How susceptible are we to certain diseases and how severe will they be? The answer to this question depends crucially on our individual chemical fingerprint. This consists of numerous small molecules in our blood, including fats, sugars and proteins. A study has now uncovered numerous regions in the genome that shape our chemical fingerprint and thus influence how our body deals with external influences. The results provide a more detailed understanding of how diseases develop and can allow predictions to be made as to which people are affected by certain drugs well or less well.
Our metabolism is influenced by numerous internal and external factors: How do we eat, what diseases do we have, what medication do we take and how much sport do we do? All of this contributes to how high our blood sugar and blood fat levels are and which proteins are found in our blood, for example to fight diseases or to transmit hormonal signals. Our genetic make-up also plays an important role. How exactly it influences our metabolism, however, has hardly been researched until now.
Large population study
A team led by Praveen Surendran from the University of Cambridge in Great Britain has now investigated which areas of the genome are involved in shaping our individual chemical fingerprint. To do this, the researchers evaluated blood samples from almost 20,000 people from two large population studies. They determined the levels of sugar, fats, hormones and other proteins in the blood and linked these results to variations in the test subjects’ genome.
“With our study, we are finally getting to the bottom of the genetic control of our metabolism using many hundreds of small metabolic products,” says co-author Claudia Langenberg from the Charité-Universitätsmedizin Berlin. “As a result, we now understand what effects these genetic differences have on the development of a wide variety of diseases, and why.” In total, the researchers included more than 900 metabolic products in their analysis and discovered 330 regions in the genome in which rare or common variants affect the level of these metabolic products influence in the blood. “These metabolic ‘hotspots’ in the genome have helped us to better understand which genes are really relevant for the altered amounts of the molecules in the blood,” says Langenberg.
Genes, metabolism and diseases
The researchers identified numerous examples of how changes in metabolism affect the risk and progression of certain diseases. For example, if the blood concentration of the amino acid homoarginine is increased, the risk of chronic kidney failure increases. Homoarginine is currently being tested as a means of preventing cardiovascular disease. “Our result underscores the need to closely monitor kidney function when homoarginine is administered,” said Surendran and his team.
The results also show that the metabolism not only contributes to maintaining health or causing diseases, but that it also significantly determines how effective or sometimes harmful drugs are. For example, in regarding a fifth of the subjects, the research team found genetic changes near a gene important for breaking down certain cancer drugs. In patients with a corresponding variation near this gene, the toxic substance is broken down more slowly, so it can build up in the blood and cause serious side effects. “Variations in the vicinity of genes that are also the target of drugs can give us clues regarding possible undesirable side effects,” explains Langenberg. From the authors’ point of view, the approach of identifying potential side effects at an early stage using genomic data might represent a quick and cost-effective way of setting priorities and avoiding errors in future randomized studies.
Make studies more efficient
The data in the current study comes from people of European descent. For further insights into the connections between genes, metabolism and health, the researchers want to carry out additional studies in other populations. “We need larger studies that better map the genetic diversity of different population groups to understand the biological and clinical effect of genetic variations that differ between certain population groups,” says Langenberg.
Quelle: Praveen Surendran (University of Cambridge, UK) et al., Nature Medicine, two: 10.1038/s41591-022-02046-0;