Chapter 67 - The role of genetic variation in CYP2R1, the principal vitamin D 25-hydroxylase, and CYP3A4 in vitamin D homeostasis

Abstract

Vitamin D from the diet or generated in the skin becomes the active hormone, calcitriol, via two sequential hydroxylations. The first step, 25-hydroxylation, occurs principally in the liver by the cytochrome P450 (CYP) enzyme CYP2R1. In the second step, 25(OH)D is converted to calcitriol. Vitamin D is metabolized to less active forms primarily by CYP24A1, but it can also be inactivated by CYP3A4. In this chapter, we provide an overview of how variation in the CYP2R1 and CYP3A4 genes affects vitamin D homeostasis. Rare complete loss-of-function mutations in CYP2R1 lead, when homozygous, to vitamin D–dependent rickets 1B, and when heterozygous, cause a milder form of vitamin D deficiency. Similarly, extremely rare heterozygotic gain-of-function mutations in CYP3A4 cause increased inactivation of vitamin D and vitamin D–dependent rickets 1C. By contrast, hypomorphic polymorphisms in CYP2R1 are common and contribute to individual variability in serum 25(OH)D and in responsiveness to vitamin D supplementation.