背景:单核苷酸多态性(SNP)和DNA甲基化是原发性高血压(EH)的关键调节因子。淀粉样前体蛋白(APP)突变与高血压的发展有关。尽管如此,关于APP基因多态性和启动子甲基化与高血压相关性的研究还很有限。因此,本病例对照旨在评估贵州人群APP基因多态性和启动子甲基化与EH的遗传关联。
目的:我们对343例EH患者和335例健康对照进行了病例对照研究(包括苗族,布依族,和中国贵州省的汉族人群)通过MassARSNRAYP分析APP基因中的11个单核苷酸多态性(rs2040273,rs63750921,rs2211772,rs2830077,rs467021,rs368196,rs466433,rs364048,rs364051,rs438031,rs463946)。使用MassARRAYEpITYPER检测启动子的甲基化水平。
结果:在汉族人群中,rs2211772基因型分布在疾病组和对照组间差异有统计学意义(χ2=6.343,P=0.039)。与TT或TC基因型相比,CC基因型降低了高血压的风险(OR0.105,95CI0.012-0.914,P=0.041)。对于苗族种群中的rs2040273,与AA基因型相比,AG或GG基因型降低了高血压的风险(OR0.533,95CI0.294-0.965,P=0.038)。单倍型TCC(rs364051-rs438031-rs463946)增加了贵州地区EH的风险(OR1.427,95CI1.020-1.996,P=0.037)。CpG_19(-613bp)甲基化水平每增加1%,高血压风险增加4.1%(OR1.041,95CI1.002-1.081,P=0.039)。CpG_1(-296bp)甲基化水平每增加1%,女性高血压风险降低8%(OR0.920,95CI0.860-0.984,P=0.015)。CpG_19与收缩压显著相关(r=0.2,P=0.03)。rs466433、rs364048和rs364051次要等位基因的高血压患者CpG_19甲基化水平低于野生型等位基因(P<0.05)。此外,rs467021和rs364051与EH有较强的协同作用(χ2=7.633,P=0.006)。CpG_11、CpG_19和rs364051与EH的协同作用较弱(χ2=19.874,P<0.001)。
结论:总之,APP基因rs2211772多态性和启动子甲基化水平可能与贵州人群EH相关。我们的发现将为高血压和阿尔茨海默病的遗传学研究提供新的见解。
BACKGROUND: Single-nucleotide polymorphisms (SNPs) and DNA methylation are crucial regulators of essential hypertension (EH). Amyloid precursor protein (APP) mutations are implicated in hypertension development. Nonetheless, studies on the association of APP gene polymorphism and promoter methylation with hypertension are limited. Therefore, this
case-control aims to evaluate the genetic association of APP gene polymorphism and promoter methylation with EH in Guizhou populations.
OBJECTIVE: We conducted a
case-control study on 343 EH patients and 335 healthy controls (including Miao, Buyi, and Han populations) in the Guizhou province of China to analyze 11 single-nucleotide polymorphisms (rs2040273, rs63750921, rs2211772, rs2830077, rs467021, rs368196, rs466433, rs364048, rs364051, rs438031, rs463946) in the APP gene via MassARRAY SNP. The MassARRAY EpiTYPER was employed to detect the methylation levels of the promoters.
RESULTS: In the Han population, the rs2211772 genotype distribution was significantly different between disease and control groups (χ2 = 6.343, P = 0.039). The CC genotype reduced the risk of hypertension compared to the TT or TC genotype (OR 0.105, 95%CI 0.012-0.914, P = 0.041). For rs2040273 in the Miao population, AG or GG genotype reduced the hypertension risk compared with the AA genotype (OR 0.533, 95%CI 0.294-0.965, P = 0.038). Haplotype TCC (rs364051-rs438031-rs463946) increased the risk of EH in Guizhou (OR 1.427, 95%CI 1.020-1.996, P = 0.037). Each 1% increase in CpG_19 (- 613 bp) methylation level was associated with a 4.1% increase in hypertension risk (OR 1.041, 95%CI 1.002-1.081, P = 0.039). Each 1% increase in CpG_1 (- 296 bp) methylation level was associated with an 8% decrease in hypertension risk in women (OR 0.920, 95%CI 0.860-0.984, P = 0.015). CpG_19 significantly correlated with systolic blood pressure (r = 0.2, P = 0.03). The methylation levels of CpG_19 in hypertensive patients with rs466433, rs364048, and rs364051 minor alleles were lower than that with wild-type alleles (P < 0.05). Moreover, rs467021 and rs364051 showed strong synergistic interaction with EH (χ2 = 7.633, P = 0.006). CpG_11, CpG_19, and rs364051 showed weak synergistic interaction with EH (χ2 = 19.874, P < 0.001).
CONCLUSIONS: In summary, rs2211772 polymorphism and promoter methylation level of APP gene may be linked to EH in Guizhou populations. Our findings will provide novel insights for genetic research of hypertension and Alzheimer\'s disease.