Research is revealing potential drug targets for the treatment of heart disease and stroke, using a mixture of genetic and observational data to separate causal from non-causal proteins.
Letter: Measured and genetically predicted protein levels and heart problems within the UK Biobank and China Kadoorie Biobank. Image source: Lightspring / Shutterstock
In a recent study published within the journal Cardiovascular research in natureinvestigators assessed the association between 2,919 different plasma proteins and heart problems (CVD) outcomes within the UK Biobank (UKB) and China Kadoorie Biobank (CKB), identifying potential causative proteins for brand new drug targets.
Background
Many studies have measured plasma protein levels in individuals with heart problems. Nonetheless, on account of the interconnected nature of proteins, it is usually difficult in observational studies to pinpoint those who have true causal significance.
One method to address this issue is thru Mendelian randomization (MR) and genetic analyzes to check whether genetic loci that regulate protein levels are also related to CVD outcomes.
Previous research has found a whole bunch of proteins related to myocardial infarction (MI) (a heart attack attributable to blockage of blood flow to the center), ischemic stroke (IS) (stroke attributable to blockage of blood vessels supplying the brain) and the center. heart failure (HF) (a condition during which the center is unable to pump blood effectively), with a limited variety of cases showing evidence of a causal relationship.
Further research is required to raised understand these causal relationships and discover recent therapeutic targets for the treatment of CVD.
In regards to the study
UKB is a big, multicentre, prospective cohort study conducted within the UK between 2006 and 2010, which included over 500,000 people aged 40–69 years. Data from 52,164 participants with valid proteomic data were included. The North West Multicenter Research Ethics Committee (UK) and the Swedish Ethical Review Board provided ethical approval and participants provided written informed consent. Baseline measurements were collected, including plasma glucose, cholesterol, and creatinine levels, blood pressure, and estimated glomerular filtration rate (eGFR).
Participants’ ethnicity was categorized and socioeconomic status was assessed using the Townsend Index of Social Deprivation. Smoking status was recorded as never, former, or current smoker. Disease outcomes, including myocardial infarction, IS, and HF, were classified using International Classification of Diseases (ICD-10) codes. Plasma levels of two,923 proteins were initially measured using the Olink EXPLORE assay, and a pair of,919 proteins passed quality control.
The CKB study included 512,000 Chinese adults employed between 2004 and 2008. Data on smoking, medical history, and education were collected. Plasma proteins were measured using the identical analytical platform as UKB. Key findings from UKB were successfully replicated in CKB, strengthening the study’s findings.
Research results
In UKB, 126 proteins were found to be significantly related to all three CVD outcomes. Of those, 118 were related to at the very least one CVD final result within the replication phase performed at CKB. Of those, 87 proteins were related to a couple of CVD, while 31 proteins were related to all three CVD outcomes (MI, IS, and HF) at a significance level of P < 0.05.
Using Mendelian randomization (MR) evaluation, genetically predicted levels of 33 proteins were related to coronary heart disease (CHD), with a very powerful proteins being lipoprotein(a) (LPA), EGF-cadherin LAG seven-pass G-type receptor 2 (CELSR2), apolipoprotein E (APOE), feline sarcoma oncogene (FES), and vesicle-associated membrane protein 5 (VAMP5). 4 proteins have been related to IS, while 18 proteins have been related to HF, with LPA, CELSR2 and fibroblast growth factor 5 (FGF5) emerging as key players in CHD and HF. Sensitivity analyzes using multiple cis-SNPs for MR evaluation yielded results consistent with initial findings, increasing the robustness of those associations.
Colocalization evaluation provided further evidence by showing that 10 proteins had strong common causal variants with CVD outcomes. Of note, CELSR2 and FGF5 were related to each CHD and HF, while FURIN was related to each CHD and stroke. These proteins, especially FURIN, have been identified as promising targets for future drug development, supported by additional discoveries regarding subclinical markers of CVD.
Interestingly, observational analyzes showed a weaker association between protein levels and CVD results compared with MRI results. In observational analyses, only 6% of proteins related to CVD outcomes were found to be causal in MR evaluation, suggesting that many observational associations aren’t causal. This discrepancy is probably going on account of systematic errors akin to residual confounding and reverse causality in observational studies.
Proteins akin to FGF5, protein C receptor (PROCR), and FURIN have shown consistent evidence of a causal association with CVD outcomes in each observational and genetic analyses, highlighting their potential as therapeutic targets. FGF5 has been related to hypertension and carotid artery dilatation, while FURIN, a protease involved in protein activation, has been related to each myocardial infarction and IS.
Conclusions
In summary, the study identified many proteins related to CVD outcomes, but genetic analyzes showed that only a small subset demonstrated a causal association. Key proteins akin to FGF5, PROCR, and FURIN have emerged as potential targets for CVD prevention and treatment.
The findings highlight the importance of distinguishing between observational and causal associations in protein research. Although lots of the observational associations weren’t causal, the usage of Mendelian randomization and colocalization analyzes improved our understanding of which proteins may play a direct role within the pathogenesis of CVD, offering promising directions for future drug development.