New Insights into the Interplay Between Genes, Proteins, and Disease
Proteins are the fundamental building blocks and functional molecules of the human body. They regulate a wide range of biological processes and play a crucial role in both health and disease. However, it is still not fully understood how genetic variation influences protein abundance and how these changes affect disease risk. An international team of researchers, led by Prof. Dr. Maik Pietzner and Prof. Dr. Claudia Langenberg from the Berlin Institute of Health at Charité (BIH), and Prof. Dr. David van Heel from the Queen Mary University of London, has now identified previously unknown genetic associations using advanced mass spectrometry-based proteomics, revealing hidden mechanisms underlying disease development. Published in Nature Genetics, the study provides an important foundation for a better understanding of complex diseases and opens new avenues for precision medicine. In this interview, Prof. Dr. Maik Pietzner discusses the study's key findings and explains their significance for biomedical research and the future development of personalized therapies.
What specific challenges did you face when developing your approach?
Almost all studies of this kind have so far been limited to participants of European ancestry, even though we know that genetic variation is far greater globally and sometimes calls for tailored treatment approaches to disease. The team led by David van Heel at Queen Mary University of London has done pioneering work here, engaging less privileged and often neglected population groups in scientific research. Only in this way can we develop medicine that truly benefits everyone. For example, clinical trials that decide about the approval of medicines often exclude a large number of people who eventually should benefit.
Collaboration with industry was also key. In this case Seer Inc., without whom the measurement of blood proteins of the participants would not have been possible. Our internationally outstanding expertise in data analysis and integration and in developing machine-learning methods then allowed us to link data on more than 13,000 proteins from over 1,500 study participants with more than 10 million genetic markers.
What surprised you and why? What was new?
The biggest surprise was the high proportion of entirely new findings, that is, regions of the genome that we could link with high confidence to lifelong changes in the blood levels of more than 1,000 proteins. This was striking above all because many of these proteins had already been examined in studies 30 times larger than ours. One technology, then, is not enough, even when it appears to cover a great fraction of all proteins in blood already. A few of the new findings could moreover be traced back to genetic variants that occur only in this population group and were therefore invisible in previous Eurocentric studies.
What significance could this success have for future patients?
The better we understand the molecular mechanisms through which inherited genetic variation manifests as disease risk, the more we can derive targeted interventions for treating and preventing a wide range of diseases.
Where do you see the translational bridge between research and application?
Mechanisms that we can derive in this way in living humans represent a unique bridge to translation, because drugs supported by similar evidence are more than twice as likely to be approved as effective therapies. This is an immensely important step when you consider that more than 90% of the drugs developed by pharmaceutical companies never reach the patient. Autoimmune diseases are one particular challenge. Here, the immune system damages the body's own organs, and they are often difficult to reproduce in animal models. We were able to reveal a possible new mechanism of action in which a protein called IGLV3-21 maybe involved in the formation of the disease-causing autoantibodies of Graves' disease, an overactivity of the thyroid. Here, too, the technical progress paid off, since we were only able to measure this protein with the help of mass spectrometry.