与先天性心脏病相关的遗传变异:种族和亚型特异性易感性的荟萃分析

IF 5.5 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Hae Sung Chon, Ji Wan Park
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引用次数: 0

摘要

背景:先天性心脏病(CHD)是最常见的异质性出生缺陷,其患病率在不同人群中存在差异。一项全面的荟萃分析可以完善遗传风险评估,增强我们对冠心病易感性的理解。方法:我们对175项病例对照研究进行了荟萃分析,调查了72个基因区域的107种遗传变异。使用6种遗传模型计算合并优势比,并按种族和冠心病亚型进行亚组分析。基因本体和网络分析阐明了相关基因的功能意义。结果:36个变异(PNRP1、MTHFR、MTRR、NOS3和DNMT1)与冠心病显著相关。10个变异,包括MAML3的rs1531070(优势比为1.52;P=5.9×10-15),超过了全基因组显著性。种族特异性分析确定了13个显著变异,包括中国人的MTHFR-rs1801131 (P=1.71×10-10),欧洲人的STX18-AS1-rs870142 (P=7.13×10-16)和中东人群的MTRR-rs1801394 (P=9.8×10-8)。亚型分析揭示了25个与特定冠心病亚型相关的变异,如房间隔缺损的STX18-AS1-rs16835979 (P=2.1×10-16)和法洛四联症的MTHFR、NRP1和PTPN11变异(P=3.0×10-17-2.33×10-10)。rs1801133变异与双出口右心室(P=3.0×10-11)和动脉导管未闭(P=6.5×10-9)有关。基因本体和网络分析突出了在冠心病发病过程中参与心脏发育和叶酸代谢的基因。结论:该荟萃分析细化了不同祖先和亚型的冠心病风险评估,强调了该疾病的复杂遗传结构。涉及心脏发育和代谢途径的变异是冠心病精准医学的有希望的靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Genetic Variants Associated With Congenital Heart Disease: A Meta-Analysis of Ethnicity and Subtype-Specific Susceptibility.

Background: Congenital heart disease (CHD) is the most common heterogeneous birth defect, with prevalence varying across populations. A comprehensive meta-analysis could refine the genetic risk estimates and enhance our understanding of CHD susceptibility.

Methods: We conducted a meta-analysis of 175 case-control studies investigating 107 genetic variants across 72 gene regions. Pooled odds ratios were calculated using 6 genetic models, with subgroup analyses by ethnicity and CHD subtype. Gene Ontology and network analyses elucidated the functional significance of implicated genes.

Results: Thirty-six variants were significantly associated with CHD (P<0.05), including 7 missense mutations in NRP1, MTHFR, MTRR, NOS3, and DNMT1. Ten variants, including rs1531070 in MAML3 (odds ratio, 1.52; P=5.9×10-15), surpassed genome-wide significance. Ethnicity-specific analyses identified 13 significant variants, including MTHFR-rs1801131 in Chinese (P=1.71×10-10), STX18-AS1-rs870142 in Europeans (P=7.13×10-16), and MTRR-rs1801394 in Middle Eastern populations (P=9.8×10-8). Subtype analyses revealed 25 variants associated with specific CHD subtypes, such as STX18-AS1-rs16835979 with atrial septal defect (P=2.1×10-16) and variants in MTHFR, NRP1, and PTPN11 with tetralogy of Fallot (P=3.0×10-17-2.33×10-10). The rs1801133 variant was linked to double-outlet right ventricle (P=3.0×10-11) and patent ductus arteriosus (P=6.5×10-9). Gene Ontology and network analyses highlighted genes involved in cardiac development and folate metabolism in CHD pathogenesis.

Conclusions: This meta-analysis refines CHD risk estimates across diverse ancestries and subtypes, underscoring the complex genetic architecture of the disease. Variants involved in cardiac development and metabolic pathways represent promising targets for precision medicine in CHD.

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来源期刊
Circulation: Genomic and Precision Medicine
Circulation: Genomic and Precision Medicine Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
9.20
自引率
5.40%
发文量
144
期刊介绍: Circulation: Genomic and Precision Medicine is a distinguished journal dedicated to advancing the frontiers of cardiovascular genomics and precision medicine. It publishes a diverse array of original research articles that delve into the genetic and molecular underpinnings of cardiovascular diseases. The journal's scope is broad, encompassing studies from human subjects to laboratory models, and from in vitro experiments to computational simulations. Circulation: Genomic and Precision Medicine is committed to publishing studies that have direct relevance to human cardiovascular biology and disease, with the ultimate goal of improving patient care and outcomes. The journal serves as a platform for researchers to share their groundbreaking work, fostering collaboration and innovation in the field of cardiovascular genomics and precision medicine.
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