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Metabolomic Study Hints At Sex-Specific Differences in Metabolite Profiles and Related Genetic Variants

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – A metabolomic study appearing online last night in PLoS Genetics suggests that differences exist between men and women in metabolite profiles as well as in the genetic variants behind these profiles.

Researchers from the German Research Center for Environmental Health, the Technical University Munich, and elsewhere found sex-specific differences in the concentrations of more than 100 metabolites when they used mass spectrometry to test blood samples from thousands of individuals from southern Germany. A genome-wide association study involving a sub-set of these individuals, meanwhile, hinted at sex-specific differences in variants found in genes that may be related to some of these metabolic processes.

"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," co-corresponding author Thomas Illig, a molecular epidemiology researcher at the German Research Center for Environmental Health, and co-authors wrote.

"Through the combination of gender-specific evaluation, genetic association studies and metabolomics we will gain a detailed understanding of how major widespread diseases such as diabetes mellitus develop," Illig said in a statement.

Recent studies have provided new information about individuals' metabolite profiles, genetic variants associated with these profiles, and some of their biological consequences, the researchers explained. Even so, they argue that sexual dimorphism may have an under-appreciated impact on the genomic and metabolomic patterns explored by such studies.

To look at these issues in more detail, the study authors explained, "we systematically assessed the effect of sex on serum metabolites in a large population-based cohort … [and] investigated whether there are sex-specific differences in the genetic determination of metabotypes."

The teams used LC/MS/MS mass spectrometry to measure the levels of 163 metabolites in blood samples from more than 3,000 individuals (1,452 men and 1,552 women) between the ages of 32 and 81 years old enrolled through the KORA F4 study. They then did replication experiments using samples from another 377 individuals (197 men and 180 women) enrolled through KORA F3.

Once they'd tossed out data for metabolites that didn't meet their quality control criteria, the researchers were left with 131 metabolites for which they had information. "The metabolites covered a biologically relevant panel that could be divided into five sub-groups such as amino acids, sugars, acylcarnitines, and phospholipids," they explained.

The team also genotyped 1,809 of the individuals at a genome-wide level with the Affymetrix 6.0 GeneChip and used the Illumina Metabo-Chip to genotype another 1,218 participants.

When they sifted through their metabolite data, the researchers saw sex-specific differences in the concentrations of 101 of the 131 metabolites tested. Rolling together data from both KORA F3 and F4 study participants pushed that number even higher, with 113 metabolites showing different concentrations in men and women from the two cohorts.

For example, investigators found that all of the amino acids but two, glycine and serine, were present at significantly higher concentrations in the men than the women. On the other hand, women tended to have higher levels of phosphatidylcholines than men.

The group's GWAS results appear to be consistent with such findings, pointing to sex-specific patterns for variants influencing some genes involved in metabolism. In particular, the researchers found genome-wide significant differences between men and women for SNPs in and around CPS1, a gene coding for an enzyme called carbamoyl-phosphate synthase 1 that's involved in amino acid metabolism.

Based on their findings so far, Illig and his colleagues believe a better understanding of sexual dimorphism could lead to improvements in everything from study design and interpretation to assessments of drug response, disease risk, and predictive biomarker selection.

"Our study provides new important insights into sex-specific differences of cell regulatory processes and underscores that studies should consider gender-specific effects in design and interpretation," they concluded. "Our findings help to understand biochemical mechanisms underlying sexual dimorphism, a phenomenon which may explain the differential susceptibility to common diseases in males and females."

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