Dec. 1, 2008 Common genetic polymorphisms induce major differentiations in the metabolic make-up of the human population, according to a new article. An international team of researchers, led by Karsten Suhre, has conducted a genome-wide association study with metabolomics, identifying genetic variants in genes involved in the breakdown of fats.
The resulting differences in metabolic capacity can affect individuals' susceptibility to complex diseases such as diabetes and hyperactivity.
In the rapidly evolving field of metabolomics, scientists aim to measure all endogenous metabolites in a cell or body fluid. These measurements provide a functional readout of the physiological state of the human body. Investigation into these so-called "genetically determined metabotypes" in their biochemical context may help determine the pathogenesis of common diseases and gene-environment interactions.
The team identified four single nucleotide polymorphisms (SNPs) located in genes coding for well-characterized enzymes of the lipid metabolism. Individuals with different genotypes in these genes have significantly different metabolic capacities with respect to the synthesis of some polyunsaturated fatty acids, the beta-oxidation of short- and medium-chain fatty acids and the breakdown of triglycerides. By simultaneous measurements of both SNPs and serum concentrations of endogenous metabolites, the researchers determined the metabolome of several hundred healthy individuals and compared it to their genetic inheritance.
“These are at least partly comparable to the different varieties of hair color which are due to genetic variations,” Karsten Suhre said. Redheads react more sensitively to sunlight than dark-haired individuals do. It may be similar with the genetic variations identified here, which are responsible for the different metabotypes.
While one group is able to react relatively robustly to “metabolic stress“, e.g. in the form of a short-term nutritional deficiency or a high-fat diet, another group may have more or less pronounced physical impairments, the precise extent of which can now be ascertained in follow-up studies. “For example, differences in hair color are apparent to the observer at first glance. However, in the case of metabolism it takes much more effort to identify the role which the respective gene variant plays in the metabolism of the affected person,“ Karsten Suhre explained.
In this study, by means of a genome-wide analysis, the cross-institutional working group succeeded for the first time in profiling a number of such relationships. The identification of such genetically induced variations in the metabolism can be utilized in the future to predict risks with respect to certain medical phenotypes, possible reactions to medical treatment, nutritional or environmental influences – a first step towards personalized medicine and nutrition, based on a combination of a genetic and metabolic characterization of the patients.
The results suggest that most individuals carry one or more risk alleles in their genetic inheritance that may determine a certain medical phenotype, the response to a given drug treatment, or the reaction to a nutritional intervention or environmental challenge. These findings may lead to more targeted approaches to health care based on a combination of genotyping and metabolic characterization. To achieve this goal, it will be necessary to identify the major genetically determined metabotypes and their association to complex diseases.
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- Gieger C, Geistlinger L, Altmaier E, Hrabe´ de Angelis M, Kronenberg F, et al. Genetics Meets Metabolomics: A Genome-Wide Association Study of Metabolite Profiles in Human Serum. PLoS Genet, 4(11): e1000282 DOI: 10.1371/journal.pgen.1000282
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