Impact of genetic and nongenetic factors on interindividual variability in 4β-hydroxycholesterol concentration

Abstract

Purpose: Individual variability in the endogenous CYP3A metabolite 4β-hydroxycholesterol (4βOHC) is substantial, but to which extent this is determined by genetic and nongenetic factors remains unclear. The aim of the study was to evaluate the explanatory power of candidate genetic variants and key nongenetic factors on individual variability in 4βOHC levels in a large naturalistic patient population.

Methods: We measured 4βOHC concentration in serum samples from 655 patients and used multiple linear regression analysis to estimate the quantitative effects of CYP3A4*22, CYP3A5*3, and POR*28 variant alleles, comedication with CYP3A inducers, inhibitors and substrates, sex, and age on individual 4βOHC levels.

Results: 4βOHC concentration ranged >100-fold in the population, and the multiple linear regression model explained about one fourth of the variability (R ² = 0.23). Only comedication with inducers or inhibitors, sex, and POR genotype were significantly associated with individual variability in 4βOHC level. The estimated quantitative effects on 4βOHC levels were greatest for inducer comedication (+>313%, P < 0.001), inhibitor comedication (-34%, P = 0.021), and female sex (+30%, P < 0.001), while only a modestly elevated 4βOHC level was observed in carriers vs. noncarriers of POR*28 (+11%, P = 0.023).

Conclusions: These findings suggest that the CYP3A4*22, CYP3A5*3, and POR*28 variant alleles are of limited importance for overall individual variability in 4βOHC levels compared to nongenetic factors.

Keywords: 4β-hydroxycholesterol; CYP3A4; CYP3A5; Inducer; Inhibitor; POR.