ASSOCIATION OF CYP3A5 GENOTYPES WITH BLOOD PRESSURE AND RENAL FUNCTION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Renal cytochrome P450 3A5 (CYP3A5) activity has been associated with blood pressure and salt sensitivity in humans. We determined whether CYP3A5 polymorphisms are associted with ambulatory blood pressure (ABP) and with glomerular filtration rate (GFR) in African families. Using a cross-sectional design, 375 individuals from 72 families, each with at least two hypertensive siblings, were recruited through a hypertension register in the Seychelles (Indian Ocean). We analyzed the association between the CYP3A5 alleles and ABP, GFR and renal sodium handling (fractional excretion of lithium), from pedigree data, allowing for other covariates and familial correlations. CYP3A5 carriers increased their daytime systolic and diastolic ABP with age (0.55 and 0.23 mmHg/year) more than non-carriers (0.21 and 0.04 mmHg/year). CYP3A5 had a significant main effect on daytime systolic/diastolic ABP [regression coefficient (SE): -29.6 (10.0)/-8.2 (4.1) mmHg, P =0.003/0.045, respectively] and this effect was modified by age (CYP3A5 x age interactions, P =0.017/0.018). For night-time ABP, the effect of CYP3A5 was modified by urinary sodium excretion, not by age. For renal function, CYP3A5 carriers had a 7.6(3.8) ml/min lower GFR(P=0.045) than non-carriers, Proximal sodium reabsorption decreased with age in non-carriers, but in CYP3A5 carriers (P for interaction = 0.02). These data demonstrate that CYP3A5 polymorphisms are associated with ambulatory BP, CYP3A5 carriers showing a higher age- and sodium- related increase in ABP than non-carriers. The age effect may be due, in part, to the action of CYP3A5 on renal sodium handling.