NEW YORK – A research team from Sweden and the UK has flagged blood plasma proteins that preceded the advent of cardiovascular disease (CVD) events such as heart attack, heart failure, or stroke. These proteins included potential drug targets with apparent causal ties to the conditions.
For a study appearing in Nature Cardiovascular Research on Wednesday, the researchers focused on 52,164 UK Biobank participants with available proteomic data. These were between the ages of 40 and 69 years when their blood samples and other data were collected at baseline.
Along with blood plasma levels for 2,919 proteins profiled using the Olink Explore proximity extension assay, the team measured blood glucose, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol, as well as creatinine, blood pressure, and kidney function. The project also collected ancestry data and considered smoking and socioeconomic status.
Over a median follow-up time of 12.6 years, nearly 2,000 UKB participants were diagnosed with a first heart failure (HF) event, while more than 1,300 had a documented myocardial infarction (MI) for the first time and 934 experienced their first ischemic stroke (IS).
The investigators identified 636 proteins that tracked with at least one of these cardiovascular disease events, including 126 plasma proteins linked to all three conditions.
In contrast to smaller observational studies in the past, which unearthed a handful of protein levels linked to CVD, the authors explained, the current study "identified 126 protein levels linked to all three CVD outcomes independently of major confounders, such as age, sex, body mass index (BMI), and glomerular filtration rate."
After validating CVD associations for 118 plasma proteins using data from the China Kadoorie Biobank (CKB) project, the team turned to Mendelian randomization and colocalization to narrow in on protein associations suspected of stemming from related genetic variants.
"[W]hile several hundred proteins were related to CVD, genetically predicted levels of only 47 proteins were linked to CHD, HF, or stroke," the authors wrote, "showing that the vast majority of protein-CVD associations found in observational settings were probably not causal."
In particular, the team's results pointed to the potential importance of three plasma proteins — FGF5, PROCR, and FURIN — with ties to all three conditions considered, prompting speculation that they may be promising drug targets for CVD prevention.
The researchers also assessed pathways that were overrepresented when it came to the genes coding for plasma proteins with CVD associations — analyses that implicated pathways involved in everything from inflammation to growth factors.