Nature Medicine: How genes and small molecules affect our individual disease risk

Everyone has their own chemical fingerprint.

The composition of small molecules such as fat or sugar in the blood determines how our body reacts to external influences, which diseases we are susceptible to and how severe
the disease is.
In an international collaboration with partners at the University of Cambridge (UK), scientists at the Berlin Institute for Health Research (Charité) (BIH) have identified more than 300 regions in the genome that are associated
with this individual chemical fingerprint.
Their findings were published in Natural Medicine.

Our bodies continuously process thousands of small molecules to maintain our metabolism and thus our health
.
Even small changes can lead to disease, and metabolism varies
from person to person as it does to person.
Scientists at the University of Bosnia and Herzegovina have now identified rare and common changes
in the genetic code that affect an individual's chemical fingerprint and personal disease profile.
Professor Claudia Langenberg, Head of the Department of Computational Medicine, said: "With our research, we have finally elucidated the genetic control of metabolism based on hundreds or thousands of small metabolites, which has never been shown in such detail
.
This means we now have a better understanding of how and why genetic differences contribute to the development of
disease.
”

Blood samples from 20,000 participants

To investigate the effects of the genome, the scientists measured the number of
small molecules such as sugars, fats or hormones from blood samples from about 20,000 participants in two large population studies.
They identified regions in the genome associated with many (often very different) metabolites
.
Professor Claudia Langenberg explains: "These metabolic 'hot spots' in the genome help us better understand which genes are associated
with changes in the number of molecules in the blood.
" She added: "With these new findings, we were able to show which changes in metabolism contribute to the development of individual diseases, such as breast cancer
.
"

Metabolism also determines the effect of the drug

The results showed that metabolism not only helps maintain health or allows disease to develop, but largely determines the effectiveness or sometimes harmful effects
of drugs.
For example, scientists found a common variation
in the genetic code close to the DPYD gene in about one in five study participants.
DPYD encodes for substances called enzymes, which are responsible for breaking down certain cancer drugs, and people who carry these gene variants are at higher risk of accumulating toxic levels in their blood
.
This means that genetic testing can adjust treatment decisions
.
"Variants near genes are also targeted by drugs, which can give us clues
about possible side effects.
" For example, we were able to show that drugs that reduce the conversion of steroid hormones in the body to counteract hair loss and prostate enlargement in men may increase the risk of depression, which is consistent with drug studies reporting," she explains
.

The scientists also found many examples of the effects of metabolites on various diseases, including an increase in blood concentrations of homoarginine that increases the risk of
chronic kidney failure.
This is relevant because trials are currently underway to use homoarginine for the prevention of cardiovascular disease
.
Therefore, for these people, special attention should be paid to maintaining kidney function
.

International cooperation makes research possible

The study is the result of many years of collaboration between scientists from Bosnia and Herzegovina and colleagues from around the world, particularly from the Department of Epidemiology of the Medical Research Council (MRC) of the University of
Cambridge.
Many experts worked together to better understand and determine the biological correlation and causal genes of the results, including from the Helmholtz Centre in Munich, Qatar, and 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 different genetic variants between specific populations.
"