Title

Genetic, anatomic, and clinical determinants of human serum sterol and vitamin D levels

Document Type

Article

Abstract

An unknown fraction of the genome participates in the metabolism of sterols and vitamin D, two classes of lipids with diverse physiological and pathophysiological roles. Here, we used mass spectrometry to measure the abundance of >60 sterol and vitamin D derivatives in 3,230 serum samples from a well-phenotyped patient population. Twenty-nine of these lipids were detected in a majority of samples at levels that varied over thousands of fold in different individuals. Pairwise correlations between sterol and vitamin D levels revealed evidence for shared metabolic pathways, additional substrates for known enzymes, and transcriptional regulatory networks. Serum levels of multiple sterols and vitamin D metabolites varied significantly by sex, ethnicity, and age. A genome-wide association study identified 16 loci that were associated with levels of 19 sterols and 25-hydroxylated derivatives of vitamin D (P < 10(-7)). Resequencing, expression analysis, and biochemical experiments focused on one such locus (CYP39A1), revealed multiple loss-of-function alleles with additive effects on serum levels of the oxysterol, 24S-hydroxycholesterol, a substrate of the encoded enzyme. Body mass index, serum lipid levels, and hematocrit were strong phenotypic correlates of interindividual variation in multiple sterols and vitamin D metabolites. We conclude that correlating population-based analytical measurements with genotype and phenotype provides productive insight into human intermediary metabolism.

Medical Subject Headings

Body Mass Index; Female; Genetic Loci (physiology); Genotype; Humans; Hydroxycholesterols (blood); Male; Steroid Hydroxylases (genetics, metabolism); Vitamin D (blood, genetics)

Publication Date

9-23-2014

Publication Title

Proceedings of the National Academy of Sciences of the United States of America

E-ISSN

1091-6490

Volume

111

Issue

38

First Page

E4006

Last Page

14

PubMed ID

25201972

Digital Object Identifier (DOI)

10.1073/pnas.1413561111

Share

COinS