Efficacy of metformin targets on cardiometabolic health in the general population and non-diabetic individuals: a Mendelian randomization study.
Efficacy of metformin targets on cardiometabolic health in the general population and non-diabetic individuals: a Mendelian randomization study.
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DOI：
10.1016/j.ebiom.2023.104803
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发表时间：
2023-10
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影响因子：
11.1
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中科院分区：
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--
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代谢物对糖尿病患者的心脏代谢健康具有有益作用。然而，在一般人群中，特别是在非糖尿病个体中的有益效果尚不清楚。我们的目的是使用孟德尔随机化（MR）来估计干扰7个二甲双胍靶点对心脏代谢健康的影响。与二甲双胍靶向基因相关的遗传变异与相应基因的表达和糖化血红蛋白（HbA 1c）水平相关，用于代表7种二甲双胍相关药物靶点的治疗效果。二甲双胍试验中选择了8种心脏代谢表型作为结局（平均N = 466，947）。生成代表二甲双胍目标对8个结局的7种效应的加权平均效应的MR估计值。单样本MR用于估计UK Biobank中338，425名非糖尿病个体的平均和目标特异性效应。5个二甲双胍目标的遗传代理平均效应，相当于HbA 1c水平降低0.62%，与冠状动脉疾病（CAD）风险降低37.8%相关（比值比[OR] = 0.62，95%置信区间[CI] = 0.46-0.84），体重指数（BMI）水平较低（β = −0.22，95%CI = −0.35至−0.09）、收缩压（SBP）（β = −0.19，95%CI = −0.28至−0.09）和舒张压（DBP）水平（β = −0.29，95%CI = −0.39至−0.19）。单样本MR表明，7个二甲双胍靶点对非糖尿病个体的BMI、SBP和DBP显示出平均和靶点特异性有益作用。这项研究表明，干扰七个二甲双胍目标对非糖尿病个体的BMI和血压具有有益影响。需要进行临床试验来研究二甲双胍药物是否可以达到类似的效果。资金信息见鸣谢。
Metformin shows beneficial effects on cardiometabolic health in diabetic individuals. However, the beneficial effects in the general population, especially in non-diabetic individuals are unclear. We aim to estimate the effects of perturbation of seven metformin targets on cardiometabolic health using Mendelian randomization (MR). Genetic variants close to metformin-targeted genes associated with expression of the corresponding genes and glycated haemoglobin (HbA1c) level were used to proxy therapeutic effects of seven metformin-related drug targets. Eight cardiometabolic phenotypes under metformin trials were selected as outcomes (average N = 466,947). MR estimates representing the weighted average effects of the seven effects of metformin targets on the eight outcomes were generated. One-sample MR was applied to estimate the averaged and target-specific effects in 338,425 non-diabetic individuals in UK Biobank. Genetically proxied averaged effects of five metformin targets, equivalent to a 0.62% reduction of HbA1c level, was associated with 37.8% lower risk of coronary artery disease (CAD) (odds ratio [OR] = 0.62, 95% confidence interval [CI] = 0.46–0.84), lower levels of body mass index (BMI) (β = −0.22, 95% CI = −0.35 to −0.09), systolic blood pressure (SBP) (β = −0.19, 95% CI = −0.28 to −0.09) and diastolic blood pressure (DBP) levels (β = −0.29, 95% CI = −0.39 to −0.19). One-sample MR suggested that the seven metformin targets showed averaged and target-specific beneficial effects on BMI, SBP and DBP in non-diabetic individuals. This study showed that perturbation of seven metformin targets has beneficial effects on BMI and blood pressure in non-diabetic individuals. Clinical trials are needed to investigate whether similar effects can be achieved with metformin medications. Funding information is provided in the Acknowledgements.
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影响因子：
30.8
作者：
Chen J;Spracklen CN;Marenne G;Varshney A;Corbin LJ;Luan J;Willems SM;Wu Y;Zhang X;Horikoshi M;Boutin TS;Mägi R;Waage J;Li-Gao R;Chan KHK;Yao J;Anasanti MD;Chu AY;Claringbould A;Heikkinen J;Hong J;Hottenga JJ;Huo S;Kaakinen MA;Louie T;März W;Moreno-Macias H;Ndungu A;Nelson SC;Nolte IM;North KE;Raulerson CK;Ray D;Rohde R;Rybin D;Schurmann C;Sim X;Southam L;Stewart ID;Wang CA;Wang Y;Wu P;Zhang W;Ahluwalia TS;Appel EVR;Bielak LF;Brody JA;Burtt NP;Cabrera CP;Cade BE;Chai JF;Chai X;Chang LC;Chen CH;Chen BH;Chitrala KN;Chiu YF;de Haan HG;Delgado GE;Demirkan A;Duan Q;Engmann J;Fatumo SA;Gayán J;Giulianini F;Gong JH;Gustafsson S;Hai Y;Hartwig FP;He J;Heianza Y;Huang T;Huerta-Chagoya A;Hwang MY;Jensen RA;Kawaguchi T;Kentistou KA;Kim YJ;Kleber ME;Kooner IK;Lai S;Lange LA;Langefeld CD;Lauzon M;Li M;Ligthart S;Liu J;Loh M;Long J;Lyssenko V;Mangino M;Marzi C;Montasser ME;Nag A;Nakatochi M;Noce D;Noordam R;Pistis G;Preuss M;Raffield L;Rasmussen-Torvik LJ;Rich SS;Robertson NR;Rueedi R;Ryan K;Sanna S;Saxena R;Schraut KE;Sennblad B;Setoh K;Smith AV;Sparsø T;Strawbridge RJ;Takeuchi F;Tan J;Trompet S;van den Akker E;van der Most PJ;Verweij N;Vogel M;Wang H;Wang C;Wang N;Warren HR;Wen W;Wilsgaard T;Wong A;Wood AR;Xie T;Zafarmand MH;Zhao JH;Zhao W;Amin N;Arzumanyan Z;Astrup A;Bakker SJL;Baldassarre D;Beekman M;Bergman RN;Bertoni A;Blüher M;Bonnycastle LL;Bornstein SR;Bowden DW;Cai Q;Campbell A;Campbell H;Chang YC;de Geus EJC;Dehghan A;Du S;Eiriksdottir G;Farmaki AE;Frånberg M;Fuchsberger C;Gao Y;Gjesing AP;Goel A;Han S;Hartman CA;Herder C;Hicks AA;Hsieh CH;Hsueh WA;Ichihara S;Igase M;Ikram MA;Johnson WC;Jørgensen ME;Joshi PK;Kalyani RR;Kandeel FR;Katsuya T;Khor CC;Kiess W;Kolcic I;Kuulasmaa T;Kuusisto J;Läll K;Lam K;Lawlor DA;Lee NR;Lemaitre RN;Li H;Lifelines Cohort Study;Lin SY;Lindström J;Linneberg A;Liu J;Lorenzo C;Matsubara T;Matsuda F;Mingrone G;Mooijaart S;Moon S;Nabika T;Nadkarni GN;Nadler JL;Nelis M;Neville MJ;Norris JM;Ohyagi Y;Peters A;Peyser PA;Polasek O;Qi Q;Raven D;Reilly DF;Reiner A;Rivideneira F;Roll K;Rudan I;Sabanayagam C;Sandow K;Sattar N;Schürmann A;Shi J;Stringham HM;Taylor KD;Teslovich TM;Thuesen B;Timmers PRHJ;Tremoli E;Tsai MY;Uitterlinden A;van Dam RM;van Heemst D;van Hylckama Vlieg A;van Vliet-Ostaptchouk JV;Vangipurapu J;Vestergaard H;Wang T;Willems van Dijk K;Zemunik T;Abecasis GR;Adair LS;Aguilar-Salinas CA;Alarcón-Riquelme ME;An P;Aviles-Santa L;Becker DM;Beilin LJ;Bergmann S;Bisgaard H;Black C;Boehnke M;Boerwinkle E;Böhm BO;Bønnelykke K;Boomsma DI;Bottinger EP;Buchanan TA;Canouil M;Caulfield MJ;Chambers JC;Chasman DI;Chen YI;Cheng CY;Collins FS;Correa A;Cucca F;de Silva HJ;Dedoussis G;Elmståhl S;Evans MK;Ferrannini E;Ferrucci L;Florez JC;Franks PW;Frayling TM;Froguel P;Gigante B;Goodarzi MO;Gordon-Larsen P;Grallert H;Grarup N;Grimsgaard S;Groop L;Gudnason V;Guo X;Hamsten A;Hansen T;Hayward C;Heckbert SR;Horta BL;Huang W;Ingelsson E;James PS;Jarvelin MR;Jonas JB;Jukema JW;Kaleebu P;Kaplan R;Kardia SLR;Kato N;Keinanen-Kiukaanniemi SM;Kim BJ;Kivimaki M;Koistinen HA;Kooner JS;Körner A;Kovacs P;Kuh D;Kumari M;Kutalik Z;Laakso M;Lakka TA;Launer LJ;Leander K;Li H;Lin X;Lind L;Lindgren C;Liu S;Loos RJF;Magnusson PKE;Mahajan A;Metspalu A;Mook-Kanamori DO;Mori TA;Munroe PB;Njølstad I;O'Connell JR;Oldehinkel AJ;Ong KK;Padmanabhan S;Palmer CNA;Palmer ND;Pedersen O;Pennell CE;Porteous DJ;Pramstaller PP;Province MA;Psaty BM;Qi L;Raffel LJ;Rauramaa R;Redline S;Ridker PM;Rosendaal FR;Saaristo TE;Sandhu M;Saramies J;Schneiderman N;Schwarz P;Scott LJ;Selvin E;Sever P;Shu XO;Slagboom PE;Small KS;Smith BH;Snieder H;Sofer T;Sørensen TIA;Spector TD;Stanton A;Steves CJ;Stumvoll M;Sun L;Tabara Y;Tai ES;Timpson NJ;Tönjes A;Tuomilehto J;Tusie T;Uusitupa M;van der Harst P;van Duijn C;Vitart V;Vollenweider P;Vrijkotte TGM;Wagenknecht LE;Walker M;Wang YX;Wareham NJ;Watanabe RM;Watkins H;Wei WB;Wickremasinghe AR;Willemsen G;Wilson JF;Wong TY;Wu JY;Xiang AH;Yanek LR;Yengo L;Yokota M;Zeggini E;Zheng W;Zonderman AB;Rotter JI;Gloyn AL;McCarthy MI;Dupuis J;Meigs JB;Scott RA;Prokopenko I;Leong A;Liu CT;Parker SCJ;Mohlke KL;Langenberg C;Wheeler E;Morris AP;Barroso I;Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC)
通讯作者：
Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC)
影响因子：
30.8
作者：
Mahajan A;Taliun D;Thurner M;Robertson NR;Torres JM;Rayner NW;Payne AJ;Steinthorsdottir V;Scott RA;Grarup N;Cook JP;Schmidt EM;Wuttke M;Sarnowski C;Mägi R;Nano J;Gieger C;Trompet S;Lecoeur C;Preuss MH;Prins BP;Guo X;Bielak LF;Below JE;Bowden DW;Chambers JC;Kim YJ;Ng MCY;Petty LE;Sim X;Zhang W;Bennett AJ;Bork-Jensen J;Brummett CM;Canouil M;Ec Kardt KU;Fischer K;Kardia SLR;Kronenberg F;Läll K;Liu CT;Locke AE;Luan J;Ntalla I;Nylander V;Schönherr S;Schurmann C;Yengo L;Bottinger EP;Brandslund I;Christensen C;Dedoussis G;Florez JC;Ford I;Franco OH;Frayling TM;Giedraitis V;Hackinger S;Hattersley AT;Herder C;Ikram MA;Ingelsson M;Jørgensen ME;Jørgensen T;Kriebel J;Kuusisto J;Ligthart S;Lindgren CM;Linneberg A;Lyssenko V;Mamakou V;Meitinger T;Mohlke KL;Morris AD;Nadkarni G;Pankow JS;Peters A;Sattar N;Stančáková A;Strauch K;Taylor KD;Thorand B;Thorleifsson G;Thorsteinsdottir U;Tuomilehto J;Witte DR;Dupuis J;Peyser PA;Zeggini E;Loos RJF;Froguel P;Ingelsson E;Lind L;Groop L;Laakso M;Collins FS;Jukema JW;Palmer CNA;Grallert H;Metspalu A;Dehghan A;Köttgen A;Abecasis GR;Meigs JB;Rotter JI;Marchini J;Pedersen O;Hansen T;Langenberg C;Wareham NJ;Stefansson K;Gloyn AL;Morris AP;Boehnke M;McCarthy MI
通讯作者：
McCarthy MI
影响因子：
82.9
作者：
Emmerson, Paul J.;Wang, Feng;Wu, Xinle
通讯作者：
Wu, Xinle
影响因子：
8.2
作者：
Luo, Shan;Schooling, C. Mary;Au Yeung, Shiu Lun
通讯作者：
Au Yeung, Shiu Lun
影响因子：
158.5
作者：
Holman, Rury R.;Paul, Sanjoy K.;Neil, H. Andrew W.
通讯作者：
Neil, H. Andrew W.