Genome-Wide Association Study of Pericardial Fat Area in 28 161 UK Biobank Participants.
Genome-Wide Association Study of Pericardial Fat Area in 28 161 UK Biobank Participants.
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28161名英国生物库参与者的心包脂肪区全基因组关联研究。
DOI：
10.1161/jaha.123.030661
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发表时间：
2023-11-07
影响因子：
5.4
通讯作者：
Raisi-Estabragh, Zahra
中科院分区：
文献类型：
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作者：
Salih, Ahmed;Ardissino, Maddalena;Wagen, Aaron Z.;Bard, Andrew;Szabo, Liliana;Ryten, Mina;Petersen, Steffen E.;Altmann, Andre;Raisi-Estabragh, Zahra
心包脂肪组织(PAT)是心脏周围的内脏脂肪组织。实验和观察研究表明，更多的PAT沉积可能介导心血管疾病，独立于全身或皮下肥胖。我们描述了肥胖调整的PAT的遗传结构，并在28名 161UK生物库参与者中确定了PAT与心脏结构和功能的不利心脏磁共振成像测量之间的因果关系。PAT表型是使用先前开发的自动图像分析工具从心脏磁共振图像中提取的，并在该队列中进行了验证。进行了一项全基因组关联研究，将PAT区域设置为表型，根据年龄、性别和其他肥胖指标进行调整。功能图谱和贝叶斯共定位被用来理解已识别的突变体的生物学作用。孟德尔随机化分析被用来检查遗传决定的PAT和心脏磁共振得出的左心室结构和功能测量之间的潜在因果联系。我们在两个不同的基因组座位上发现了12个全基因组显著的变异，其中2个独立的前哨变异(rs6428792，P=4.20×10−9和rs11992444，P=1.30×10−12)，通过功能注释被定位到3个潜在的致病基因：T盒转录因子15(Tbx15)、色氨酸tRNA合成酶2、线粒体(WARS2)和早期B细胞因子2(EBF2)。贝叶斯共定位还暗示了Rp4-712E4.1的作用。基因预测的肥胖调整后的PAT差异与不良的左心室重构有因果关系。这项研究提供了对决定差异PAT沉积的遗传结构的见解，确定了与左侧结构和功能参数的因果联系，并提供了关于肥胖分布的病理生理学重要性的新数据。
Pericardial adipose tissue (PAT) is the visceral adipose tissue compartment surrounding the heart. Experimental and observational research has suggested that greater PAT deposition might mediate cardiovascular disease, independent of general or subcutaneous adiposity. We characterize the genetic architecture of adiposity‐adjusted PAT and identify causal associations between PAT and adverse cardiac magnetic resonance imaging measures of cardiac structure and function in 28 161 UK Biobank participants. The PAT phenotype was extracted from cardiac magnetic resonance images using an automated image analysis tool previously developed and validated in this cohort. A genome‐wide association study was performed with PAT area set as the phenotype, adjusting for age, sex, and other measures of obesity. Functional mapping and Bayesian colocalization were used to understand the biologic role of identified variants. Mendelian randomization analysis was used to examine potential causal links between genetically determined PAT and cardiac magnetic resonance–derived measures of left ventricular structure and function. We discovered 12 genome‐wide significant variants, with 2 independent sentinel variants (rs6428792, P=4.20×10−9 and rs11992444, P=1.30×10−12) at 2 distinct genomic loci, that were mapped to 3 potentially causal genes: T‐box transcription factor 15 (TBX15), tryptophanyl tRNA synthetase 2, mitochondrial (WARS2) and early B‐cell factor‐2 (EBF2) through functional annotation. Bayesian colocalization additionally suggested a role of RP4‐712E4.1. Genetically predicted differences in adiposity‐adjusted PAT were causally associated with adverse left ventricular remodeling. This study provides insights into the genetic architecture determining differential PAT deposition, identifies causal links with left structural and functional parameters, and provides novel data about the pathophysiological importance of adiposity distribution.
影响因子：
4.5
作者：
Fox CS;White CC;Lohman K;Heard-Costa N;Cohen P;Zhang Y;Johnson AD;Emilsson V;Liu CT;Chen YD;Taylor KD;Allison M;Budoff M;CARDIoGRAM Consortium;Rotter JI;Carr JJ;Hoffmann U;Ding J;Cupples LA;Liu Y
通讯作者：
Liu Y