Variation in the SERPINA6/SERPINA1 locus alters morning plasma cortisol, hepatic corticosteroid binding globulin expression, gene expression in peripheral tissues, and risk of cardiovascular disease.
Variation in the SERPINA6/SERPINA1 locus alters morning plasma cortisol, hepatic corticosteroid binding globulin expression, gene expression in peripheral tissues, and risk of cardiovascular disease.
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SERPINA6/SERPINA1位点的变异改变了早晨血浆皮质醇、肝皮质类固醇结合球蛋白表达、外周组织基因表达和心血管疾病的风险。
DOI：
10.1038/s10038-020-00895-6
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发表时间：
2021-06
影响因子：
3.5
通讯作者：
CORtisol NETwork (CORNET) consortium
中科院分区：
文献类型：
--
作者：
Crawford AA;Bankier S;Altmaier E;Barnes CLK;Clark DW;Ermel R;Friedrich N;van der Harst P;Joshi PK;Karhunen V;Lahti J;Mahajan A;Mangino M;Nethander M;Neumann A;Pietzner M;Sukhavasi K;Wang CA;Bakker SJL;Bjorkegren JLM;Campbell H;Eriksson J;Gieger C;Hayward C;Jarvelin MR;McLachlan S;Morris AP;Ohlsson C;Pennell CE;Price J;Rudan I;Ruusalepp A;Spector T;Tiemeier H;Völzke H;Wilson JF;Michoel T;Timpson NJ;Smith GD;Walker BR;CORtisol NETwork (CORNET) consortium
应激激素皮质醇调节能量代谢、心血管稳态、情绪、炎症和认知。皮质醇网络（CORNET）协会先前确定了一个与早晨血浆皮质醇相关的单一位点。确定更多解释皮质醇变异的其他遗传变异可以为皮质醇生物学提供新的见解，并提供统计能力来测试皮质醇在常见疾病中的致病作用。CORNET联盟在17个欧洲血统的人群队列中，将其对早晨血浆皮质醇的全基因组关联荟萃分析从12，597名受试者扩展到25，314名受试者，SNP从约2.2 M扩展到约7 M。我们证实了与SERPINA 6/SERPINA 1的遗传关联。该基因座含有编码皮质类固醇结合球蛋白（CBG）和α1-抗胰蛋白酶的基因。在600个个体的STARNET队列中进行的表达数量性状基因座（eQTL）分析表明，SERPINA 6/SERPINA 1基因座内的特定遗传变异影响肝脏中SERPINA 6而不是SERPINA 1的表达。此外，trans-eQTL分析表明对脂肪组织基因表达的影响，表明CBG水平的变化对皮质醇向外周组织的递送有影响。双样本孟德尔随机化分析提供的证据表明，在UK Biobank中，早晨血浆皮质醇的每个遗传学确定的标准差（SD）增加与慢性缺血性心脏病（0.32，95% CI 0.06-0.59）和心肌梗死（0.21，95% CI 0.00-0.43）的几率增加相关，在CARDIOGRAMplusC 4D中也相似。这些发现揭示了CBG在外周组织中决定皮质醇作用的致病途径，从而有助于心血管疾病的病因学。
The stress hormone cortisol modulates fuel metabolism, cardiovascular homoeostasis, mood, inflammation and cognition. The CORtisol NETwork (CORNET) consortium previously identified a single locus associated with morning plasma cortisol. Identifying additional genetic variants that explain more of the variance in cortisol could provide new insights into cortisol biology and provide statistical power to test the causative role of cortisol in common diseases. The CORNET consortium extended its genome-wide association meta-analysis for morning plasma cortisol from 12,597 to 25,314 subjects and from ~2.2 M to ~7 M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1. This locus contains genes encoding corticosteroid binding globulin (CBG) and α1-antitrypsin. Expression quantitative trait loci (eQTL) analyses undertaken in the STARNET cohort of 600 individuals showed that specific genetic variants within the SERPINA6/SERPINA1 locus influence expression of SERPINA6 rather than SERPINA1 in the liver. Moreover, trans-eQTL analysis demonstrated effects on adipose tissue gene expression, suggesting that variations in CBG levels have an effect on delivery of cortisol to peripheral tissues. Two-sample Mendelian randomisation analyses provided evidence that each genetically-determined standard deviation (SD) increase in morning plasma cortisol was associated with increased odds of chronic ischaemic heart disease (0.32, 95% CI 0.06–0.59) and myocardial infarction (0.21, 95% CI 0.00–0.43) in UK Biobank and similarly in CARDIoGRAMplusC4D. These findings reveal a causative pathway for CBG in determining cortisol action in peripheral tissues and thereby contributing to the aetiology of cardiovascular disease.
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影响因子：
30.8
作者：
Bulik-Sullivan, Brendan K.;Loh, Po-Ru;Finucane, Hilary K.;Ripke, Stephan;Yang, Jian;Patterson, Nick;Daly, Mark J.;Price, Alkes L.;Neale, Benjamin M.
通讯作者：
Neale, Benjamin M.
影响因子：
30.8
作者：
Finucane HK;Bulik-Sullivan B;Gusev A;Trynka G;Reshef Y;Loh PR;Anttila V;Xu H;Zang C;Farh K;Ripke S;Day FR;ReproGen Consortium;Schizophrenia Working Group of the Psychiatric Genomics Consortium;RACI Consortium;Purcell S;Stahl E;Lindstrom S;Perry JR;Okada Y;Raychaudhuri S;Daly MJ;Patterson N;Neale BM;Price AL
通讯作者：
Price AL
DOI：
10.1126/science.aad6970
发表时间：
2016-08-19
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Franzén O;Ermel R;Cohain A;Akers NK;Di Narzo A;Talukdar HA;Foroughi-Asl H;Giambartolomei C;Fullard JF;Sukhavasi K;Köks S;Gan LM;Giannarelli C;Kovacic JC;Betsholtz C;Losic B;Michoel T;Hao K;Roussos P;Skogsberg J;Ruusalepp A;Schadt EE;Björkegren JL
通讯作者：
Björkegren JL
影响因子：
5.8
作者：
Phillips, DIW;Barker, DJP;Walker, BR
通讯作者：
Walker, BR
影响因子：
5.8
作者：
Reynolds, RM;Walker, BR;Phillips, DIW
通讯作者：
Phillips, DIW