Association of the CYBA, PPARGC1A, PPARG3, and PPARD gene variants with coronary artery disease and metabolic risk factors of coronary atherosclerosis in a Russian population.

Abnormalities in lipid metabolism and enhanced oxidative stress are considered as major risk factors for coronary atherosclerosis. Functional genetic variations in genes whose products are involved in lipid metabolism and antioxidant defense could therefore modulate risk of coronary artery disease (CAD). In this study, we evaluate whether the PPARGC1A Gly482Ser, PPARG3 (-681)C/G, PPARD +294T/C, and CYBA +242C/T gene variants confer the risk of CAD in a Russian population. A total of 313 CAD patients and 132 controls with no clinical sign of CAD were studied. The polymorphic markers were tested using a TaqMan assay. Allele and genotype frequencies in CAD patients and controls were compared using the Yates chi(2) test. Association of the genetic markers with metabolic risk factors of arterial atherosclerosis was studied using the analysis of variance test and then adjusted for conventional risk factors in the multiple regression analysis. For CYBA +242C/T, both the allele T and genotype T/T showed significant association with higher risk of CAD (odds ratio =1.49 and 3.89, respectively). The allele C and genotype C/C of the +294T/C marker of PPARD were associated with increased risk of CAD providing an odds ratio of 2.12 and 2.78, respectively. The risk variants of CYBA +242C/T and PPARD +294T/C markers were associated with higher low-density lipoprotein cholesterol and increased total serum cholesterol, respectively. In conclusion, the CYBA +242C/T and PPARD +294T/C variants modulate risk of CAD through their associations with atherogenic serum lipid profiles.

Association of CYP2D6 and ADRB1 genes with hypotensive and antichronotropic action of betaxolol in patients with arterial hypertension.

Betaxolol is a selective antagonist of beta(1)-adrenergic receptors. Personal response to the drug widely varies and depends on its properties and individual features including innate characteristics. Our aim was to study the association between the clinical response to betaxolol in patients with essential hypertension (EH) and polymorphous markers of two genes: beta(1) adrenergic receptor gene (ADRB1) and cytochrome P450 2D6 gene (CYP2D6). Eighty-one patients with EH were selected. Mean age was 52.2 +/- 1.22 years. Betaxolol monotherapy provided effective blood pressure control (BP < 140/90 mmHg) in 68 patients, 56 of them continued treatment with initial dose. The systolic (SBP) and diastolic (DBP) blood pressure declined significantly at the end of the study. We have not found any significant association of rest and exercise BP and heart rate (HR) with polymorphous marker Arg389Gly of ADRB1 gene except the nighttime variability of DBP. But in case of the polymorphous marker Pro34Ser of CYP2D6 gene we have found significant association with response to betaxolol therapy. The rest HR declined more significantly in Ser/Pro genotype carriers (-32.6 +/- 4.77 beats/min and -18.4 +/- 2.01 beats/min, P = 0.023). These patients demonstrated more significant increase of exercise time (4.58 +/- 0.90 and 0.59 +/- 0.58 min, P = 0.045). Maximal exercise HR and DBP were also significantly lower in Ser/Pro genotype carriers in comparison with Ser/Ser genotype carriers. Decline of mean daytime SBP in 24-h ambulatory blood pressure monitoring was more significant in Pro allele carriers (-21.0 +/- 2.55 mmHg vs. -5.2 +/- 2.27 mmHg in patients with Ser/Ser genotype, P = 0.001). Betaxolol effect on HR and BP significantly depends on variability of the gene determining the drug metabolism. The carriers of Pro34 allele of CYP2D6 gene (8.6%) are more sensitive to betaxolol therapy. Because of the relatively small group sizes our data should be considered as preliminary ones. The increase of our groups and the replication in other studies will permit to estimate the contribution of genetic factors to betaxolol effect on HR and BP.