Gene diversity can alter metabolic individuality

Print 09 September 2016
John Fox / BioWorld

HONG KONG – A new Japanese study of the effects of environmental and genetic influences on individual differences in proteomics and metabolomics has identified biomarkers for early disease prevention and diagnosis, through the identification and quantification of blood metabolites.

Such genomic studies can contribute significantly to the advancement of personalized prevention and treatment of human diseases, in addition to identifying previously unknown disease mechanisms, and possibly to the development of new treatments.

"Most of the common diseases are caused by combinations of many kinds of genetic and environmental factors, and metabolites in blood are largely influenced by both genetic and environmental (lifestyle) factors, so association studies between metabolites and genetic variants are important for finding the causal variants affecting metabolites," said study leader Seizo Koshiba, an associate professor in the Department of Integrative Genomics at Tohoku University.

"Therefore, metabolomics in combination with genetics is important for estimating the effects of such genetic and environmental factors for individual health, resulting to biomarker discovery. These biomarkers are important not only for finding diseases but also estimating the effects of treatments," Koshiba told BioWorld Today.

The researchers reported their research on genetic diversity and the metabolome in the Sept. 1, 2016, edition of the open access journal Scientific Reports. Their findings were based on an analysis of blood samples taken from 512 healthy participants in the Tohoku Medical Megabank Project Community-Based Cohort Study and the Birth and Three-Generation Cohort Study.

"Such cohort studies were originally designed as part of the reconstruction project from the damage of [the] Great East Japan Earthquake [in] 2011. We can search and [monitor] the longitudinal effect on the residents' health of the disaster, by the cohort studies. We also planned to establish the base for the next-generation medicine through biobank-constructed thorough cohort studies," Fuji Nagama, a professor and the public communication director of researchers, the Tohoku Medical Megabank Organization at Tohoku University, toldBioWorld Today.

"We discovered genetic variants affecting enzymatic activities in healthy people," said Koshiba. "Our study shows that genetic polymorphisms, structural location of mutation and effect for phenotype correlate with each other in the human population, [which implies] that metabolic individuality and susceptibility for diseases are possibly resulted from the moderate variants and much more deleterious, but rare, variants."

That is a highly significant finding, noted Koshiba. "Most common diseases are caused by the combinations of a number of genetic and environmental factors. However, it was not well known which genetic variants really affect the individual nature. Our results revealed the variants significantly affecting metabolites in blood, and metabolic profiles are significantly different, even if in healthy people because of genetic variants. These effects may also influence the individual susceptibility [to] diseases."

In their analyses, the researchers investigated the relationship between structural variants of enzymes and metabolic phenotypes in the human population and surveyed the association between metabolite concentrations and whole genome sequence analysis data.

Five associations between metabolites and gene variants were identified, with four of the gene variants being known to be related to metabolic diseases. The residues substituted by those variants were located in the peripheral regions of the catalytic sites or related regulatory domains of enzymes.

"Most of the genetic variants in this work are located in enzymes involved in metabolic disorders. These results are important as they indicate that metabolic individuality may influence the susceptibility for diseases," noted Koshiba.

"In this study, we showed that the effects of rare genetic variants are larger than those of the common variant," he explained. "These variants are located in phenylalanine hydroxylase, one of the most famous enzymes involved in metabolic disorders. We also found that the common variants are located in peripheral regions of the catalytic sites or related regulatory regions, while the rare variants are located near the catalytic site. These results firstly demonstrate that variant frequency, structural location and effect for phenotype correlate with each other in [a] human population, and imply that metabolic individuality and susceptibility for diseases may be elicited from the moderate variants and much more deleterious but rare variants."

Asked about future research, Koshiba said that "metabolites in blood are largely influenced by both genetic and environmental factors. Therefore, in the future, we will perform large-scale metabolomics research in our cohort studies to investigate these factors as they affect metabolic individuality, in order to elucidate the way for the prevention of diseases. We have also opened our website, in order to share our data with researchers worldwide."

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