Chen Jie, Jin Ye, Wang Hong, Wei Sisi, Chen Dan, Ying Li, Zhou Qing, Li Gang, Li Joyce, Gao Jimin, Kato Naoya, Hu Wei, Li Yigang, Wang Yuepeng
Molecular Cardiology Research Laboratory, Department of Cardiology, Affiliated Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Department of Ultrasound, Affiliated Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
PLoS One. 2015 Dec 31;10(12):e0145602. doi: 10.1371/journal.pone.0145602. eCollection 2015.
The role of genetic abnormality of δ-sarcoglycan (δ-SG) gene in dilated (DCM) and hypertrophied (HCM) cardiomyopathy patients is still unfolding. In this study we first defined the promoter region and then searched for polymorphisms/mutations among the promoter, 5'-untranslated region, and the encoding exons in δ-SG gene in 104 Chinese patients with DCM, 145 with HCM, and 790 normal controls. Two novel polymorphisms were found, an 11 base-pair (bp) deletion (c.-100-110; -) in the promoter region and a missense polymorphism of A848G resulting in p.Q283R in the highly conserved C-terminus. The prevalence of homozygous genotype -/- of c.-100-110 was slightly higher in DCM (14.42%) and HCM patients (14.48%), as compared with normal controls (11.01%). The prevalence of genotype of 848A/G was significantly higher in DCM (6.73%; OR = 9.43; p = 0.0002), but not in HCM patients (1.38%; OR = 1.37; p = 0.62), as compared with controls (0.76%). Haplotype -_G consisting c.-100-110 and A848G was associated with increased risk of DCM (OR = 17.27; 95%CI = 3.19-93.56; p = 0.001) but not associated with HCM (OR = 1.90; 95%CI = 0.38-9.55; p = 0.44). Co-occurrence of the genotypes -/- of c.-100-110 and 848A/G was found in 5 patients with DCM (4.81%; OR = 39.85; p = 0.0001), none of HCM patients, and only 1 of the controls (0.13%). Both polymorphisms were also found in the Japanese population, but not in the Africans and Caucasians. C.-100-110 resulted in a decrease of δ-SG promoter activity to 64±3% of the control level (p<0.01). Both co-immunoprecipitation and in vitro protein pull-down assays demonstrated that δ-SG-283R interacts normally to β- and γ-SG, but significantly decreased localization of β/δ/γ-SG on the plasma membrane. In conclusion, haplotype -_G composed of c.-100-110 and A848G confers higher susceptibility to DCM in the Mongoloid population.
δ-肌聚糖（δ-SG）基因的遗传异常在扩张型心肌病（DCM）和肥厚型心肌病（HCM）患者中的作用仍在逐步显现。在本研究中，我们首先确定了启动子区域，然后在104例中国DCM患者、145例HCM患者和790例正常对照者中，对δ-SG基因的启动子、5'-非翻译区和编码外显子进行多态性/突变筛查。发现了两个新的多态性位点，一个是启动子区域11个碱基对（bp）的缺失（c.-100-110；-），另一个是A848G错义多态性，导致高度保守的C末端出现p.Q283R。与正常对照者（11.01%）相比，c.-100-110纯合基因型-/-在DCM患者（14.42%）和HCM患者（14.48%）中的患病率略高。与对照者（0.76%）相比，848A/G基因型在DCM患者中的患病率显著更高（6.73%；OR = 9.43；p = 0.0002），但在HCM患者中不高（1.38%；OR = 1.37；p = 0.62）。由c.-100-110和A848G组成的单倍型-_G与DCM风险增加相关（OR = 17.27；95%CI = 3.19 - 93.56；p = 0.001），但与HCM无关（OR = 1.90；95%CI = 0.38 - 9.55；p = 0.44）。在5例DCM患者（4.81%；OR = 39.85；p = 0.0001）中发现了c.-100-110的-/-基因型和848A/G的共出现，HCM患者中未发现，而在对照者中仅1例（0.13%）。在日本人群中也发现了这两种多态性，但在非洲人和高加索人群中未发现。C.-100-110导致δ-SG启动子活性降至对照水平的64±3%（p<0.01）。共免疫沉淀和体外蛋白质下拉试验均表明，δ-SG-283R与β-和γ-SG正常相互作用，但显著降低了β/δ/γ-SG在质膜上的定位。总之，由c.-100-110和A848G组成的单倍型-_G使蒙古人种人群对DCM的易感性更高。
