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

Abstract

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.

Pharmacogenetics of Antidepressant Response

“…Variations in CYP2D6 have been associated with a vast list of diseases (e.g., arterial hypertension, 12 leukemia, 13 childhood apnea, 13 thyroid cancer, 14 Alzheimer disease and Parkinson disease, [15][16][17][18][19] hepatic disease, 20 pulmonary disease, 21,22 breast cancer, 23 porphyrias 24 ) and with people's ability to metabolize antidepressants. 25 To date, up to 75 different alleles have been reported for CYP2D6 (descriptions available at www .imm.ki .se/cypalleles); more than 15 of these encode an inactive isoform or no enzyme, whereas other variations consist of gene duplications.…”

Pharmacogenetics of antidepressant response

“…Variations in CYP2D6 have been associated with a vast list of diseases (e.g., arterial hypertension, 12 leukemia, 13 childhood apnea, 13 thyroid cancer, 14 Alzheimer disease and Parkinson disease, [15][16][17][18][19] hepatic disease, 20 pulmonary disease, 21,22 breast cancer, 23 porphyrias 24 ) and with people's ability to metabolize antidepressants. 25 To date, up to 75 different alleles have been reported for CYP2D6 (descriptions available at www .imm.ki .se/cypalleles); more than 15 of these encode an inactive isoform or no enzyme, whereas other variations consist of gene duplications.…”

Pharmacogenetically Tailored Treatments for Heart Disease

“…Atenolol or metoprolol treatment has also been associated with significant decreases in systolic, diastolic and mean arterial blood pressure in Arg389 homozygous compared to Gly389 homozygous patients, with heterozygous showing intermediate response, potentially indicating a gene dosage effect [104][105][106][107][108]. However, divergent results have been obtained by other studies which have failed to find an association between the Arg389Gly polymorphism and antihypertensive drug treatments [109][110][111][112].…”