Oxford researchers have taken part in 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.
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, for a various reasons, including a long-standing challenge in human genetics: identifying the 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 our metabolism or fighting 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 of the genetic causes of disease, the authors found new insights into how human physiology works and how this might inform drug development.
Among the authors was Jemma Hopewell, Professor of Precision Medicine and Epidemiology at the University of Oxford’s Big Data Institute and Theme Lead for Cardiovascular Medicine in the NIHR Biomedical Research: Oxford.
In this study, published in Cell, scientists brought together data from 38 studies involving 78,664 participants. They 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 revealed biomedical data suggesting that TYK2 inhibitors, which are currently used to treat psoriasis, could potentially be repurposed for rheumatoid arthritis.
It also highlighted that higher levels of furin, a protein found in many tissues in the body, especially the liver, were consistently associated with cardiovascular disease.
One of the authors, 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 protein 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.
This major international collaboration, which involved 118 investigators from 89 institutions, was led by researchers from Queen Mary University of London and the Berlin Institute of Health.