Genetic associations of adult height with risk of cardioembolic and other subtypes of ischemic stroke: A mendelian randomization study in multiple ancestries.
Genetic associations of adult height with risk of cardioembolic and other subtypes of ischemic stroke: A mendelian randomization study in multiple ancestries.
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DOI：
10.1371/journal.pmed.1003967
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发表时间：
2022-04
期刊：
影响因子：
15.8
通讯作者：
中科院分区：
文献类型：
--
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在孟德尔随机化(MR)研究中，成人身高越高，患缺血性心脏病的风险越低，但关于身高与不同类型的缺血性中风之间的因果关系知之甚少。本研究探讨了身高与不同亚型缺血性卒中的因果关系。以前的全基因组关联研究(GWAS)中与身高相关的遗传变异(高达2337个)被用来在不同的祖先群体中构建遗传工具。采用双样本磁共振方法，在多个祖先(MEGASTROKE联盟，其中包括对中风和中风亚型的全基因组研究：60,341例缺血性中风)中，通过额外的英国白人血统(英国生物库：4,055例)和中国血统(中国嘉道理生物库：10,297例)病例，检验了基因决定的身高与缺血性卒中及其亚型(心栓性卒中、大动脉卒中和小血管卒中)的相关性。来自UKB的336,750名参与者和来自CKB的58,277名参与者研究了遗传决定的身高与既定的心血管和其他风险因素的关联。在MEGASTROKE患者中，基因决定的身高与缺血性中风风险降低4%(优势比[OR]0.96；95%可信区间[CI]0.94，0.99；p=0.007)有关，但这掩盖了身高与心源性中风的更强的正相关(风险增加13%，OR 1.13[95%CI 1.07，1.19]，p<；与大动脉卒中(风险降低11%，OR0.89[0.84，0.95]，p<；0.001)和小血管卒中(风险降低13%，OR0.87[0.83，0.92]，p<；0.001)的相关性更强。UKB和CKB的结果与MEGASTROKE的结果在方向上是一致的，但没有达到统计学意义：对于推测的心栓性卒中，UKB和CKB的OR分别为1.08(95%CI 0.86，1.35；p=0.53)和1.20(0.77，1.85；p=0.43)，对于UKB的其他缺血性卒中亚型，OR为0.97(95%CI 0.90，1.05；p=0.49)；CKB中其他非腔隙卒中和腔隙卒中的OR值分别为0.89(0.80，1.00；p=0.06)和0.99(0.88，1.12；p=0.85)。此外，在英国和中国的祖先中，基因决定的身高与房颤(仅在UKB中可用)、瘦体重和肺功能呈正相关，与低密度脂蛋白(LDL)胆固醇呈负相关。这项研究的局限性包括遗传变异的分类交配或多效性效应带来的潜在偏见，以及遗传工具对不同群体的不完全普适性。这一发现支持了在不同的祖先中，成人身高较高与心源性中风风险较高、其他缺血性中风亚型风险较低之间的因果关系。需要进一步的研究来了解身高和中风风险之间潜在的共同生物和物理途径，这可能会确定预防中风的治疗的潜在靶点。在孟德尔随机研究中，Andrew B.Linden及其同事研究了来自MEGASTROKE联盟、中国Kadoorie Biobank和UK Biobank的个体的身高与中风亚型风险之间的关系。身高较高的人患缺血性中风和心脏病的风险较低，但患房颤的风险较高。然而，关于身高对不同亚型缺血性卒中(心源性卒中、大动脉卒中和小血管卒中)风险的影响知之甚少。了解身高和中风风险之间潜在的共同生物和物理途径可以确定预防中风的潜在治疗目标。不同收入和祖先的人群的平均身高和不同中风亚型的比率有很大差异，因此，对不同祖先的调查是重要的。我们使用孟德尔随机化(MR)方法来研究具有不同祖先的人群中身高遗传变异与缺血性中风亚型风险之间的关联。与身高相关的基因变异与心源性中风的风险更高，而大动脉和小血管中风的风险更低。这些发现在不同遗传祖先的人群中和使用不同的分析方法时是一致的。这一发现支持了成人身高较高与房颤和心源性中风风险较高以及其他缺血性中风亚型风险较低之间的因果关系。需要进一步的研究来阐明身高与缺血性中风亚型之间联系的生物学和物理途径，这可能会为预防中风的治疗确定新的靶点。
Taller adult height is associated with lower risks of ischemic heart disease in mendelian randomization (MR) studies, but little is known about the causal relevance of height for different subtypes of ischemic stroke. The present study examined the causal relevance of height for different subtypes of ischemic stroke. Height-associated genetic variants (up to 2,337) from previous genome-wide association studies (GWASs) were used to construct genetic instruments in different ancestral populations. Two-sample MR approaches were used to examine the associations of genetically determined height with ischemic stroke and its subtypes (cardioembolic stroke, large-artery stroke, and small-vessel stroke) in multiple ancestries (the MEGASTROKE consortium, which included genome-wide studies of stroke and stroke subtypes: 60,341 ischemic stroke cases) supported by additional cases in individuals of white British ancestry (UK Biobank [UKB]: 4,055 cases) and Chinese ancestry (China Kadoorie Biobank [CKB]: 10,297 cases). The associations of genetically determined height with established cardiovascular and other risk factors were examined in 336,750 participants from UKB and 58,277 participants from CKB. In MEGASTROKE, genetically determined height was associated with a 4% lower risk (odds ratio [OR] 0.96; 95% confidence interval [CI] 0.94, 0.99; p = 0.007) of ischemic stroke per 1 standard deviation (SD) taller height, but this masked a much stronger positive association of height with cardioembolic stroke (13% higher risk, OR 1.13 [95% CI 1.07, 1.19], p < 0.001) and stronger inverse associations with large-artery stroke (11% lower risk, OR 0.89 [0.84, 0.95], p < 0.001) and small-vessel stroke (13% lower risk, OR 0.87 [0.83, 0.92], p < 0.001). The findings in both UKB and CKB were directionally concordant with those observed in MEGASTROKE, but did not reach statistical significance: For presumed cardioembolic stroke, the ORs were 1.08 (95% CI 0.86, 1.35; p = 0.53) in UKB and 1.20 (0.77, 1.85; p = 0.43) in CKB; for other subtypes of ischemic stroke in UKB, the OR was 0.97 (95% CI 0.90, 1.05; p = 0.49); and for other nonlacunar stroke and lacunar stroke in CKB, the ORs were 0.89 (0.80, 1.00; p = 0.06) and 0.99 (0.88, 1.12; p = 0.85), respectively. In addition, genetically determined height was also positively associated with atrial fibrillation (available only in UKB), and with lean body mass and lung function, and inversely associated with low-density lipoprotein (LDL) cholesterol in both British and Chinese ancestries. Limitations of this study include potential bias from assortative mating or pleiotropic effects of genetic variants and incomplete generalizability of genetic instruments to different populations. The findings provide support for a causal association of taller adult height with higher risk of cardioembolic stroke and lower risk of other ischemic stroke subtypes in diverse ancestries. Further research is needed to understand the shared biological and physical pathways underlying the associations between height and stroke risks, which could identify potential targets for treatments to prevent stroke. In a Mendelian randomization study, Andrew B. Linden and colleagues study the relationship between height and risk of stroke subtypes among individuals from the MEGASTROKE consortium, China Kadoorie Biobank, and UK Biobank. Taller people have lower risks of ischemic stroke and heart disease, but higher risks of atrial fibrillation. However, little is known about the effects of height on the risks of different subtypes of ischemic stroke (cardioembolic stroke, large-artery stroke, and small-vessel stroke). Understanding the shared biological and physical pathways underlying the associations between height and stroke risks could identify potential targets for treatments to prevent stroke. Mean height and the rates of different stroke subtypes vary considerably across different income and ancestry populations, and, therefore, investigation across diverse ancestries is important. We used a mendelian randomization (MR) approach to study the association between genetic variants for height and risk of ischemic stroke subtypes in populations with different ancestries. Genetic variants associated with taller height were associated with higher risks of cardioembolic stroke and lower risks of large-artery and small-vessel stroke. The findings were consistent across populations of different genetic ancestries and use of different analytical methods. The findings support a causal association of taller adult height with higher risks of atrial fibrillation and cardioembolic stroke and lower risks of other ischemic stroke subtypes. Further research is needed to clarify the biological and physical pathways underlying the associations of height with ischemic stroke subtypes, which could identify novel targets for treatments to prevent stroke.
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影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
30.8
作者：
Malik R;Chauhan G;Traylor M;Sargurupremraj M;Okada Y;Mishra A;Rutten-Jacobs L;Giese AK;van der Laan SW;Gretarsdottir S;Anderson CD;Chong M;Adams HHH;Ago T;Almgren P;Amouyel P;Ay H;Bartz TM;Benavente OR;Bevan S;Boncoraglio GB;Brown RD Jr;Butterworth AS;Carrera C;Carty CL;Chasman DI;Chen WM;Cole JW;Correa A;Cotlarciuc I;Cruchaga C;Danesh J;de Bakker PIW;DeStefano AL;den Hoed M;Duan Q;Engelter ST;Falcone GJ;Gottesman RF;Grewal RP;Gudnason V;Gustafsson S;Haessler J;Harris TB;Hassan A;Havulinna AS;Heckbert SR;Holliday EG;Howard G;Hsu FC;Hyacinth HI;Ikram MA;Ingelsson E;Irvin MR;Jian X;Jiménez-Conde J;Johnson JA;Jukema JW;Kanai M;Keene KL;Kissela BM;Kleindorfer DO;Kooperberg C;Kubo M;Lange LA;Langefeld CD;Langenberg C;Launer LJ;Lee JM;Lemmens R;Leys D;Lewis CM;Lin WY;Lindgren AG;Lorentzen E;Magnusson PK;Maguire J;Manichaikul A;McArdle PF;Meschia JF;Mitchell BD;Mosley TH;Nalls MA;Ninomiya T;O'Donnell MJ;Psaty BM;Pulit SL;Rannikmäe K;Reiner AP;Rexrode KM;Rice K;Rich SS;Ridker PM;Rost NS;Rothwell PM;Rotter JI;Rundek T;Sacco RL;Sakaue S;Sale MM;Salomaa V;Sapkota BR;Schmidt R;Schmidt CO;Schminke U;Sharma P;Slowik A;Sudlow CLM;Tanislav C;Tatlisumak T;Taylor KD;Thijs VNS;Thorleifsson G;Thorsteinsdottir U;Tiedt S;Trompet S;Tzourio C;van Duijn CM;Walters M;Wareham NJ;Wassertheil-Smoller S;Wilson JG;Wiggins KL;Yang Q;Yusuf S;AFGen Consortium;Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium;International Genomics of Blood Pressure (iGEN-BP) Consortium;INVENT Consortium;STARNET;Bis JC;Pastinen T;Ruusalepp A;Schadt EE;Koplev S;Björkegren JLM;Codoni V;Civelek M;Smith NL;Trégouët DA;Christophersen IE;Roselli C;Lubitz SA;Ellinor PT;Tai ES;Kooner JS;Kato N;He J;van der Harst P;Elliott P;Chambers JC;Takeuchi F;Johnson AD;BioBank Japan Cooperative Hospital Group;COMPASS Consortium;EPIC-CVD Consortium;EPIC-InterAct Consortium;International Stroke Genetics Consortium (ISGC);METASTROKE Consortium;Neurology Working Group of the CHARGE Consortium;NINDS Stroke Genetics Network (SiGN);UK Young Lacunar DNA Study;MEGASTROKE Consortium;Sanghera DK;Melander O;Jern C;Strbian D;Fernandez-Cadenas I;Longstreth WT Jr;Rolfs A;Hata J;Woo D;Rosand J;Pare G;Hopewell JC;Saleheen D;Stefansson K;Worrall BB;Kittner SJ;Seshadri S;Fornage M;Markus HS;Howson JMM;Kamatani Y;Debette S;Dichgans M
通讯作者：
Dichgans M
影响因子：
5.9
作者：
Marouli, Eirini;Del Greco, M. Fabiola;Deloukas, Panos
通讯作者：
Deloukas, Panos
影响因子：
8.3
作者：
Hindy G;Engström G;Larsson SC;Traylor M;Markus HS;Melander O;Orho-Melander M;Stroke Genetics Network (SiGN)
通讯作者：
Stroke Genetics Network (SiGN)
影响因子：
8.3
作者：
Ay, Hakan;Benner, Thomas;Sorensen, A. Gregory
通讯作者：
Sorensen, A. Gregory