Tiny molecules with a big effect

The human organism needs a large number of small molecules such as sugar or fats in order to function properly. The composition of these so-called metabolites and their interaction – the metabolism – varies from person to person and depends not only on external influences such as diet, but also to a considerable extent on natural variations in our genetic make-up. In an international study, scientists from the Berlin Institute for Health (BIH) and the Charité – Universitätsmedizin Berlin, together with colleagues from Great Britain, Australia and the USA, discovered hundreds of previously unknown variations of genes that sometimes have drastic effects on the concentration of these small molecules in the blood . The researchers have now published their results in the journal Nature Genetics.

The concentration and composition of metabolites – small molecules in the blood or in tissue fluid – provide information about biological processes in the human body. They therefore serve as important biomarkers in clinical medicine, for example when diagnosing diseases or when checking the effectiveness of a therapy. Interestingly, the composition of the metabolites differs from person to person, regardless of external influences such as illness or diet. This is because the blueprints for the proteins that affect metabolite concentration, such as enzymes and transporter proteins, also differ between individuals. Often the smallest genetic variants can lead to a metabolic enzyme being more or less active or a transporter protein being more or less efficient, whereby the concentration of the metabolites is increased or decreased.

Data from 85,000 people analyzed

The team around Claudia Langenberg, BIH professor for Computational Medicine, has now examined the effect of genetic variants on 174 different metabolites. “We have found a surprising number of correlations between certain genetic variants and changes in the concentration of small molecules in the blood,” reports the epidemiologist. “In most cases, the genetic variants cause changes in the blueprint of important metabolic regulators such as enzymes or transporters.”

In order to investigate these relationships, the Langenberg team needed huge amounts of data. “For our studies we used large databases that provided us with the results of blood tests and genetic information from a total of around 85,000 people,” explains Maik Pietzner, lead author of the study and scientist in the Langenberg laboratory. “In this way we were able to successfully demonstrate that it is possible to jointly evaluate data from a large number of small individual studies, even across technological boundaries.”

Genetic variants can contribute to common diseases

The work of the scientists is highly relevant to medicine as it can explain how naturally occurring genetic variants that affect metabolism contribute to the occurrence of common diseases such as diabetes mellitus, as well as rare diseases. For example, high levels of the amino acid serine in the blood seem to offer protection against a rare eye disease known as macular telangiectasia – knowledge that opens up new therapeutic avenues. In another study, the authors were also able to show that an individual’s genetic risk for an altered serine metabolism can be helpful in the early detection of this serious eye disease. They also identified a new mechanism that explains how impaired transmission of signals via the GLP-2 receptor increases the risk of developing type 2 diabetes.

“The special thing about our study was the extreme effects we observed and their potential relevance for medical research,” explains Langenberg. “For example, we were able to identify genetic variants that have a three times greater influence on metabolism than the already known effects of more frequent genetic variations, for example on the body mass index.”

Data is only relevant when it is used

The team has set up an interactive website at so that scientists around the world can link their respective fields to their data. Ultimately, according to Langenberg, data is only relevant if it can be used: “We very much hope that these convincing examples will encourage other scientists and doctors to apply our results to their specific research or disease cases.”


Luca A Lotta, Maik Pietzner, Claudia Langenberg: “A cross-platform approach identifies genetic regulators of human metabolism and health.” Nature Genetics 2021, DOI 10.1038 / s41588-020-00751-5

About the Berlin Institute for Health (BIH)

The mission of the Berlin Institute for Health (BIH) is medical translation: transferring biomedical research results into novel approaches for personalized prediction, prevention, diagnostics and therapy, and vice versa, using clinical observations to develop new research ideas. The aim is to offer relevant medical benefits to patients and the general public. The BIH has also set itself the goal of establishing a comprehensive translational ecosystem as a translational research area at the Charité – one that focuses on a system-wide understanding of health and disease and promotes change in the biomedical research culture. The BIH is funded 90 percent by the Federal Ministry of Education and Research (BMBF) and 10 percent by the State of Berlin. The two founding institutions Charité – Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) were independent member organizations within the BIH until 2020. From 2021 the BIH was integrated into the Charité as the so-called BIH, third pillar; The MDC is a privileged partner of the BIH.

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