Background

Smokers are at increased risk of type 2 diabetes (T2D), but the underlying mechanisms are unclear. We investigated if the smoking-T2D association is mediated by alterations in the metabolome and assessed potential interaction with genetic susceptibility to diabetes or insulin resistance.

Methods

In UK Biobank (n = 93,722), cross-sectional analyses identified 208 metabolites associated with smoking, of which 131 were confirmed in Mendelian Randomization analyses, including glycoprotein acetyls, fatty acids, and lipids. Elastic net regression was applied to create a smoking-related metabolic signature. We estimated hazard ratios (HR) of incident T2D in relation to baseline smoking/metabolic signature and calculated the proportion of the smoking-T2D association mediated by the signature. Additive interaction between the signature and genetic risk scores for T2D (GRS-T2D) and insulin resistance (GRS-IR) on incidence of T2D was assessed as relative excess risk due to interaction (RERI).

Findings

The HR of T2D was 1·73 (95% confidence interval (CI) 1·54 − 1·94) for current versus never smoking, and 38·3% of the excess risk was mediated by the metabolic signature. The metabolic signature and its mediation role were replicated in TwinGene. The metabolic signature was associated with T2D (HR: 1·61, CI 1·46 − 1·77 for values above vs. below median), with evidence of interaction with GRS-T2D (RERI: 0·81, CI: 0·23 − 1·38) and GRS-IR (RERI 0·47, CI: 0·02 − 0·92).

Interpretation

The increased risk of T2D in smokers may be mediated through effects on the metabolome, and the influence of such metabolic alterations on diabetes risk may be amplified in individuals with genetic susceptibility to T2D or insulin resistance.

中文翻译：

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吸烟的代谢特征、与 2 型糖尿病的关联以及与遗传易感性的相互作用

背景

吸烟者患 2 型糖尿病 (T2D) 的风险增加，但其潜在机制尚不清楚。我们研究了吸烟与 T2D 的关联是否是由代谢组的改变介导的，并评估了与糖尿病或胰岛素抵抗的遗传易感性之间的潜在相互作用。

方法

在英国生物银行 ( n  = 93,722) 中，横断面分析确定了 208 种与吸烟相关的代谢物，其中 131 种在孟德尔随机分析中得到证实，包括糖蛋白乙酰基、脂肪酸和脂质。应用弹性网络回归来创建与吸烟相关的代谢特征。我们估计了与基线吸烟/代谢特征相关的 T2D 事件的风险比 (HR)，并计算了特征介导的吸烟与 T2D 关联的比例。 T2D 特征与遗传风险评分 (GRS-T2D) 和胰岛素抵抗 (GRS-IR) 之间对 T2D 发病率的加性交互作用被评估为交互作用导致的相对超额风险 (RERI)。

发现

目前与从不吸烟相比，T2D 的 HR 为 1·73（95% 置信区间 (CI) 1·54 – 1·94），38·3% 的超额风险是由代谢特征介导的。 TwinGene 中复制了代谢特征及其中介作用。代谢特征与 T2D 相关（HR：1·61，CI 1·46 – 1·77，高于中值与低于中值），有证据表明与 GRS-T2D 相互作用（RERI：0·81，CI：0· 23 − 1·38) 和 GRS-IR (RERI 0·47, CI: 0·02 − 0·92)。

解释

吸烟者患 T2D 风险的增加可能是通过对代谢组的影响来介导的，而这种代谢改变对糖尿病风险的影响可能会在对 T2D 遗传易感性或胰岛素抵抗的个体中放大。