Gender-Specific Effect of CYP2C8*3 on the Risk of Essential Hypertension in Bulgarian Patients

Abstract

We conducted a case-control study to determine the contribution of polymorphisms in CYP2C8 (CYP2C8*3) and CYP2J2 (CYP2J2*7) to increased risk of coronary artery disease and essential hypertension in Bulgarians. The current analysis included 192 unrelated hypertensive patients, 261 patients with angiographically documented CAD (153 with myocardial infarction and 108 without myocardial infarction), and 496 population controls. The CYP2C8*3 and CYP2J2*7 polymorphisms were genotyped by TaqMan SNP Genotyping Assay. PLINK version 1.07 was used for the statistical analysis. No overall association was observed for the studied polymorphisms with coronary artery disease and essential hypertension. The frequency of -50T mutant allele of CYP2J2*7 was significantly higher in male with coronary artery disease without history of myocardial infarction (OR 2.16 95% CI 1.04-4.48 p = 0.035) compared to population control group, but this association did not survive after Bonferroni correction (p adj = 0.07). A significant association of CYP2C8*3 allele with increased risk of essential hypertension has found in men (OR 2.12 95% CI 1.18-3.81 p = 0.015) and this relationship remained significant after adjustment for multiple comparisons (p adj = 0.03). This is the first study showing significant gene-sex interaction for CYP2C8*3 with twofold increase in the relative risk of essential hypertension and a similar tendency for CYP2J2*7 associated with coronary artery disease without myocardial infarction in Bulgarian males. The association is not seen in females and in the whole group of patients. This result could be partly explained by the effect of estrogens on the vascular tone of coronary arteries and CYP2C8 gene expression.

Associations between CYP2C8 rs10509681 and rs11572080 gene polymorphisms and age-related macular degeneration

“…CYP2C8 gene polymorphisms were found to be associated with essential hypertension (EH) ( 21 ). CYP2C8 *3 allele was statistically significantly more frequent in men with EH ( 21 ).…”

A comprehensive study revealed SNP–SNP interactions and a sex-dependent relationship between polymorphisms of the CYP2J2 gene and hypertension risk

“…Only one study performed by Fava and colleagues [20] investigated the relationship among the rs890293 poly morphism, blood pressure and hypertension risk in a large urban-based sample of Swedes with hypertension (N = 1858). The results from these studies have been conflicting: two studies performed in Russian [31] and Saudi Arabian [32] populations indicated a strong positive association between SNP rs890293 and hypertension risk; in contrast, one study in white Americans showed a negative associa tion of this polymorphism and disease risk [28], whereas studies conducted in Swedish [20], Bulgarian [33] and African American [29] populations did not identify a rela tionship between the SNP and hypertension susceptibility.…”

“…To date, only seven studies have been conducted to assess associations between polymorphisms of the CYP2J2 gene and hypertension susceptibility: four studies in Caucasians [20,28,31,33], two studies in Asians [30,32] and one study in blacks [29]. Five of these studies investigated the association of hypertension with the only one SNP rs890293 (-5 0 or -76G>T) located at the promoter of CYP2J2 in small population samples (<200 EH patients).…”

“…Taking into account the multifaceted cardiovascular and renal actions of EETs, single nucleotide polymorphisms (SNP) of the CYP2J2 gene have become the targets for genetic association studies of cardiovascular disorders in various populations [16][17][18][19][20][21][22][23][24][25][26][27]. However, a limited number of studies has been conducted to date to investigate the contribution of CYP2J2 gene polymorphisms to hypertension suscept ibility [28][29][30][31][32][33]. Many of these association studies have shown inconsistent and inconclusive results, which may be due to different genetic factors underlying hypertension in diverse populations and different patterns of linkage disequilibrium between the investigated loci and the causal variant.…”

Characterization of the Tissue Distribution of the MouseCyp2cSubfamily by Quantitative PCR Analysis

“…Human CYP2C8 and CYP2C9, thought to be the primary CYP2C epoxygenases, are both abundantly expressed in kidney and have a similar function (Enayetallah et al, 2004). Studies with the human single nucleotide polymorphism CYP2C8*3 have shown either a small but significant association with hypertension (Tzveova et al, 2015) or no association with hypertension (Dreisbach et al, 2005;King et al, 2005). Further studies will be needed to clarify the association between polymorphisms such as CYP2C8*3 and hypertension in humans.…”