Distinct metabolic features of genetic liability to type 2 diabetes and coronary artery disease: a reverse Mendelian randomization study.
Distinct metabolic features of genetic liability to type 2 diabetes and coronary artery disease: a reverse Mendelian randomization study.
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2 型糖尿病和冠状动脉疾病遗传易感性的独特代谢特征：反向孟德尔随机化研究。
DOI：
10.1016/j.ebiom.2023.104503
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发表时间：
2023-04
期刊：
影响因子：
11.1
通讯作者：
Bell, Joshua A.
中科院分区：
文献类型：
--
作者：
Smith, Madeleine L.;Bull, Caroline J.;V. Holmes, Michael;Smith, George Davey;Sanderson, Eleanor;Anderson, Emma L.;Bell, Joshua A.
2型糖尿病（T2 D）和冠状动脉疾病（CAD）都有已知的遗传决定因素，但其相关遗传变异导致疾病发作的机制仍然知之甚少。我们在双样本反向孟德尔随机化（MR）框架中使用大规模代谢组学数据，以估计T2 D和CAD遗传易感性对英国生物库中249种循环代谢物的影响（N = 118，466）。我们通过进行年龄分层的代谢物分析，研究了药物使用扭曲效应估计的可能性。使用逆方差加权（IVW）模型，估计对T2 D的较高遗传易感性可降低高密度脂蛋白胆固醇（HDL-C）和低密度脂蛋白胆固醇（LDL-C）（例如，HDL-C：−0.05 SD; 95%CI −0.07至−0.03，每增加一倍的责任），同时增加所有甘油三酯组和支链氨基酸（BCAA）。IVW对CAD易感性的估计表明对降低HDL-C以及升高极低密度脂蛋白胆固醇（VLDL-C）和LDL-C有影响。在多效性稳健模型中，T2 D易感性仍估计会增加BCAA，但一些较高CAD易感性的估计值逆转并支持LDL-C和载脂蛋白-B降低。不同年龄的非HDL-C特征对CAD易感性的估计影响有很大差异，只有在他汀类药物使用普遍的老年人中，CAD易感性越高，LDL-C越低。总的来说，我们的研究结果在很大程度上支持了T2 D和CAD遗传易感性的不同代谢特征，说明了预防这些常见并发疾病的挑战和机遇。 [218495/Z/19/Z]，[MC_UU_00011/1; MC_UU_00011/4]，英国糖尿病[17/0005587]，[IIG_2019_2009]。
Type 2 diabetes (T2D) and coronary artery disease (CAD) both have known genetic determinants, but the mechanisms through which their associated genetic variants lead to disease onset remain poorly understood. We used large-scale metabolomics data in a two-sample reverse Mendelian randomization (MR) framework to estimate effects of genetic liability to T2D and CAD on 249 circulating metabolites in the UK Biobank (N = 118,466). We examined the potential for medication use to distort effect estimates by conducting age-stratified metabolite analyses. Using inverse variance weighted (IVW) models, higher genetic liability to T2D was estimated to decrease high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) (e.g., HDL-C: −0.05 SD; 95% CI −0.07 to −0.03, per doubling of liability), whilst increasing all triglyceride groups and branched chain amino acids (BCAAs). IVW estimates for CAD liability suggested an effect on reducing HDL-C as well as raising very-low density lipoprotein cholesterol (VLDL-C) and LDL-C. In pleiotropy-robust models, T2D liability was still estimated to increase BCAAs, but several estimates for higher CAD liability reversed and supported decreased LDL-C and apolipoprotein-B. Estimated effects of CAD liability differed substantially by age for non-HDL-C traits, with higher CAD liability lowering LDL-C only at older ages when statin use was common. Overall, our results support largely distinct metabolic features of genetic liability to T2D and CAD, illustrating both challenges and opportunities for preventing these commonly co-occurring diseases. [218495/Z/19/Z], [MC_UU_00011/1; MC_UU_00011/4], the , Diabetes UK [17/0005587], [IIG_2019_2009].
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影响因子：
20.9
作者：
Bell, Joshua A.;Richardson, Tom G.;Wang, Qin;Sanderson, Eleanor;Palmer, Tom;Walker, Venexia;O'Keeffe, Linda M.;Timpson, Nicholas J.;Cichonska, Anna;Julkunen, Heli;Wurtz, Peter;V. Holmes, Michael;Smith, George Davey
通讯作者：
Smith, George Davey
影响因子：
2.1
作者：
Bowden J;Davey Smith G;Haycock PC;Burgess S
通讯作者：
Burgess S
影响因子：
5
作者：
Gu X;Al Dubayee M;Alshahrani A;Masood A;Benabdelkamel H;Zahra M;Li L;Abdel Rahman AM;Aljada A
通讯作者：
Aljada A
影响因子：
5.2
作者：
Chi Y;Wang X;Jia J;Huang T
通讯作者：
Huang T
BMI是2型糖尿病的可修改风险因素：使用门德利随机化的炼油和理解因果估计。
影响因子：
7.7
作者：
Corbin LJ;Richmond RC;Wade KH;Burgess S;Bowden J;Smith GD;Timpson NJ
通讯作者：
Timpson NJ