The influence of genes and small molecules on personal disease risk

Each individual has a unique chemical fingerprint. Small molecules in the blood, like fats or sugars, have a significant impact on how the human body responds to stress, which diseases people are predisposed to, and how serious an illness will be.

Scientists from the Berlin Institute of Health at the Charité (BIH) have now identified more than 300 regions in the genome that contribute to this unique chemical fingerprint through an international collaboration with partners from Cambridge (UK). Their findings have been published in Nature Medicine.

Thousands of small molecules are constantly processed by the body to keep the metabolism and, by extension, our health, in check. The disease can be brought on by even minor changes, and each person has a unique metabolism.

Researchers at BIH have now identified both uncommon and frequent genetic code changes that affect both the unique disease profile and the individual’s chemical fingerprint.

With our study, we are finally illuminating the genetic control of our metabolism based on many hundreds of small metabolites, which has never been shown in such detail. This means we now better understand how and why genetic differences contribute to the development of diseases.”

Claudia Langenberg, Professor and Head, Computational Medicine Department, Berlin Institute of Health

Blood samples from 20,000 participants

In two significant population studies involving close to 20,000 participants, the researchers measured the concentration of small molecules like sugars, fats, and hormones in blood samples to examine the role of the genome. They discovered genomic regions that are connected to a variety of metabolites, many of which are quite distinct.

Professor Langenberg added, “These metabolic ‘hotspots’ in the genome have helped us to better understand which genes are relevant to the changing amounts of molecules in the blood. 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.”

Metabolism also determines drug effects

The findings demonstrate that metabolism not only plays a role in preserving health or allowing diseases to progress, but it also plays a significant role in determining how effective or occasionally harmful drugs are. One-fifth of the study participants, for instance, had a common variation in the genetic code near the DPYD gene, according to the researchers.

A product called an enzyme that breaks down some cancer drugs is encoded by the gene DPYD, and people who carry that genetic variation are more likely to develop toxic blood levels. This implies that treatment choices can be customized through genetic testing.

“Variations near genes that are also the target of drugs can give us clues about possible unwanted side effects. For example, we were able to show that drugs that reduce the conversion of steroid hormones in the body and thus counteract male hair loss and prostate enlargement may increase the risk of depression, which is consistent with reports from drug studies,” Langenberg further added.

The scientists have also discovered numerous instances of how metabolites can affect different diseases, such as an elevated homoarginine blood concentration that raises the risk of chronic renal failure.

This is significant because homoarginine administration is currently being investigated as a cardiovascular disease prevention strategy. Therefore, maintaining kidney function in these people requires special attention.

International cooperation makes research possible

The investigation is the result of many years of collaboration between researchers from the BIH and associates from around the globe, particularly from the Medical Research Council (MRC) Epidemiology Unit at the University of Cambridge.

The Helmholtz Centre in Munich, Qatar, and the pharmaceutical company Pfizer are just a few of the experts who have collaborated to better understand and identify the biological relevance and causal genes of the findings.

Claudia Langenberg is already in charge of a new endeavor.

“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 certain populations,” Langenberg further stated.