How genes and small molecules affect our personal risk of disease – News

Our bodies are constantly processing thousands of small molecules to keep our metabolism, and therefore our health, running. Even the smallest changes can make you sick, metabolism is as individual as a person. BIH scientists have now discovered rare and common changes in the genetic code that affect personal chemical fingerprints and individual disease profiles. “With our study, we are finally getting to the bottom of the genetic control of our metabolism by many hundreds of small metabolic products, which has never been demonstrated in such detail,” says Professor Claudia Langenberg, Head of Computational Medicine, adding: “As a result, we now understand the impact of these genetic differences on the development of various diseases and why”.

Blood samples from 20,000 participants

In the current study, researchers determined the amount of small molecules such as sugar, fat or hormones from blood samples of about 20,000 participants in two large population-based studies to investigate the influence of the genome. They identified regions in the genome that are associated with many, often very different, metabolic products. “These metabolic ‘hotspots’ in the genome helped us better understand which genes are really relevant to the changed amounts of molecules in the blood,” explains Professor Claudia Langenbergová. “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,” he adds.

Metabolism also determines the effects of drugs

The results show that metabolism not only contributes to maintaining health or causes disease, but also significantly determines how effective or sometimes harmful drugs are. For example, the researchers found genetic changes close to the gene in about a fifth of the study participants DPYD, which slows the breakdown of some cancer drugs. As a result, patients accumulate toxic levels of substances in the blood. “Variants near genes that are also targeted by drugs can give us clues about possible unwanted side effects. We were able to show that drugs that reduce the conversion of steroid hormones in the body, thereby counteracting male pattern baldness and prostate enlargement, can increase the risk of depression, which is consistent with reports from drug studies,” he explains.

Scientists have also identified many examples of metabolites influencing a wide range of diseases. For example, an increased level of homoarginine in the blood increases the risk of chronic kidney disease. This is acutely relevant because the administration of homoarginine is currently being tested for the prevention of cardiovascular disease. Therefore, special attention should be paid to preserving renal function in these people.

International cooperation enables research

The study is the result of many years of collaboration between scientists from BIH and colleagues from around the world, especially from the University of Cambridge. Many experts collaborated to better understand and assign the biological relevance and causative genes of the results, including genes 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 impact of genetic variations that differ between specific populations.”

Original publication: “Rare and common genetic determinants of metabolic individuality and their effects on human health”, Natural medicine on November 10, 2022; DOI: 10.1038/s41591-022-02046-0;

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