Background Many observational studies support light-to-moderate alcohol intake as potentially protective against premature death. We used a genetic approach to evaluate the linear and nonlinear relationships between alcohol consumption and mortality from different underlying causes. Methods We used data from 278 093 white-British UK Biobank participants, aged 37–73 years at recruitment and with data on alcohol intake, genetic variants, and mortality. Habitual alcohol consumption was instrumented by 94 variants. Linear Mendelian randomization (MR) analyses were conducted using five complementary approaches, and nonlinear MR analyses by the doubly-ranked method. Results There were 20 834 deaths during the follow-up (median 12.6 years). In conventional analysis, the association between alcohol consumption and mortality outcomes was ‘J-shaped’. In contrast, MR analyses supported a positive linear association with premature mortality, with no evidence for curvature (Pnonlinearity ≥ 0.21 for all outcomes). The odds ratio [OR] for each standard unit increase in alcohol intake was 1.27 (95% confidence interval [CI] 1.16–1.39) for all-cause mortality, 1.30 (95% CI 1.10–1.53) for cardiovascular disease, 1.20 (95% CI 1.08–1.33) for cancer, and 2.06 (95% CI 1.36–3.12) for digestive disease mortality. These results were consistent across pleiotropy-robust methods. There was no clear evidence for an association between alcohol consumption and mortality from respiratory diseases or COVID-19 (1.32, 95% CI 0.96–1.83 and 1.46, 95% CI 0.99–2.16, respectively; Pnonlinearity ≥ 0.21). Conclusion Higher levels of genetically predicted alcohol consumption had a strong linear association with an increased risk of premature mortality with no evidence for any protective benefit at modest intake levels.

中文翻译：

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饮酒与全因和特定原因死亡的风险——线性和非线性孟德尔随机化研究

背景 许多观察性研究支持少量至适量饮酒可能有助于预防过早死亡。我们使用遗传方法来评估饮酒与不同根本原因导致的死亡率之间的线性和非线性关系。方法 我们使用了 278 093 名英国白人生物银行参与者的数据，这些参与者在招募时年龄为 37-73 岁，并包含酒精摄入量、遗传变异和死亡率的数据。习惯性饮酒有 94 种变体。使用五种互补方法进行线性孟德尔随机化 (MR) 分析，并使用双排序方法进行非线性 MR 分析。结果 随访期间（中位时间12.6年）共有20 834人死亡。在传统分析中，饮酒与死亡率结果之间的关联呈“J 形”。相比之下，MR 分析支持与过早死亡率呈正线性相关，但没有曲率证据（所有结果的 P 非线性≥ 0.21）。酒精摄入量每增加一个标准单位，全因死亡率的优势比 [OR] 为 1.27（95% 置信区间 [CI] 1.16–1.39），心血管疾病为 1.30（95% CI 1.10–1.53），心血管疾病为 1.20（95% CI 1.10–1.53）。癌症死亡率 % CI 1.08–1.33)，消化系统疾病死亡率 2.06 (95% CI 1.36–3.12)。这些结果在多效性稳健方法中是一致的。没有明确的证据表明饮酒与呼吸系统疾病或 COVID-19 死亡率之间存在关联（分别为 1.32，95% CI 0.96-1.83 和 1.46，95% CI 0.99-2.16；P 非线性 ≥ 0.21）。结论 较高水平的基因预测饮酒量与过早死亡风险增加具有很强的线性相关性，但没有证据表明适度摄入水平有任何保护作用。