Unit of Molecular Epidemiology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.
PLoS Genet. 2011 Aug;7(8):e1002215. doi: 10.1371/journal.pgen.1002215. Epub 2011 Aug 11.
Metabolomic profiling and the integration of whole-genome genetic association data has proven to be a powerful tool to comprehensively explore gene regulatory networks and to investigate the effects of genetic variation at the molecular level. Serum metabolite concentrations allow a direct readout of biological processes, and association of specific metabolomic signatures with complex diseases such as Alzheimer's disease and cardiovascular and metabolic disorders has been shown. There are well-known correlations between sex and the incidence, prevalence, age of onset, symptoms, and severity of a disease, as well as the reaction to drugs. However, most of the studies published so far did not consider the role of sexual dimorphism and did not analyse their data stratified by gender. This study investigated sex-specific differences of serum metabolite concentrations and their underlying genetic determination. For discovery and replication we used more than 3,300 independent individuals from KORA F3 and F4 with metabolite measurements of 131 metabolites, including amino acids, phosphatidylcholines, sphingomyelins, acylcarnitines, and C6-sugars. A linear regression approach revealed significant concentration differences between males and females for 102 out of 131 metabolites (p-values<3.8×10(-4); Bonferroni-corrected threshold). Sex-specific genome-wide association studies (GWAS) showed genome-wide significant differences in beta-estimates for SNPs in the CPS1 locus (carbamoyl-phosphate synthase 1, significance level: p<3.8×10(-10); Bonferroni-corrected threshold) for glycine. We showed that the metabolite profiles of males and females are significantly different and, furthermore, that specific genetic variants in metabolism-related genes depict sexual dimorphism. Our study provides new important insights into sex-specific differences of cell regulatory processes and underscores that studies should consider sex-specific effects in design and interpretation.
代谢组学分析和全基因组遗传关联数据的整合已被证明是一种全面探索基因调控网络并研究遗传变异在分子水平上影响的强大工具。血清代谢物浓度可以直接反映生物过程，并且已经显示出特定代谢组学特征与阿尔茨海默病和心血管及代谢紊乱等复杂疾病的关联。性别与疾病的发病率、患病率、发病年龄、症状和严重程度以及对药物的反应之间存在众所周知的相关性。然而，迄今为止发表的大多数研究都没有考虑性二态性的作用，也没有按性别对其数据进行分层分析。本研究调查了血清代谢物浓度的性别特异性差异及其潜在的遗传决定因素。在发现和复制阶段，我们使用了来自 KORA F3 和 F4 的 3300 多名独立个体，这些个体的代谢物测量包括 131 种代谢物，包括氨基酸、磷脂酰胆碱、神经鞘磷脂、酰基肉碱和 C6-糖。线性回归方法显示，在 131 种代谢物中有 102 种（p 值<3.8×10(-4); 经 Bonferroni 校正的阈值）在男性和女性之间存在显著的浓度差异。性别特异性全基因组关联研究（GWAS）显示，在 CPS1 基因座（氨基甲酰磷酸合成酶 1，显著性水平：p<3.8×10(-10); 经 Bonferroni 校正的阈值）的 SNP 中，甘氨酸的 beta 估计值存在全基因组显著差异。我们表明，男性和女性的代谢物谱存在显著差异，此外，代谢相关基因中的特定遗传变异表现出性别二态性。我们的研究为细胞调控过程中的性别差异提供了新的重要见解，并强调研究在设计和解释时应考虑性别特异性影响。
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