Department of Internal Medicine III, University Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
Eur Heart J. 2014 Apr;35(16):1069-77. doi: 10.1093/eurheartj/eht251. Epub 2013 Jul 12.
Dilated cardiomyopathy (DCM) is one of the leading causes for cardiac transplantations and accounts for up to one-third of all heart failure cases. Since extrinsic and monogenic causes explain only a fraction of all cases, common genetic variants are suspected to contribute to the pathogenesis of DCM, its age of onset, and clinical progression. By a large-scale case-control genome-wide association study we aimed here to identify novel genetic risk loci for DCM.
Applying a three-staged study design, we analysed more than 4100 DCM cases and 7600 controls. We identified and successfully replicated multiple single nucleotide polymorphism on chromosome 6p21. In the combined analysis, the most significant association signal was obtained for rs9262636 (P = 4.90 × 10(-9)) located in HCG22, which could again be replicated in an independent cohort. Taking advantage of expression quantitative trait loci (eQTL) as molecular phenotypes, we identified rs9262636 as an eQTL for several closely located genes encoding class I and class II major histocompatibility complex heavy chain receptors.
The present study reveals a novel genetic susceptibility locus that clearly underlines the role of genetically driven, inflammatory processes in the pathogenesis of idiopathic DCM.
扩张型心肌病（DCM）是心脏移植的主要原因之一，占所有心力衰竭病例的三分之一。由于外在和单基因原因仅能解释所有病例的一小部分，因此常见的遗传变异体被怀疑导致 DCM 的发病机制、发病年龄和临床进展。通过一项大规模的病例对照全基因组关联研究，我们旨在确定 DCM 的新的遗传风险位点。
应用三阶段研究设计，我们分析了超过 4100 例 DCM 病例和 7600 例对照。我们在 6p21 染色体上鉴定并成功复制了多个单核苷酸多态性。在联合分析中，位于 HCG22 中的 rs9262636 获得了最显著的关联信号（P=4.90×10(-9)），在一个独立的队列中也可以再次复制。利用表达数量性状基因座（eQTL）作为分子表型，我们鉴定出 rs9262636 是编码 I 类和 II 类主要组织相容性复合物重链受体的几个紧密相邻基因的 eQTL。
本研究揭示了一个新的遗传易感位点，明确强调了遗传驱动的炎症过程在特发性 DCM 发病机制中的作用。
