for disease prevention across ancestries and illustrate the value of meta-analysis of biobanks in drug development

Exploring the utility of alcohol flushing as an instrumental variable for alcohol intake in Koreans

Abstract Previous studies have indicated an association of higher alcohol intake with cardiovascular disease and related traits, but causation has not been definitively established. In this study, the causal effect of alcohol intake on hypertension in 2,011 men and women from the Ansan-Ansung cohort was estimated using an instrumental variable (IV) approach, with both a phenotypic and genotypic instrument for alcohol intake: alcohol flushing and the rs671 genotype (in the alcohol dehydrogenase 2 [ALDH2] gene), respectively. Both alcohol flushing and the rs671 genotype were associated with alcohol intake (difference in alcohol intake with alcohol flushers vs. non-flushers: −9.07 g/day; 95% confidence interval [CI]: −11.12, −7.02; P-value: 8.3 × 10−18 and with the rs671 GA + AA vs. GG genotype: −7.94 g/day; 95% CI: −10.20, −5.69; P-value: 6.1 × 10−12). An increase in alcohol intake, as predicted by both the absence of alcohol flushing and the presence of the rs671 GG genotype in the IV analyses, was associated with an increase in blood pressure in men from this Korean population. In conclusion, this study supports a causal effect of alcohol intake on hypertension and indicated that alcohol flushing may be a valid proxy for the ALDH2 rs671 polymorphism, which influences alcohol intake in this Korean population