Stiles Ashlee R, Kozlitina Julia, Thompson Bonne M, McDonald Jeffrey G, King Kevin S, Russell David W
Departments of Molecular Genetics.
Internal Medicine, and.
Proc Natl Acad Sci U S A. 2014 Sep 23;111(38):E4006-14. doi: 10.1073/pnas.1413561111. Epub 2014 Sep 8.
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.
基因组中未知比例的部分参与了甾醇和维生素D的代谢，这两类脂质具有多种生理和病理生理作用。在此，我们使用质谱法测量了来自一个具有详细表型的患者群体的3230份血清样本中60多种甾醇和维生素D衍生物的丰度。其中29种脂质在大多数样本中被检测到，其水平在不同个体中变化超过数千倍。甾醇和维生素D水平之间的成对相关性揭示了共享代谢途径、已知酶的额外底物以及转录调控网络的证据。多种甾醇和维生素D代谢物的血清水平在性别、种族和年龄方面存在显著差异。一项全基因组关联研究确定了16个位点，这些位点与19种甾醇和维生素D的25-羟基化衍生物的水平相关（P < 10^(-7)）。针对其中一个这样的位点（CYP39A1）进行的重测序、表达分析和生化实验，揭示了多个功能丧失等位基因，它们对编码酶的底物氧甾醇24S-羟基胆固醇的血清水平具有累加效应。体重指数、血清脂质水平和血细胞比容是多种甾醇和维生素D代谢物个体间变异的强表型相关因素。我们得出结论，将基于人群的分析测量与基因型和表型相关联，可为人类中间代谢提供有价值的见解。
