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.
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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According to Hill, the findings offer promise for the treatment of patients with hearing disorders and people with ciliopathies, disorders marked by poor cilia function. These conditions include sperm-related infertility, polycystic kidney disease, lung and respiratory disorders, swelling of the brain and reversal of the internal organs' sites from one side of the body to the other.
"The idea that physical movement can influence vertebrate development is very provocative," said Hill. "Scientists typically look at whether a particular gene is switched on or off, or if a particular protein is activated that determines if a tissue develops normally. In this case, microscopic currents in the fluid surrounding developing tissue are affecting its development. We need to understand more details of this process and determine how common it is during development."
The study was supported by grants from the National Institutes of Health, the National Science Foundation, the Human Frontier Science Program and the Arnold and Mabel Beckman Foundation.
Hill's collaborators included co-first coauthor Jessica Colantonio, Adam Langenbacher and Jau-Nian Chen of the David Geffen School of Medicine at UCLA; and co-first author Julien Vermot, David Wu and Scott Fraser of the Beckman Institute California Institute of Technology.
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