Laboratory of Population Genetics, Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, Bangladesh.
National Institute of Cardiovascular Diseases, Sher-e-Bangla Nagar, Dhaka, 1207, Bangladesh.
Biochem Genet. 2021 Oct;59(5):1116-1145. doi: 10.1007/s10528-021-10049-8. Epub 2021 Mar 7.
Non-coding variants or single-nucleotide polymorphisms (SNPs) play pivotal roles in orchestrating pathogeneses of polygenic diseases, including hypertension (HTN) and diabetes. Renin-angiotensin system (RAS) components-renin and (pro)renin receptor [(P)RR]-maintain homeostasis of body fluids. Genetic variants of RAS components are associated with risk of HTN and type 2 diabetes (T2D) in different ethnic groups. We identified associations of SNPs within the renin and (P)RR genes with HTN, T2D, and T2D-associated hypertension in 911 unrelated Bangladeshi individuals. Five non-coding SNPs were involved in modulating regulatory elements in diverse cell types when tagged with other SNPs. rs61827960 was not associated with any disease; rs3730102 was associated with increased risk of HTN and T2D while under dominant model, it showed protective role against T2D-associated HTN. SNP rs11571079 was associated with increased risk of HTN and T2D-associated HTN and decreased risk of T2D, exerting a protective effect. Renin haplotypes GCA and GTG were related to increased risk of T2D and T2D-associated HTN, respectively. Heterogeneous linkage of genotypic and allelic frequencies of rs2968915 and rs3112298 of (P)RR was observed. The (P)RR haplotype GA was associated with increased risk of HTN and significantly decreased risk of T2D. These findings highlight important roles of non-coding variants of renin and (P)RR genes in the etiology of several polygenic diseases.
非编码变异或单核苷酸多态性 (SNP) 在调节多基因疾病的发病机制中发挥着关键作用，包括高血压 (HTN) 和糖尿病。肾素-血管紧张素系统 (RAS) 成分——肾素和 (前) 肾素受体 [(P)RR]——维持体液的内稳态。RAS 成分的遗传变异与不同种族群体的 HTN 和 2 型糖尿病 (T2D) 风险相关。我们在 911 名无血缘关系的孟加拉个体中鉴定了肾素和 (P)RR 基因内 SNP 与 HTN、T2D 和 T2D 相关的 HTN 的关联。当与其他 SNP 标记时，五个非编码 SNP 参与调节不同细胞类型的调节元件。rs61827960 与任何疾病均无关联；rs3730102 与 HTN 和 T2D 的发病风险增加相关，而在显性模型下，它对 T2D 相关的 HTN 具有保护作用。SNP rs11571079 与 HTN 和 T2D 相关的 HTN 的发病风险增加和 T2D 的发病风险降低相关，发挥保护作用。肾素单倍型 GCA 和 GTG 分别与 T2D 和 T2D 相关的 HTN 的发病风险增加相关。观察到 (P)RR 的 rs2968915 和 rs3112298 基因型和等位基因频率的异质连锁。(P)RR 单倍型 GA 与 HTN 的发病风险增加相关，与 T2D 的发病风险显著降低相关。这些发现强调了肾素和 (P)RR 基因的非编码变异在几种多基因疾病发病机制中的重要作用。
