Discovery of Sexual Dimorphisms in Metabolic and Genetic Biomarkers

Kirstin Mittelstrass, Janina S Ried, Zhonghao Yu, Jan Krumsiek, Christian Gieger, Cornelia Prehn, Werner Roemisch-Margl, Alexey Polonikov, Annette Peters, Fabian J Theis, Thomas Meitinger, Florian Kronenberg, Stephan Weidinger, Heinz Erich Wichmann, Karsten Suhre, Rui Wang-Sattler, Jerzy Adamski and Thomas Illig

PLOS Genetics, 2011, vol. 7, issue 8, 1-12

Abstract: 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 3,300 population-based samples (KORA F3/F4) revealed significant differences in the metabolite profile of males and females. Furthermore, a genome-wide picture of sex-specific genetic variations in human metabolism (>2,000 subjects from KORA F3/F4 cohorts) was investigated. Sex-specific genome-wide association studies (GWAS) showed differences in the effect of genetic variations on metabolites in men and women. SNPs in the CPS1 (carbamoyl-phosphate synthase 1) locus showed genome-wide significant differences in beta-estimates of sex-specific association analysis (significance level: 3.8×10−10) for glycine. As global metabolomic techniques are more and more refined to identify more compounds in single biological samples, the predictive power of this new technology will greatly increase. This suggests that metabolites, which may be used as predictive biomarkers to indicate the presence or severity of a disease, have to be used selectively depending on sex.

Date: 2011
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pgen00:1002215

DOI: 10.1371/journal.pgen.1002215

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