The role of the cytochrome P450 3A5 enzyme for blood pressure regulation in the general Caucasian population

Abstract

Cytochrome P450 3A (CYP3A) enzymes are important for drug metabolism in gut and liver. The CYP3A5 isoenzyme is also expressed in the kidney and has been implicated in renal sodium reabsorption and blood pressure regulation. Its expression and activity is strongly linked to a polymorphism (i.e. 6986G > A). Thus, appreciable expression is found in carriers of the CYP3A5*1 (6986A) but not in homozygous carriers of the CYP3A5*3 (6986G) allele. We tested whether the presence of CYP3A5*1 affects blood pressure in Caucasian individuals who were enrolled in the Prevention of REnal and Vascular ENd stage Disease (PREVEND) study. In addition, we evaluated whether the genetic effect of CYP3A5*1 on blood pressure is modulated by sodium intake. CYP3A5*1 was found in 13.3% (901 individuals) of the cohort (6777 individuals). Diastolic blood pressure was not affected by CYP3A5*1. Overall, systolic and pulse pressure were significantly lower in carriers of CYP3A5*1, both after univariate analysis adjusted for age (P = 0.012 and P = 0.008) and in logistic regression analysis (P = 0.015 and P = 0.012). The effect on systolic blood pressure was significantly modulated by sodium intake (P = 0.038). In separate analysis according to gender, CYP3A5*1 accounted for a significant age adjusted decrease in systolic blood pressure (-1.6 mmHg, P = 0.04) and pulse pressure (-1.2 mmHg, P = 0.04) in females but not in men. The present study demonstrates that the CYP3A5*1 allele affects systolic blood pressure and pulse pressure in the general population. Its role in hypertensive disease and potential gender differences should be investigated in further studies.

Association of the CYP3A5 polymorphism (6986G>A) with blood pressure and hypertension

“…Since then, several studies have been performed to investigate the association in different ethnic populations; however, the results have been inconsistent. For example, a large population-based study (n¼6777, age range: 28-75 years) by Kreutz et al 35 showed that the CYP3A5*1 allele was associated with lower SBP only in women. In a study of an elderly Finnish Caucasian population (n¼373, age: X75 years), CYP3A5*1 carriers had a significantly greater hypertension risk.…”

“…27,29,31,32,[35][36][37][38][39][40] As shown in Figures 2 and 3, there was evidence of heterogeneity between studies (systolic BP (SBP): Figure 4 and Table 3). The stability of these results was also confirmed by sensitivity analysis (data not shown).…”

“…27,[33][34][35]38 Overall, there was evidence of heterogeneity between studies (P¼0.064, Isquared¼44.2%). Under a random-effects model, the meta-analysis result showed no association between the CYP3A5 rs776746 polymorphism and hypertension (OR¼1.123, 95% CI 0.906 to 1.394, P¼0.290).…”

“…30 Therefore, 12 papers met the inclusion criteria and were included in the meta-analysis. 27,29,[31][32][33][34][35][36][37][38][39][40] Individuals carrying at least one CYP3A5*1 allele were combined as CYP3A5*1 carriers in one group (high expression), and individuals without a CYP3A5*1 allele were combined as CYP3A5*1 non-carriers in the other group (low expression). The characteristics of the included studies are listed in Tables 1 and 2.…”

Emerging Role of Pharmacogenetic in Organ Transplantation

“…There are a number of conflicting reports regarding the CYP3A genotype influence on cyclosporine pharmacokinetic [27,28]. Therefore, a clear role of this polymorphism on cyclosporine metabolism has not been demonstrated.…”