Sorbonne Université, INSERM, UMR-S1166, Research Unit on Cardiovascular Disorders, Metabolism and Nutrition, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris 75013, France.
ICAN Institute for Cardiometabolism and Nutrition, Paris 75013, France.
Eur Heart J. 2021 May 21;42(20):2000-2011. doi: 10.1093/eurheartj/ehab030.
Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure.
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 × 10-11 and 7.7 × 10-4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10-8 and 1.4 × 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.
This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure.
我们的目的是更好地了解扩张型心肌病（DCM）的遗传基础，DCM 是收缩性心力衰竭的主要原因。
我们进行了迄今为止最大规模的 DCM 全基因组关联研究，在发现人群中包括 2719 例病例和 4440 例对照。我们确定并复制了染色体 3p25.1 上的两个新的 DCM 相关位点[先导单核苷酸多态性（SNP）rs62232870，在发现和复制步骤中的 P 值分别为 8.7×10-11 和 7.7×10-4]和染色体 22q11.23（先导 SNP rs7284877，在发现和复制步骤中的 P 值分别为 3.3×10-8 和 1.4×10-3），同时确认了染色体 10 和 1 上的两个先前确定的 DCM 位点 BAG3 和 HSPB7。从这四个 DCM 位点的风险等位基因数量构建的遗传风险评分显示，与携带 5 个风险等位基因的个体相比，携带 8 个风险等位基因的个体患 DCM 的风险增加了 3 倍（参考人群的中位数）。对 iPSC 衍生的心肌细胞进行的计算机注释和功能性 4C 测序分析确定 SLC6A6 为 3p25.1 位点最有可能的 DCM 基因。该基因编码一种牛磺酸转运体，其在人类和动物中的心肌功能障碍和 DCM 中的作用得到了大量观察结果的支持。在 22q11.23 位点，计算机注释和数据挖掘注释，以及在较小程度上的功能分析，强烈提示 SMARCB1 为候选罪魁祸首基因。
这项研究提供了对 DCM 遗传结构的更好理解，并揭示了心力衰竭潜在的新生物学途径。
