A genetic atlas of metabolism

An international consortium has produced a comprehensive atlas of the genes that influence human metabolism and identify variants that together control the blood concentration of key metabolites. 

The findings, published last month in Nature Genetics¹, could eventually lead to new drug treatments for a wide variety of diseases.

In 2008, a team of researchers led by physiologist Karsten Suhre, who now works at the Weill Cornell Medical College in Doha, Qatar, reported that they had identified a handful of single nucleotide polymorphisms (SNPs, or variations occurring at a specific location in the DNA sequence) that account for 12% of the variation in levels of certain metabolites in the blood².

The researchers followed this with a wider study, which identified 37 additional SNPs linked to metabolism, some of which account for up to 60% of the individual differences in blood plasma levels of specific metabolites³.

The latest study is a progression from the earlier work, and used the same methods on a much larger scale. Karsten and his colleagues analysed the genomes of 7,824 participants in two large European studies, focusing on 2.1 million individual SNPs. They also took blood samples from each participant, and measured the plasma concentration of more than 400 key metabolites.  

By integrating the genetic and metabolic data with information about genes known to be associated with diseases, the researchers identified 145 variants that have significant effects on the body’s metabolic activity. Many are located within genes encoding enzymes that synthesize fats, sugars and amino acids, and influence metabolism by altering the activity of the enzymes.

The atlas shows the interconnected pathways between the genes, enzymes, and metabolites, identifying many potential drug targets and disease biomarkers. It also identifies possible links between individual SNPs, metabolites and disease, and shows how some drug targets might have unwanted side-effects.

“The central new idea we bring up is that of rational metabolic engineering,” says Suhre. “Based on the knowledge in the atlas we are now in a position to target specific genes in order to modify disease-relevant metabolic pathways in a rationally designed way.” 

Suhre’s team and their collaborators are now looking for potential clinical applications, focusing on diabetes and cancer. Diabetes is a disorder of sugar metabolism, whereas cancer almost always involves altered energy metabolism. The researchers hope their work will lead to the development of new drugs that modify the pathways involved and restore normal metabolic activity.

“We are initially targeting cancer cell lines, and eventually will try to modify irregular metabolism associated with all kinds of diseases,” says Suhre.