Esslinger Ulrike, Garnier Sophie, Korniat Agathe, Proust Carole, Kararigas Georgios, Müller-Nurasyid Martina, Empana Jean-Philippe, Morley Michael P, Perret Claire, Stark Klaus, Bick Alexander G, Prasad Sanjay K, Kriebel Jennifer, Li Jin, Tiret Laurence, Strauch Konstantin, O'Regan Declan P, Marguiles Kenneth B, Seidman Jonathan G, Boutouyrie Pierre, Lacolley Patrick, Jouven Xavier, Hengstenberg Christian, Komajda Michel, Hakonarson Hakon, Isnard Richard, Arbustini Eloisa, Grallert Harald, Cook Stuart A, Seidman Christine E, Regitz-Zagrosek Vera, Cappola Thomas P, Charron Philippe, Cambien François, Villard Eric
Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR-S1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France.
ICAN Institute for Cardiometabolism and Nutrition, Paris, France.
PLoS One. 2017 Mar 15;12(3):e0172995. doi: 10.1371/journal.pone.0172995. eCollection 2017.
Dilated cardiomyopathy (DCM) is an important cause of heart failure with a strong familial component. We performed an exome-wide array-based association study (EWAS) to assess the contribution of missense variants to sporadic DCM.
116,855 single nucleotide variants (SNVs) were analyzed in 2796 DCM patients and 6877 control subjects from 6 populations of European ancestry. We confirmed two previously identified associations with SNVs in BAG3 and ZBTB17 and discovered six novel DCM-associated loci (Q-value<0.01). The lead-SNVs at novel loci are common and located in TTN, SLC39A8, MLIP, FLNC, ALPK3 and FHOD3. In silico fine mapping identified HSPB7 as the most likely candidate at the ZBTB17 locus. Rare variant analysis (MAF<0.01) demonstrated significant association for TTN variants only (P = 0.0085). All candidate genes but one (SLC39A8) exhibit preferential expression in striated muscle tissues and mutations in TTN, BAG3, FLNC and FHOD3 are known to cause familial cardiomyopathy. We also investigated a panel of 48 known cardiomyopathy genes. Collectively, rare (n = 228, P = 0.0033) or common (n = 36, P = 0.019) variants with elevated in silico severity scores were associated with DCM, indicating that the spectrum of genes contributing to sporadic DCM extends beyond those identified here.
We identified eight loci independently associated with sporadic DCM. The functions of the best candidate genes at these loci suggest that proteostasis regulation might play a role in DCM pathophysiology.
扩张型心肌病（DCM）是心力衰竭的重要病因，具有很强的家族性因素。我们进行了一项基于外显子组芯片的全基因组关联研究（EWAS），以评估错义变异对散发性DCM的影响。
对来自6个欧洲血统人群的2796例DCM患者和6877例对照受试者的116,855个单核苷酸变异（SNV）进行了分析。我们证实了先前在BAG3和ZBTB17中鉴定出的与SNV的两个关联，并发现了六个新的DCM相关位点（Q值<0.01）。新位点的主要SNV很常见，位于TTN、SLC39A8、MLIP、FLNC、ALPK3和FHOD3中。计算机精细定位确定HSPB7是ZBTB17位点最可能的候选基因。罕见变异分析（MAF<0.01）仅显示TTN变异有显著关联（P = 0.0085）。除一个基因（SLC39A8）外，所有候选基因在横纹肌组织中均有优先表达，已知TTN、BAG3、FLNC和FHOD3中的突变会导致家族性心肌病。我们还研究了一组48个已知的心肌病基因。总体而言，计算机预测严重程度评分升高的罕见（n = 228，P = 0.0033）或常见（n = 36，P = 0.019）变异与DCM相关，表明导致散发性DCM的基因谱超出了此处鉴定的基因。
我们鉴定出八个与散发性DCM独立相关 的位点。这些位点上最佳候选基因的功能表明，蛋白质稳态调节可能在DCM病理生理学中起作用。
