Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, & Collaborative Innovation Center for Prevention and Control of Endemic and Ethnic Regional Diseases Co-constructed by the Province and Ministry, Guizhou Medical University, Guiyang, 550004, Guizhou, China.
Department of Cardiovascular Medicine, Affiliated Hospital of Guizhou Medical University, Guiyang, China.
Hum Genomics. 2023 Mar 20;17(1):25. doi: 10.1186/s40246-023-00462-y.
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.
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.
In the Han population, the rs2211772 genotype distribution was significantly different between disease and control groups (χ = 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 (χ = 7.633, P = 0.006). CpG_11, CpG_19, and rs364051 showed weak synergistic interaction with EH (χ = 19.874, P < 0.001).
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.
单核苷酸多态性 (SNP) 和 DNA 甲基化是原发性高血压 (EH) 的关键调节因素。淀粉样前体蛋白 (APP) 突变与高血压的发展有关。然而，关于 APP 基因多态性和启动子甲基化与高血压的关联研究有限。因此，本病例对照研究旨在评估 APP 基因多态性和启动子甲基化与贵州人群 EH 的遗传关联。
我们在中国贵州省进行了一项病例对照研究，纳入了 343 名 EH 患者和 335 名健康对照者（包括苗族、布依族和汉族人群），以分析 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），采用 MassARRAY SNP 进行分析。采用 MassARRAY EpiTYPER 检测启动子的甲基化水平。
在汉族人群中，疾病组和对照组之间 rs2211772 基因型分布差异有统计学意义（χ²=6.343，P=0.039）。CC 基因型与 TT 或 TC 基因型相比，降低了高血压的发病风险（OR 0.105，95%CI 0.012-0.914，P=0.041）。在苗族人群中，与 AA 基因型相比，AG 或 GG 基因型降低了高血压的发病风险（OR 0.533，95%CI 0.294-0.965，P=0.038）。APP 基因的 rs364051-rs438031-rs463946 单体型 TCC 增加了贵州 EH 的发病风险（OR 1.427，95%CI 1.020-1.996，P=0.037）。CpG_19（-613 bp）甲基化水平每增加 1%，高血压发病风险增加 4.1%（OR 1.041，95%CI 1.002-1.081，P=0.039）。女性 CpG_1（-296 bp）甲基化水平每增加 1%，高血压发病风险降低 8%（OR 0.920，95%CI 0.860-0.984，P=0.015）。CpG_19 与收缩压显著相关（r=0.2，P=0.03）。rs466433、rs364048 和 rs364051 等位基因携带者的 CpG_19 甲基化水平低于野生型等位基因携带者（P<0.05）。此外，rs467021 和 rs364051 与 EH 具有强烈的协同交互作用（χ²=7.633，P=0.006）。CpG_11、CpG_19 和 rs364051 与 EH 具有较弱的协同交互作用（χ²=19.874，P<0.001）。
综上所述，APP 基因多态性和启动子甲基化水平可能与贵州人群的 EH 有关。我们的研究结果为高血压和阿尔茨海默病的遗传研究提供了新的见解。
