CYP3A4 and CYP3A5 polymorphisms and blood pressure response to amlodipine among African-American men and women with early hypertensive renal disease

Abstract

Purpose: To explore the association between CYP3A4 and CYP3A5 gene polymorphisms and blood pressure response to amlodipine among participants from the African-American Study of Kidney Disease and Hypertension Trial randomized to amlodipine (n = 164).

Methods: Cox proportional hazards models were used to determine the risk of reaching a target mean arterial pressure (MAP) of < or =107 mm Hg by CYP3A4 (A-392G and T16090C) and CYP3A5 (A6986G) gene polymorphisms, stratified by MAP randomization group (low or usual) and controlling for other predictors for blood pressure response.

Results: Women randomized to a usual MAP goal with an A allele at CYP3A4 A-392G were more likely to reach a target MAP of 107 mm Hg. The adjusted hazard ratio (AA/AG compared to GG) with 95% confidence interval was 3.41 (1.20-9.64; p = 0.020). Among participants randomized to a lower MAP goal, those with the C allele at CYP3A4 T16090C were more likely to reach target MAP: The adjusted hazard ratio was 2.04 (1.17-3.56; p = 0.010). After adjustment for multiple testing using a threshold significance level of p = 0.016, only the CYP3A4 T16090C SNP remained significant. CYP3A5 A6986G was not associated with blood pressure response.

Conclusions: Our findings suggest that blood pressure response to amlodipine among high-risk African-Americans appears to be determined by CYP3A4 genotypes, and sex specificity may be an important consideration. Clinical applications of CYP3A4 genotype testing for individualized treatment regimens warrant further study.

Fig. 1

CYP3A4 and CYP3A5 polymorphisms population frequencies. CYP3A4 and CYP3A5 are located in tandem on chromosome 7q21. Two CYP3A4 and one CYP3A5 SNP were selected: (1) CYP3A4 T16090C, a T to C polymorphism within intron-7, 16,090 base pairs from the CYP3A4 cap site (rs2246709); (2) CYP3A4 A–392G, an A to G polymorphism, and also the most common variant of CYP3A4, located in the 5′-flanking region (rs2740574), and (3) CYP3A5 A6986G, an A to G polymorphism located in intron-3, responsible for alternative splicing and protein truncation (rs776746). The extent of linkage disequilibrium between loci is represented as R-squared (R²). Allele frequencies in Caucasian and African-Americans made available dbSNP (http://www.ncbi.nlm.nih.gov/SNP) or the Pharmacogenomics Knowledge Base (http://www.pharmgkb.org) and in the AASK population are also shown.

Fig. 2

Adjusted Cox regression survival curves by CYP3A4 promoter A–392G (usual MAP goal 102–107 mm Hg treatment group). Among men and women randomized to usual MAP treatment goal, there was not a significant difference in rate of reaching a target MAP of 107 mm Hg by A–392G genotypes (a; adjusted p = 0.77). Upon gender stratification, there was no difference among men (b; adjusted p = 0.82); however, women with A/A or A/G (compared to G/G) genotype were over 3 times more likely to reach a target MAP of 107 mm Hg (c; adjusted p = 0.02).

Fig. 3

Adjusted Cox regression survival curves by CYP3A4 T16090C (low MAP goal <92 mm Hg). Among more aggressively managed men and women, those with a C/C or T/C compared to a T/T genotype were twice as likely to reach a target MAP of 107 mm Hg (a; adjusted p = 0.01). Stratified analyses suggested similar results among men (b; adjusted p = 0.05) and women (c; adjusted p = 0.05).