Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23
Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23
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DOI：
10.1093/eurheartj/ehab030
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发表时间：
2021-03-03
影响因子：
39.3
通讯作者：
Charron, Philippe
中科院分区：
文献类型：
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作者：
Garnier, Sophie;Harakalova, Magdalena;Charron, Philippe
目的：我们的目标是更好地了解扩张型心肌病（DCM），收缩性heart failure.Methods和results的主要原因的遗传基础：我们进行了迄今为止在DCM中进行的最大的全基因组关联研究，发现人口中有2719例和4440例对照。我们在染色体3p25.1 [前导单核苷酸多态性（SNP）rs62232870，发现和复制步骤中的P值分别为8.7 x 10（-11）和7.7 x 10（-4）]和染色体22q11.23上鉴定并复制了两个新的DCM相关基因座。（前导SNP rs7284877，在发现和复制步骤中分别P = 3.3 × 10（-8）和1.4 × 10（-3）），同时确认了染色体10和1上的两个先前鉴定的DCM基因座，BAG 3和HSPB 7。从这四个DCM基因座的风险等位基因数量构建的遗传风险评分显示，与具有5个风险等位基因的个体相比，具有8个风险等位基因的个体患DCM的风险增加了3倍（转诊人群的中位数）。对iPSC衍生的心肌细胞的计算机注释和功能性4C测序分析将SLC 6A 6鉴定为3p25.1基因座处最可能的DCM基因。该基因编码牛磺酸转运蛋白，其参与心肌功能障碍和扩张型心肌病得到了人类和动物中大量观察结果的支持。在22q11.23位点，在硅片和数据挖掘注释，并在较小程度上的功能分析，强烈建议SMARCB 1作为候选人的罪魁祸首gene.Conclusion：这项研究提供了一个更好的理解DCM的遗传结构，揭示了新的生物学途径的基础上心力衰竭。[图片]
Aims: Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure.Methods and results: We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 x 10(-11) and 7.7 x 10(-4) in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 x 10(-8) and 1.4 x 10(-3) in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 3-fold increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene.Conclusion: This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure.[GRAPHICS]