Our bodies continuously process thousands of small molecules to keep our metabolism, and therefore our health, running. Even the smallest changes can make you ill, the metabolism is just as individual as the human being. BIH scientists have now discovered rare and common changes in the genetic code that influence personal chemical fingerprints and individual disease profiles. “With our study, we are finally getting to the bottom of the genetic control of our metabolism using many hundreds of small metabolic products, which has never been shown in this detail,” says Professor Claudia Langenberg, head of the Computational Medicine department, adding: ” As a result, we now understand what impact these genetic differences have on the development of various diseases and why.”.
Blood samples from 20,000 participants
In the current study, the scientists determined the amount of small molecules, such as sugar, fats or hormones, from blood samples from around 20,000 participants in two large population studies in order to investigate the influence of the genome. They have identified areas in the genome that are related to many, often very different, metabolic products. “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,” explains Professor Claudia Langenberg. “With these new findings, we were then able to show which changes in metabolism contribute to the development of individual diseases, such as breast cancer,” she adds.
Metabolism also determines drug effects
The results show that the metabolism not only contributes to maintaining health or causing diseases, but also significantly determines how effective or sometimes harmful drugs are. For example, the scientists found genetic changes close to the gene in regarding a fifth of the study participants DPYD, which slows down the breakdown of certain cancer drugs. As a result, patients accumulate toxic levels of the substances in their blood. “Variations near genes that are also the target of drugs can give us clues regarding possible unwanted side effects. We were able to show that drugs that reduce the conversion of steroid hormones in the body and thus counteract male pattern baldness and prostate enlargement can increase the risk of depression, which is consistent with reports from drug studies,” she explains.
The scientists have also identified many examples of the influence of metabolites on a wide variety of diseases. For example, elevated blood levels of homoarginine increase the risk of chronic kidney disease. This is acutely relevant, since the administration of homoarginine is currently being tested for the prevention of cardiovascular diseases. In these people, special attention should therefore be paid to maintaining kidney function.
International cooperation enables research
The study is the result of many years of cooperation between BIH scientists and colleagues around the world, in particular from the University of Cambridge. Many experts have worked together to better understand and assign the biological relevance and causative genes of the results, including from the Helmholtz Zentrum in Munich, from Qatar and from the pharmaceutical company Pfizer.
Claudia Langenberg is already leading a new initiative. “We need larger studies that better map the genetic diversity of different populations to understand the biological and clinical effect of genetic variations that differ between specific populations.”
Originalpublikation: “Rare and common genetic determinants of metabolic individuality and their effects on human health”, Nature Medicine on 10 November 2022; DOI: 10.1038/s41591-022-02046-0; https://www.nature.com/articles/s41591-022-02046-0
