Alpha-adducin 1 (rs4961) gene and its expression associated with sodium sensitivity in hypertensive patients: a cohort study in the western Ukrainian population

• DOI: 10.2478/enr-2024-0023
• Publication Date: 2024-10-01T16:09:28Z
• Authors: Larysa Sydorchuk; Bogdan Lytvyn; Andrii Sydorchuk; Yulia Yarynych; Sai Praveen Daruvuri; Svitlana Semenenko; Alisa Hoshovska; Ruslan Sydorchuk; Igor Biryuk
• Keywords: Male; Adult; arterial hypertension; alpha-adducin (rs4961) gene; Quantitative Trait Loci; sodium resistance; Polymorphism, Single Nucleotide; Diseases of the endocrine glands. Clinical endocrinology; Cohort Studies; Humans; Genetic Predisposition to Disease; transcriptional activity; Aged; sodium sensitivity; Sodium; Middle Aged; RC648-665; Case-Control Studies; Hypertension; genes expression; Female; Calmodulin-Binding Proteins; Essential Hypertension; Ukraine; metabolism; chronic kidney disease

Abstract

Objective. The aim of this study was to evaluate the association of the α-adducin-1 gene (ADD1) (Gly460Trp [rs4961]) polymorphism and its expression in association with renal dysfunction and sodium sensitivity in hypertensive patients in western Ukrainian population.

Methods. One-hundred patients with essential arterial hypertension (EAH) and hypertensive-mediated target organ damage (stage 2), moderate, high, and very high cardiovascular risk were enrolled in case-control study. Sixty healthy individuals were assigned as controls. Sodium sensitivity and sodium resistance were determined by salt load reaction. The ADD1 (rs4961) genotyping was performed in RT-PCR.

Results. The expression of the quantitative trait loci (eQTL) of ADD1 gene (rs4961) (chr4:2906707 [hg19]) was confirmed in 37 tissues and organs with 23 phenotypic traits. Two hundred eQTL associations revealed - all cis-variants (cis-QTL); 73 methylation QTL (mQTL), 34 splicing QTL (sQTL), 14 histone modification QTL (hQTL), 2 protein QTL (pQTL), 23 transcript utilization QTL (tuQTL), and 4 loci of incorporated long noncoding areas of RNA (lncRNA). GG-genotype unreliably enhances EAH risk (OR=1.92; 95%CI: 0.90–4.10; p=0.066). Sodium sensitivity was observed in 54.0% of patients and in 20.0% of controls (c2=17.89; p<0.001). Sodium sensitivity in T-allele carriers of the ADD1 gene (1378G>T; rs4961) dominated 12-fold in general (OR 95%CI: 2.24–64.29; p=0.001), in women – 4.71 times (OR 95%CI: 1.92–11.56; p<0.001), and in men – 4.09 times (OR 95%CI: 1.03–16.28; p=0.041). Sodium sensitivity elevated the likelihood of severe EAH twice (OR=2.19; OR 95%CI: 1.00–5.05; p=0.049).

Conclusion. T-allele associates with sodium sensitivity in essential arterial hypertension patients and increases the risk of hypertension regardless the gender. Sodium sensitivity enhances the probability of severe essential arterial hypertension in observed population.