GENETIC VARIATION AND PREDICTED PHENOTYPES IN CYP2C9, CYP2C19, CYP3A4, CYP3A5 AND CYP2D6 GENES AMONG 552 PATIENTS WITH UNCONTROLLED TREATED HYPERTENSION

Abstract

Objective: Altered drug metabolism may be a contributing factor to uncontrolled hypertension. Beta-blockers, alpha-blockers, calcium antagonists and angiotensin receptor blockers undergo hepatic metabolism by cytochrome P450 (CYP) enzymes. Genetic variation can contribute to interindividual variation, lack of treatment response or side effects with discontinuation of treatment. We aimed to determine common CYP gene variations in patients with treated but uncontrolled hypertension and to compare the distribution with the prevalence in the overall Caucasian population. Design and method: In this national multicenter study we mapped CYP2D6, CYP2C9, CYP2C19, CYP3A4 and CYP3A5 polymorphisms in 552 patients prescribed > = 2 antihypertensive agents and with systolic daytime ambulatory blood pressure (ABPM) > = 135 mmHg. On the (MALDI-TOF) MassARRAY analyzer, single nucleotide variants and small insertions/deletions (indels) were investigated with the VeriDose Core Panel and CYP2D6 copy-number variation with the VeriDose CYP2D6 CNV Panel (Agena Biosciences). Each allele is associated with either normal, decreased, absent, increased or unknown enzyme function based on activity scores defined by the The Clinical Pharmacogenetics Implementation Consortium (CPIC) and describe function and phenotypes for genes (IM = Intermediate metabolizer, PM = poor metabolizer, RM = rapid metabolizer and UM = ultra-rapid metabolizer). Results: 94% of patients were Caucasian. Mean daytime ABPM was 146/84 mmHg (135-190/55-106 mmHg), median age 63 (26-86) years and 35% were female. The distributions of the predicted phenotypes (illustrated in colors in Figure) for each enzyme did not differ from that reported in Caucasian population by The Pharmacogenomics Knowledgebase (PharmGK) (gray). 11% had normal phenotype in all five enzymes whereas 49% had > = 2 enzymes affected by gene variants. Conclusions: The phenotype distribution of five relevant CYP genes in patients with uncontrolled hypertension did not differ from the general Caucasian population. Dosing guidelines based on CYP2D6 genotype currently exist for metoprolol, but for other antihypertensive drugs further investigation is needed. The low proportion of patients with five normal enzymes and the high proportion with > = 2 enzymes affected suggest that pharmacogenetic CYP-testing may be useful for individualizing drug treatment in patients with uncontrolled hypertension.