Dissecting the IL-6 pathway in cardiometabolic disease: A Mendelian randomization study on both IL6 and IL6R.
Dissecting the IL-6 pathway in cardiometabolic disease: A Mendelian randomization study on both IL6 and IL6R.
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DOI：
10.1111/bcp.15191
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发表时间：
2022-06
影响因子：
3.4
通讯作者：
中科院分区：
文献类型：
--
作者：
慢性炎症是心血管疾病（CVD）的危险因素。通过IL-6或IL-6 R阻断的IL-6信号转导干扰可能对心血管风险具有潜在益处。目前尚不清楚靶向IL-6或IL-6受体是否会对CVD和不良事件产生类似的影响。我们比较了靶向IL-6和IL-6受体对心脏代谢风险和潜在副作用的预期影响。我们设计了四种工具：两种主要工具，其中IL 6和IL 6 R基因座中的遗传变异体因其与CRP的关联而加权，两种工具在首先过滤变异体后因其与IL-6或IL-6 R表达的关联而加权。对冠状动脉疾病（CAD）、缺血性卒中、房颤（AF）、心力衰竭、2型糖尿病（T2 D）、类风湿性关节炎（RA）、感染终点以及定量血液学、代谢和人体测量参数进行分析。通过IL 6仪器测定，CRP降低1 mg/L与CAD（比值比[OR] 0.86，95%置信区间[CI] 0.77;0.96）、AF和T2 D风险降低相关。IL-6 R仪器测定CRP降低1 mg/L与CAD降低（OR 0.90，95% CI 0.86;0.95）、任何卒中和缺血性卒中、AF、RA风险和肺炎风险升高相关。eQTL过滤结果与主要结果一致，但置信区间更宽。IL-6或IL-6 R基因工具对IL-6信号传导的干扰与多种心脏代谢疾病的风险降低相似，表明IL-6和IL-6 R都是降低CVD的潜在治疗靶点。此外，IL-6而不是IL-6 R抑制可能具有更有利的肺炎风险。
Chronic inflammation is a risk factor for cardiovascular disease (CVD). IL‐6 signalling perturbation through IL‐6 or IL‐6R blockade may have potential benefit on cardiovascular risk. It is unknown whether targeting either IL‐6 or IL‐6 receptor may result in similar effects on CVD and adverse events. We compared the anticipated effects of targeting IL‐6 and IL‐6 receptor on cardiometabolic risk and potential side effects. We constructed four instruments: two main instruments with genetic variants in the IL6 and IL6R loci weighted for their association with CRP, and two after firstly filtering variants for their association with IL‐6 or IL‐6R expression. Analyses were performed for coronary artery disease (CAD), ischemic stroke, atrial fibrillation (AF), heart failure, type 2 diabetes (T2D), rheumatoid arthritis (RA), infection endpoints, and quantitative haematological, metabolic and anthropometric parameters. A 1 mg/L lower CRP by the IL6 instrument was associated with lower CAD (odds ratio [OR] 0.86, 95% confidence interval [CI] 0.77;0.96), AF and T2D risk. A 1 mg/L lower CRP by the IL6R instrument was associated with lower CAD (OR 0.90, 95% CI 0.86;0.95), any stroke and ischemic stroke, AF, RA risk and higher pneumonia risk. The eQTL‐filtered results were in concordance with the main results, but with wider confidence intervals. IL‐6 signalling perturbation by either IL6 or IL6R genetic instruments is associated with a similar risk reduction for multiple cardiometabolic diseases, suggesting that both IL‐6 and IL‐6R are potential therapeutic targets to lower CVD. Moreover, IL‐6 rather than IL‐6R inhibition might have a more favourable pneumonia risk.
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影响因子：
7.7
作者：
Bowden J;Del Greco M F;Minelli C;Davey Smith G;Sheehan NA;Thompson JR
通讯作者：
Thompson JR
影响因子：
3.5
作者：
Farahi N;Paige E;Balla J;Prudence E;Ferreira RC;Southwood M;Appleby SL;Bakke P;Gulsvik A;Litonjua AA;Sparrow D;Silverman EK;Cho MH;Danesh J;Paul DS;Freitag DF;Chilvers ER
通讯作者：
Chilvers ER
影响因子：
30.8
作者：
Nielsen JB;Thorolfsdottir RB;Fritsche LG;Zhou W;Skov MW;Graham SE;Herron TJ;McCarthy S;Schmidt EM;Sveinbjornsson G;Surakka I;Mathis MR;Yamazaki M;Crawford RD;Gabrielsen ME;Skogholt AH;Holmen OL;Lin M;Wolford BN;Dey R;Dalen H;Sulem P;Chung JH;Backman JD;Arnar DO;Thorsteinsdottir U;Baras A;O'Dushlaine C;Holst AG;Wen X;Hornsby W;Dewey FE;Boehnke M;Kheterpal S;Mukherjee B;Lee S;Kang HM;Holm H;Kitzman J;Shavit JA;Jalife J;Brummett CM;Teslovich TM;Carey DJ;Gudbjartsson DF;Stefansson K;Abecasis GR;Hveem K;Willer CJ
通讯作者：
Willer CJ
影响因子：
168.9
作者：
Ferreira, Manuel A. R.;Matheson, Melanie C.;Duffy, David L.;Marks, Guy B.;Hui, Jennie;Le Souef, Peter;Danoy, Patrick;Baltic, Svetlana;Nyholt, Dale R.;Jenkins, Mark;Hayden, Catherine;Willemsen, Gonneke;Ang, Wei;Kuokkanen, Mikko;Beilby, John;Cheah, Faang;de Geus, Eco J. C.;Ramasamy, Adaikalavan;Vedantam, Sailaja;Salomaa, Veikko;Madden, Pamela A.;Heath, Andrew C.;Hopper, John L.;Visscher, Peter M.;Musk, Bill;Leeder, Stephen R.;Jarvelin, Marjo-Riitta;Pennell, Craig;Boomsma, Dorret I.;Hirschhorn, Joel N.;Walters, Haydn;Martin, Nicholas G.;James, Alan;Jones, Graham;Abramson, Michael J.;Robertson, Colin F.;Dharmage, Shyamali C.;Brown, Matthew A.;Montgomery, Grant W.;Thompson, Philip J.
通讯作者：
Thompson, Philip J.
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