Researchers from Oxford Population Health have helped lead one of the largest studies to date exploring how genetic differences influence the proteins circulating in our blood, offering new clues about why diseases develop and where new treatments might be found. The study is published in Cell.
Large-scale genetic studies have been conducted for various diseases in the past two decades, with hundreds of thousands of participants involved. Although these studies revealed fundamental insights, their translation into tangible changes on how we treat patients have been limited so far due to various reasons, including a longstanding challenge in human genetics: identifying disease-causing genes, proteins and mechanisms underlying diseases.
Proteins are often described as the “building blocks of life”. Our genetic code’s main purpose is to produce instructions for making proteins, which play a vital role in every part of human health, ranging from building tissues to their role in metabolism or to fight infections.
Blood proteins offer a fundamental and dynamic view into human health. By studying the genetic regulation of blood proteins and linking this to knowledge on genetic disease causes, the authors identified new insights into how human physiology works and how such knowledge can inform drug development.
In this study, researchers brought together data from 38 studies involving up to 78,664 participants. The team examined more than 1,100 blood proteins and identified over 24,000 genetic signals linked to their levels. These proteins are important because they can provide an early readout of changes in the body and may point to biological processes involved in disease.
A key finding from this study was that many genetic effects do not act directly on the gene that makes a protein. Instead, they act indirectly through wider biological pathways, tissues, and cell types. The researchers found especially strong evidence for the role of protein glycosylation, a process cells use to fold, modify, and transport proteins correctly. This helps explain how changes in one part of the body can alter protein levels measured in blood.
The work also showed how these genetic insights could help identify promising drug targets and opportunities to repurpose existing medicines. For example, the study highlighted protein signatures linked to disease risk and provided genetic support for potential treatment opportunities, including TYK2 inhibitors for rheumatoid arthritis. It also pointed to proteins such as furin as possible players in cardiovascular disease.
Dr Karl Smith-Byrne, Associate Professor and Senior Molecular Epidemiologist at Oxford Population Health, said ‘This study is our best look into the majority of genetics that drive circulating protein level - those that lie away from the protein’s coding gene - which are challenging to understand. As part of this study, we were able to shed light on the mechanisms by which these genetic variants drive levels and, in some cases, in which tissues and for what gene.'
The researchers note, however, that most participants were of European ancestry, and they emphasise the need to extend this kind of work to populations that have historically been under-represented in genetic research.