Objective To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease. Design Mendelian randomisation meta-analysis of 56 epidemiological studies. Participants 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers. Main outcome measures Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption. Results Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (−0.88 (−1.19 to −0.56) mm Hg), interleukin-6 levels (−5.2% (−7.8 to −2.4%)), waist circumference (−0.3 (−0.6 to −0.1) cm), and body mass index (−0.17 (−0.24 to −0.10) kg/m²). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)). Conclusions Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.

Objectives: To determine the effects of low-to-moderate levels of maternal alcohol consumption in pregnancy on pregnancy and longer-term offspring outcomes. Search strategy: Medline, Embase, Web of Science and Psychinfo from inception to 11 July 2016. Selection criteria: Prospective observational studies, negative control and quasiexperimental studies of pregnant women estimating effects of light drinking in pregnancy (≤32 g/week) versus abstaining. Pregnancy outcomes such as birth weight and features of fetal alcohol syndrome were examined. Data collection and analysis: One reviewer extracted data and another checked extracted data. Random effects meta-analyses were performed where applicable, and a narrative summary of findings was carried out otherwise. Main results: 24 cohort and two quasiexperimental studies were included. With the exception of birth size and gestational age, there was insufficient data to meta-analyse or make robust conclusions. Odds of small for gestational age (SGA) and preterm birth were higher for babies whose mothers consumed up to 32 g/week versus none, but estimates for preterm birth were also compatible with no association: summary OR 1.08, 95% CI (1.02 to 1.14), I ² 0%, (seven studies, all estimates were adjusted) OR 1.10, 95% CI (0.95 to 1.28), I ² 60%, (nine studies, includes one unadjusted estimates), respectively. The earliest time points of exposure were used in the analysis. Conclusion: Evidence of the effects of drinking ≤32 g/week in pregnancy is sparse. As there was some evidence that even light prenatal alcohol consumption is associated with being SGA and preterm delivery, guidance could advise abstention as a precautionary principle but should explain the paucity of evidence.

Background: Disturbed folate metabolism is associated with an increased risk of some cancers. Our objective was to determine whether blood levels of folate, vitamin B₁₂, and related metabolites were associated with prostate cancer risk. Methods: Matched case-control study nested within the U.K. population–based Prostate testing for cancer and Treatment (ProtecT) study of prostate-specific antigen–detected prostate cancer in men ages 50 to 69 years. Plasma concentrations of folate, B₁₂ (cobalamin), holo-haptocorrin, holo-transcobalamin total transcobalamin, and total homocysteine (tHcy) were measured in 1,461 cases and 1,507 controls. ProtecT study estimates for associations of folate, B₁₂, and tHcy with prostate cancer risk were included in a meta-analysis, based on a systematic review. Results: In the ProtecT study, increased B₁₂ and holo-haptocorrin concentrations showed positive associations with prostate cancer risk [highest versus lowest quartile of B₁₂ odds ratio (OR) = 1.17 (95% confidence interval, 0.95-1.43); P_trend = 0.06; highest versus lowest quartile of holo-haptocorrin OR = 1.27 (1.04-1.56); P_trend = 0.01]; folate, holo-transcobalamin, and tHcy were not associated with prostate cancer risk. In the meta-analysis, circulating B₁₂ levels were associated with an increased prostate cancer risk [pooled OR = 1.10 (1.01-1.19) per 100 pmol/L increase in B₁₂; P = 0.002]; the pooled OR for the association of folate with prostate cancer was positive [OR = 1.11 (0.96-1.28) per 10 nmol/L; P = 0.2) and conventionally statistically significant if ProtecT (the only case-control study) was excluded [OR = 1.18 (1.00-1.40) per 10 nmol/L; P = 0.02]. Conclusion: Vitamin B₁₂ and (in cohort studies) folate were associated with increased prostate cancer risk. Impact: Given current controversies over mandatory fortification, further research is needed to determine whether these are causal associations. Cancer Epidemiol Biomarkers Prev; 19(6); 1632–42. ©2010 AACR.

Studying the long-term causal effects of alcohol drinking is notoriously difficult. Epidemiological studies that use conventional analytical approaches are likely to be confounded and affected by reporting/recall bias and reverse causality, specifically in the form of the sick quitter effect (individuals quitting or never starting to consume alcohol due to underlying ill health).1 Decades of observational data showing J-shaped relationships of alcohol with risk of disease and in particular cardiovascular disease,2 fuelled by confirmation bias, have resulted in alcohol policies such that individuals are recommended to drink in moderation, due to putative cardioprotective effects. Critically, randomized controlled trials (RCTs) to investigate the long-term effects of alcohol drinking are not feasible for reasons including lack of suitable and ethical interventions and extended duration (and hence cost and likely high loss to follow-up).