How genes and small molecules affect our personal risk of disease

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11/21/2022 10:48

How genes and small molecules affect our personal risk of disease

Each person has an individual chemical fingerprint. The composition of small molecules in the blood, such as fat or sugar, helps determine how our body reacts to external influences, which diseases it is susceptible to and how severe a disease will be. In an international collaboration, scientists from the Berlin Institute of Health in the Charité (BIH) and partners in Cambridge (UK) have now discovered more than 300 regions in the genome that contribute to this single chemical fingerprint. They published their findings in the journal Nature Medicine.

Our bodies continuously process 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 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 department of computational medicine, 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 this study, the scientists determined the amount of small molecules, such as sugar, fat or hormones, from blood samples of about 20,000 participants in two large population studies to investigate the influence of the genome. They identified areas in the genome related to many, often very different, metabolic products. “These metabolic ‘hot spots’ in the genome have helped us to better understand which genes are really relevant to the altered amounts of the molecules in the blood,” explains Professor Claudia Langenberg. “With these new findings, we were therefore able to show which changes in metabolism contribute to the development of individual diseases, such as breast cancer,” she adds.

Metabolism also determines the effects of the drug

The findings show that metabolism not only contributes to maintaining health or causing disease, but also significantly determines how effective or sometimes harmful drugs are. For example, scientists found genetic changes near the DPYD gene in about a fifth of study participants, meaning that some cancer drugs are broken down slower. As a result, patients build up toxic levels of the substances in their blood. “Variations 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 and therefore counteract male pattern baldness and prostate enlargement may increase the risk of depression, which is consistent with drug study reports,” explains.

Scientists have also identified many examples of the influence of metabolites on a wide variety of diseases. For example, high blood levels of homoarginine increase the risk of chronic kidney disease. This is extremely relevant, since the administration of homoarginine is currently being tested for the prevention of cardiovascular disease. In these people, therefore, particular attention should be paid to maintaining renal function.

International cooperation enables research

The study is the result of many years of collaboration between BIH scientists and colleagues from around the world, particularly from the University of Cambridge. Many experts worked together to better understand and assign the biological relevance and causative genes of the findings, including from the Helmholtz Zentrum in Munich, Qatar and 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.”

Original publication: “Rare and common genetic determinants of metabolic individuality and their effects on human health,” Nature Medicine, November 10, 2022; DOI: 10.1038/s41591-022-02046-0; https://www.nature.com/articles/s41591-022-02046-0

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Information on the Berlin Institute of Health in the Charité (BIH)
The mission of the Berlin Institute of Health in the Charité (BIH) is medical translation: the results of biomedical research are transferred to new approaches for personalized prediction, prevention, diagnostics and therapy, while observations in daily clinical practice lead to new research ideas. The goal is to obtain a relevant medical benefit for patients and citizens. To this end, BIH is creating a comprehensive translational ecosystem as a translational research area in the Charité, builds on an interorgan understanding of health and disease, and promotes a translational culture change in biomedical research. The BIH was founded in 2013 and is funded 90% by the Federal Ministry of Education and Research (BMBF) and 10% by the State of Berlin. The founding institutions Charité – Universitätsmedizin Berlin and the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) were independent member bodies of the BIH until 2020. Since 2021 the BIH has been integrated into the Charité as a so-called third pillar, the MDC is a partner privileged of the BIH.

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Institute of Health in der Charité Berlin (BIH)

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