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

Ashlee R. Stiles, Julia Kozlitina, Bonne M. Thompson, Jeffrey G. McDonald, Kevin S. King, David W. Russell

Research output: Contribution to journalArticlepeer-review

57 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)E4006-E4014
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number38
StatePublished - Sep 23 2014


  • Genotype-phenotype correlation
  • Human genetics

ASJC Scopus subject areas

  • General


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