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

Significance Cholesterol is the major sterol in blood and in excess causes cardiovascular disease. In addition to cholesterol, numerous other sterols of unknown function and pathogenicity circulate in the bloodstream. Here, we use chemical methods to screen for over 60 different sterols and sterol derivatives in the sera of 3,230 clinically well-characterized individuals. Twenty-seven sterols and two sterol derivatives (vitamin D2 and D3) were routinely detected in vastly different amounts in a majority of individuals. Genes, ethnicity, gender, age, clinical phenotype, and anatomy were identified as significant sources of interindividual variation in these lipid metabolites. 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.