Division of Cardiology, Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Province Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China; Department of Nutrition and Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Division of Cardiology, Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Hubei Province Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China.
J Mol Cell Cardiol. 2020 Jul;144:54-62. doi: 10.1016/j.yjmcc.2020.05.003. Epub 2020 May 11.
Recent genome-wide association studies identified several polymorphisms in the APOA5/A4/C3/A1 gene cluster influencing lipids level and risk of coronary heart disease (CHD). However, few studies explored the molecular mechanism. The purposes of this study were to fine-map noncoding region between APOA1 and APOC3 and then explore the clinical relevance in CHD and potential underlying mechanisms. In this study, a 2.7-kb length of the non-coding region between APOA1 and APOC3 was screened and five polymorphisms were investigated in the case-control study. The molecular mechanism was explored. Our data confirmed the association between rs7123454, rs12721030, rs10750098, and rs12721028 with CHD in 828 patients and 828 controls and replicated it in an independent population of 405 patients and 405 controls. In addition, the rs10750098 and rs12721030 are significantly associated with decreased serum APOA1 levels (P = 4.2 × 10 and P = 3.2 × 10, combined analysis), while a significant association was observed between serum APOA1 level and CHD (OR: 0.43, 95% CI: 0.28-0.64, P < .01) with adjustment for clinical covariates and different population sets. In vitro evaluation of potential function of non-coding variants between APOA1 and APOC3 demonstrated that rs10750098 as being the most sufficient to confer the haplotype-specific effect on the regulation of APOs gene transcription. Our results strongly implicate the involvement of common noncoding DNA variants in APOA5/A4/C3/A1 gene cluster in the pathogenesis of dyslipidemia and the risk of CHD.
最近的全基因组关联研究鉴定出 APOA5/A4/C3/A1 基因簇中的几个多态性，这些多态性影响血脂水平和冠心病 (CHD) 的风险。然而，很少有研究探讨其分子机制。本研究旨在精细定位 APOA1 和 APOC3 之间的非编码区，然后探讨其在 CHD 中的临床相关性和潜在的机制。在这项研究中，我们筛选了 APOA1 和 APOC3 之间的 2.7kb 长的非编码区，并在病例对照研究中研究了 5 个多态性。探索了分子机制。我们的数据证实了 rs7123454、rs12721030、rs10750098 和 rs12721028 与 828 例患者和 828 例对照者 CHD 之间的关联，并在 405 例患者和 405 例对照者的独立人群中进行了验证。此外，rs10750098 和 rs12721030 与血清 APOA1 水平降低显著相关(P=4.2×10-6和 P=3.2×10-6，联合分析)，而血清 APOA1 水平与 CHD 之间存在显著相关性(OR:0.43，95%CI:0.28-0.64，P<0.01)，调整了临床协变量和不同人群集。APOA1 和 APOC3 之间非编码变异的潜在功能的体外评估表明，rs10750098 作为最充分的因素，赋予了对 APOs 基因转录调节的单体型特异性效应。我们的研究结果强烈表明，APOA5/A4/C3/A1 基因簇中的常见非编码 DNA 变异与血脂异常和 CHD 的发病机制有关。
