Gender-specific pathway differences in the human serum metabolome.
Gender-specific pathway differences in the human serum metabolome.
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DOI：
10.1007/s11306-015-0829-0
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发表时间：
2015
期刊：
影响因子：
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通讯作者：
Kastenmüller G
中科院分区：
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作者：
Krumsiek J;Mittelstrass K;Do KT;Stückler F;Ried J;Adamski J;Peters A;Illig T;Kronenberg F;Friedrich N;Nauck M;Pietzner M;Mook-Kanamori DO;Suhre K;Gieger C;Grallert H;Theis FJ;Kastenmüller G
男性和女性对各种疾病的易感性以及对治疗的反应有很大差异。作为特定性别的个性化医疗保健的基础，需要对两性之间的分子差异进行广泛的表征。在目前的研究中，我们对来自德国KORA F4研究的1756名参与者(903名女性和853名男性)的507个代谢标志物进行了大规模的代谢组学分析。三分之一的代谢物在男性和女性之间显示出显著的差异。通径分析表明，类固醇代谢、脂肪酸和进一步的脂类、大部分氨基酸、氧化磷酸化、嘌呤代谢和伽马-谷氨酰二肽存在显著差异。然后，我们通过基于网络的集群方法扩展了这一分析。使用高斯图形模型估计代谢物相互作用，以获得无偏见的、完全由数据驱动的代谢网络表示。这种方法不限于可能的任意途径边界，甚至可以包括劣质或未特化的代谢物。网络分析揭示了不同途径上的几个严格的性别管制的子模块。最后，进行了性别分层的全基因组关联研究，以确定观察到的性别差异是否由遗传多态对代谢组的影响中的二态引起。由于只有一次全基因组范围内的重大打击，我们的结果表明，这种情况并非如此。总之，我们报告了人类血清代谢组的性别差异的广泛特征和解释，为未来的分析提供了广泛的基础。本文的在线版本(doi：10.1007/s11306-0150829-0)包含补充材料，授权用户可以使用。
The susceptibility for various diseases as well as the response to treatments differ considerably between men and women. As a basis for a gender-specific personalized healthcare, an extensive characterization of the molecular differences between the two genders is required. In the present study, we conducted a large-scale metabolomics analysis of 507 metabolic markers measured in serum of 1756 participants from the German KORA F4 study (903 females and 853 males). One-third of the metabolites show significant differences between males and females. A pathway analysis revealed strong differences in steroid metabolism, fatty acids and further lipids, a large fraction of amino acids, oxidative phosphorylation, purine metabolism and gamma-glutamyl dipeptides. We then extended this analysis by a network-based clustering approach. Metabolite interactions were estimated using Gaussian graphical models to get an unbiased, fully data-driven metabolic network representation. This approach is not limited to possibly arbitrary pathway boundaries and can even include poorly or uncharacterized metabolites. The network analysis revealed several strongly gender-regulated submodules across different pathways. Finally, a gender-stratified genome-wide association study was performed to determine whether the observed gender differences are caused by dimorphisms in the effects of genetic polymorphisms on the metabolome. With only a single genome-wide significant hit, our results suggest that this scenario is not the case. In summary, we report an extensive characterization and interpretation of gender-specific differences of the human serum metabolome, providing a broad basis for future analyses. The online version of this article (doi:10.1007/s11306-015-0829-0) contains supplementary material, which is available to authorized users.