Abstract
Objective
Mutations in LIM domain binding 3 (LDB3) gene cause idiopathic dilated cardiomyopathy (IDCM), a structural heart disease with a complicated genetic background. However, the association of polymorphisms in the LDB3 gene with susceptibility to IDCM in Chinese populations remains unexplored as dose the impact on clinical presentation.
Methods
We sequenced all exons and the adjacent part of introns of the LDB3 gene in 159 Chinese Han IDCM patients and 247 healthy controls. Then we detected the distribution of polymorphisms in the LDB3 gene in all participants and assessed their associations with risk of IDCM. Additionally, we conducted a stratified genotypephenotype correlation analysis.
Results
The A allele of rs4468255 was significantly associated with IDCM (P<0.01). The rs4468255, rs11812601, rs56165849, and rs3740346 were also associated with diastolic blood pressure (DBP) and left ventricular ejection fraction (LVEF) (P<0.05). Notably, a higher frequency of rs4468255 polymorphism was observed in implantable cardioverter defibrillator (ICD) recipients under a recessive model (P<0.01), whereas the significant association disappeared after adjusting for potential confounders. However, in the dominant model, notable correlations could only be observed after adjusting for multi parameters.
Conclusions
The rs4468255 was significantly correlated with IDCM of Chinese Han population. A allele of rs4468255 is higher in IDCM patients with ICD implantation, suggesting the influence of genetic background in the generation of this response. In addition, rs11812601, rs56165849, and rs3740346 in LDB3 show association with brain natriuretic peptide, DBP, and LVEF levels in patients with IDCM but did not show any association with IDCM susceptibility.
抽象
目 的
探讨 LDB3 (LIM domain binding 3) 基因多态性 与中国汉族特发性扩张型心肌病发病的相关性, 并分析 LDB3 基因多态性对患者临床表现和植入 型心律转复除颤器 (ICD) 植入的影响。
创新点
首次明确 LDB3 基因多态性与中国汉族特发性扩 张型心肌病发病密切相关, 发现了三个与脑钠 肽、舒张压、左室射血分数相关的多态性位点和 一个与植入心律转复除颤器相关的多态性位点。
方 法
本研究纳入我院 159 例中国汉族特发性扩张型心 肌病患者和 247 例无亲缘关系健康对照并收集基 线临床资料。 提取外周血 DNA 后, 聚合酶链式 反应扩增 LDB3 基因的14 个外显子, 经 Sanger 一代测序, 获得基因突变位点。 通过关联分析, 研究基因多态性与特发性扩张型心肌病发病之 间的相关性。 根据连锁不平衡系数和基因分布频 率进行单倍体分析, 研究不同单倍体分型对特发 性扩张型心肌病发病的影响。
结 论
在 LDB3 基因多态性分析中, 发现9 个多态性位 点符合哈代-温伯格平衡。 其中 rs4468255 位点多 态性与中国汉族特发性扩张型心肌病发病密切 相关。rs11812601、rs56165849 和 rs3740346 位点 多态性与患者舒张压、左室射血分数存在显著关 联 (P<0.05)。 且携带 rs4468255 多态性的患者 更倾向于安装植入型心律转复除颤器。
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Project supported by the Key Projects of Zhejiang Medical and Health Science and Technology Plan (Provincial and Ministerial Co-construction) (No. WKJ-ZJ-1819), the Fundamental Research Funds for the Zhejiang Province Universities (No. 2019XZZX003-15), and the National Natural Science Foundation of China (No. 81470370)
Contributors
Dong-fei WANG, Jia-lan LYU, and Juan FANG prepared samples and conceived the experiment. Dong-fei WANG, Hong-qiang CHENG, and Xiao-gang GUO designed the experiment. Jian-mei JIN and Fang-hong DONG collected the data. Jia-qi HUANG and Shu-dong XIA compared the sequencing results with the templates. Dong-fei WANG, Jia-lan LYU, and Jian CHEN processed and analyzed data. Dong-fei WANG, Wan-wan CHEN, Ying-ke XU, and Xiao-gang GUO wrote the manuscript with input from all authors.
Compliance with ethics guidelines
Dong-fei WANG, Jia-lan LYU, Juan FANG, Jian CHEN, Wan-wan CHEN, Jia-qi HUANG, Shu-dong XIA, Jian-mei JIN, Fang-hong DONG, Hong-qiang CHENG, Ying-ke XU, and Xiao-gang GUO declare that they have no conflict of interest.
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5). Informed consent was obtained from all patients for being included in the study.
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Wang, Df., Lyu, Jl., Fang, J. et al. Impact of LDB3 gene polymorphisms on clinical presentation and implantable cardioverter defibrillator (ICD) implantation in Chinese patients with idiopathic dilated cardiomyopathy. J. Zhejiang Univ. Sci. B 20, 766–775 (2019). https://doi.org/10.1631/jzus.B1900017
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DOI: https://doi.org/10.1631/jzus.B1900017
Key words
- Idiopathic dilated cardiomyopathy
- Implantable cardioverter defibrillator (ICD)
- LIM domain binding 3 (LDB3)
- Polymorphism
- Han Chinese