Sex-Specific Features of the Correlation between GWAS-Noticeable Polymorphisms and Hypertension in Europeans of Russia

Abstract

The aim of the study was directed at studying the sex-specific features of the correlation between genome-wide association studies (GWAS)-noticeable polymorphisms and hypertension (HTN). In two groups of European subjects of Russia (<i>n</i> = 1405 in total), such as men (<i>n</i> = 821 in total: <i>n</i> = 564 HTN, <i>n</i> = 257 control) and women (<i>n</i> = 584 in total: <i>n</i> = 375 HTN, <i>n</i> = 209 control), the distribution of ten specially selected polymorphisms (they have confirmed associations of GWAS level with blood pressure (BP) parameters and/or HTN in Europeans) has been considered. The list of studied loci was as follows: (<i>PLCE1</i>) rs932764 A > G, (<i>AC026703.1</i>) rs1173771 G > A, (<i>CERS5</i>) rs7302981 G > A, (<i>HFE</i>) rs1799945 C > G, (<i>OBFC1</i>) rs4387287 C > A, (<i>BAG6</i>) rs805303 G > A, (<i>RGL3</i>) rs167479 T > G, (<i>ARHGAP42</i>) rs633185 C > G, (<i>TBX2</i>) rs8068318 T > C, and (<i>ATP2B1</i>) rs2681472 A > G. The contribution of individual loci and their inter-locus interactions to the HTN susceptibility with bioinformatic interpretation of associative links was evaluated separately in men's and women's cohorts. The men-women differences in involvement in the disease of the BP/HTN-associated GWAS SNPs were detected. Among women, the HTN risk has been associated with <i>HFE</i> rs1799945 C > G (genotype GG was risky; OR_GG = 11.15 p_permGG = 0.014) and inter-locus interactions of all 10 examined SNPs as part of 26 intergenic interactions models. In men, the polymorphism <i>BAG6</i> rs805303 G > A (genotype AA was protective; OR_AA = 0.30 p_permAA = 0.0008) and inter-SNPs interactions of eight loci in only seven models have been founded as HTN-correlated. HTN-linked loci and strongly linked SNPs were characterized by pronounced polyvector functionality in both men and women, but at the same time, signaling pathways of HTN-linked genes/SNPs in women and men were similar and were represented mainly by immune mechanisms. As a result, the present study has demonstrated a more pronounced contribution of BP/HTN-associated GWAS SNPs to the HTN susceptibility (due to weightier intergenic interactions) in European women than in men.