Combined effects of ACE (I/D) and eNOS (894T>G) genes polymorphism in patients with arterial hypertension in the realization of molecular mechanisms of left ventricular hypertrophy

Abstract

Aim: To determine the frequency of alleles and genotypes of insertion-deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) (dbSNP id: rs4646994) and a missense mutation (894T<G polymorphism) of the endothelial NO-synthase (eNOS) gene (dbSNP id: rs1799983 ) in patients with essential arterial hypertension (EAH) residents of Western Ukraine (Bukovina), depending on the severity of EAH and their association with the frequency and patterns of left ventricular hypertrophy (LVH). Materials and methods: 120 patients with EAH I-III stages (48.3% - women, 51.7% - men, average age 52.9±9.24 years) and 40 practically healthy persons were observed. Alleles of polymorphic locus was studied by polymerase chain reaction (PCR). Structural and functional changes of the myocardium and LVH models - by echocardiography, ECG. The results analyzed according to the European guidelines ESC / ESH (2009). Results and discussions: One-third of patients with EAH (35.8%) have a mutation in the coding regions of the ACE gene (I/D, intron 16, 17q23, dbSNP id: rs4646994) or eNOS (894T<G, codon 298 of exon 7, 7q35-36, dbSNP id: rs1799983). Every fourth patients (28.3%) is the carrier of a pathological DD-genotype of ACE gene in a haplotype, whereas the combination of homozygous mutations of eNOS observed in 4.7 times less (7.5%). A combination of two abnormal genotypes of both genes (DD/TT) was not observed at all. The most common in the observed population is ID/TG and ID/GG haplotypes (48.1%) among patients with EAH (25.8% and 20.0%, p=0.014) and in the control group (32.5% and 22.5%, p=0.039), respectively. High-risk groups of LVH among patients with EAH are male carriers of DD-genotype and female carriers of D-allele of the ACE gene, and men with TT-genotype of eNOS gene. High risk groups of the more frequent of the eccentric or concentric LV hypertrophy models presence are D-allele carriers of ACE gene and the T-allele carriers of eNOS gene. The combination of D and T “mutant” alleles in haplotypes (ID/TG and DD/TG options) increases the relative risk of LVH and EAH II and III stages in the 1.19-2.25 times (OR=4.75-13, p≤0.021-0.001), a finding consistent with the severity of the clinical course of the disease, with the lowest chance for a normal geometry or concentric LV remodeling, or milder EAH I st. course (OR=0.07-0.17, p≤0.031-0.001). The absence of mutations in haplotypes (II/GG variant) is a protective factor against LVH (OR=0.13, p=0.047), target organ damage in EAH patients (OR=0.56, p<0.05), increases chances for EAH I st. in 1.44 times (OR=1.80, p>0.05) and “good” patterns of left ventricular geometric structure in 2.53 times (OR=7.87, p=0.04). Conclusions: ID/TG and DD/TG combination of genotypes of the ACE gene (I/D) and eNOS (893T>G) is an additional independent predictor of target-organ damage, in particular the appearance of left ventricular hypertrophy, and the severity of EAH.