Do smoking and alcohol behaviours influence risk of type 2 diabetes? A Mendelian randomisation study.

Zoe E Reed, Hannah M Sallis, Rebecca C Richmond, Angela S Attwood, Deborah A Lawlor, Marcus R Munafo
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Abstract

Background: Previous studies suggest that smoking and higher alcohol consumption are both associated with greater risk of type 2 diabetes (T2D). However, studies examining whether these associations reflect causal relationships are limited and do not consider continuous glycaemic traits. The aim of the study was to determine whether there are causal effects of smoking and alcohol consumption on T2D risk and related glycaemic traits. Methods and Findings: We conducted both two-sample and one-sample MR to examine the effects of lifetime smoking index (LSI) and alcoholic drinks per week on T2D and continuous traits (fasting glucose, fasting insulin and glycated haemoglobin, HbA1c). For two-sample MR we used results from genome-wide association studies (GWAS) of LSI (N=462,690), alcohol consumption (N=941,280), T2D (N= 148,726 cases and 965,732 controls) and continuous traits (N=149,289 to 209,605). We used inverse variance weighting (IVW) for our main analyses and conducted several sensitivity analyses to explore violation of MR assumptions. We compared two-sample MR to one-sample MR results for alcohol effects on T2D and HbA1c in UK Biobank (N=336,984). Only these analyses were conducted to avoid sample overlap and due to data availability. The main IVW two-sample MR results suggested possible causal effects of higher LSI on T2D risk (OR per 1SD higher LSI=1.42, 95% CI=1.22 to 1.64); however, sensitivity analyses did not consistently support this finding, and there was evidence of potential horizontal pleiotropy. There was no robust evidence that higher drinks per week influenced risk of T2D from our main IVW two-sample MR analyses (OR per 1 SD higher log-transformed drinks per week=1.04, 95% CI=0.40 to 2.65), despite evidence of causal effects on higher fasting glucose (difference in mean fasting glucose in mmol/l per 1SD higher log-transformed drinks per week=0.34, 95% CI=0.09 to 0.59). One-sample MR results suggested a possible causal effect of higher drinks per week on T2D risk (OR per 1 SD higher log-transformed drinks per week=1.71, 95% CI: 1.24 to 2.36), but in contrast, lower HbA1c levels (difference in mean SD of log transformed HbA1c (mol/mol) per 1 SD higher log-transformed drinks per week=-0.07, 95% CI: -0.11 to -0.02). Key limitations include limited generalisability of results due to analyses being conducted in European populations, and potential selection bias in UK Biobank influencing results. Conclusion: Our results suggest effective public health interventions to prevent and/or reduce smoking and alcohol consumption are unlikely to reduce the prevalence of T2D.
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吸烟和酗酒行为会影响罹患 2 型糖尿病的风险吗?孟德尔随机研究
背景:以往的研究表明,吸烟和饮酒都与罹患 2 型糖尿病(T2D)的风险增加有关。然而,研究这些关联是否反映了因果关系的研究非常有限,而且没有考虑连续的血糖特征。本研究旨在确定吸烟和饮酒对 2 型糖尿病风险及相关血糖特征是否存在因果关系。方法和结果:我们进行了双样本和单样本 MR,研究终生吸烟指数(LSI)和每周饮酒量对 T2D 和连续性特征(空腹血糖、空腹胰岛素和糖化血红蛋白,HbA1c)的影响。对于双样本 MR,我们使用了 LSI(462,690 人)、酒精消耗量(941,280 人)、T2D(148,726 例病例和 965,732 例对照)和连续性性状(149,289 至 209,605 人)的全基因组关联研究(GWAS)结果。我们在主要分析中使用了反方差加权法(IVW),并进行了多项敏感性分析,以探讨是否违反了 MR 假设。我们比较了英国生物库中酒精对 T2D 和 HbA1c 影响的双样本 MR 和单样本 MR 结果(样本数=336,984)。为了避免样本重叠以及数据的可用性,我们只进行了这些分析。主要的 IVW 双样本 MR 结果表明,较高的 LSI 可能会对 T2D 风险产生因果效应(每高 1SD LSI 的 OR=1.42,95% CI=1.22-1.64);但是,敏感性分析并不完全支持这一结果,而且有证据表明存在潜在的水平褶积效应。尽管有证据表明每周较高的饮酒量对较高的空腹血糖有因果效应(每周较高的对数转换饮酒量每增加 1 SD,平均空腹血糖的 mmol/l 差值=0.34,95% CI=0.09-0.59),但我们的主要 IVW 双样本 MR 分析(每周较高的对数转换饮酒量每增加 1 SD,OR=1.04,95% CI=0.40-2.65)没有有力的证据表明每周较高的饮酒量会影响 T2D 风险。单样本 MR 结果表明,每周饮酒量增加可能对 T2D 风险产生因果效应(每周对数转换饮酒量每增加 1 SD 的 OR=1.71,95% CI:1.24 至 2.36),但与此相反,HbA1c 水平降低(每周对数转换饮酒量每增加 1 SD 的对数转换 HbA1c 平均 SD 差异(mol/mol)=-0.07,95% CI:-0.11 至 -0.02)。主要局限性包括:由于分析是在欧洲人群中进行的,因此结果的普遍性有限;英国生物库中的潜在选择偏差会影响结果。结论:我们的研究结果表明,预防和/或减少吸烟和饮酒的有效公共卫生干预措施不太可能降低终末期糖尿病的患病率。
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