Despite recent advances in prevention and treatment, cardiovascular disease (CVD) remains a leading cause of premature death and disability globally, with a rising burden in many low- and middle-income countries. Several modifiable determinants of CVD are well-established (eg, smoking, hypertension, obesity, dyslipidaemia), but they do not fully explain temporal trends and large variations in disease rates between different populations. Moreover, the causal relevance of certain CVD risk factors and/or their associated biological mechanisms is still incompletely understood. High-throughput affinity-based proteomic assays now enable quantification of several thousand protein markers in the blood, and their application in large epidemiological and clinical studies will facilitate the development of precision cardiovascular medicine. This review describes recent findings from large population-based studies to illustrate the value of proteomics in cardiology for improved risk prediction, diagnosis and patient stratification; better understanding of disease aetiology and pathophysiology; and identification of repurposing and novel therapeutic targets. To overcome the current limitations, future studies should aim to further increase the sample size, number of proteins measured reliably (eg, via multiple assay platforms) and longitudinally, and ancestry population diversity, to expedite clinical translation of key research findings that will help to transform development of precision medicine in cardiology globally.
H. Fry, Pek-Kei Im, P. Yao et al.· Heart· 0 citations
BACKGROUND
Most drugs target proteins, and proteome-wide genetic analyses in diverse populations could discover potential novel and repurposed targets for improved prevention and treatment of ischemic heart disease (IHD) beyond statin therapy.
OBJECTIVES
The purposes of this study were to use cis-acting single nucleotide polymorphisms (cis-pQTLs) identified for plasma proteins in East Asians and Europeans to discover and validate potential drug targets for IHD.
METHODS
We measured plasma levels of 9,520 (Olink/SomaScan: 2,923/7,297) proteins in a case-cohort study of IHD (1,976 incident cases and 2,001 subcohort controls) in statin-free individuals in the prospective China Kadoorie Biobank (CKB). Genome-wide association studies identified 2,895 (Olink/SomaScan: 1,301/1,594) cis-pQTLs for these proteins in CKB. Two-sample Mendelian randomization (MR) and colocalization analyses assessed associations of all available cis-pQTLs for these proteins with IHD in East Asians (n = 29,319 cases), with further replication in Europeans (n = 181,522 cases) and comparison with findings in previous MR studies.
RESULTS
In CKB observational analyses, a total of 959 (Olink/SomaScan: 426/533) proteins were associated at false discovery rate-corrected P < 0.05 with IHD after adjusting for major IHD risk factors. Two-sample MR analyses provided genetic support for 54 unique (Olink/SomaScan: 36/28) proteins in IHD etiology. Colocalization analyses confirmed shared gene-protein-IHD associations (posterior probability of hypothesis 4 [PPH4] ≥0.8) for 15 unique (Olink/SomaScan: 10/10) proteins, including 8 lipid-related, 3 inflammation-related, 1 blood pressure-related, and 3 alcohol-related proteins in East Asians. In Europeans, MR analyses of 12 non-alcohol-related proteins showed directionally concordant results for 8 proteins, with 5 having strong colocalization evidence of shared gene-protein-IHD associations (PPH4 ≥0.8), including 4 lipid-related (proprotein convertase subtilisin/kexin type 9, LPA, APOE, cadherin-1) and 1 systolic blood pressure-related (fibroblast growth factor 5) protein. However, 4 proteins showed directionally discordant MR results, including 2 lipid-related (APOA5, SORT1) and 1 inflammation-related (transforming growth factor beta 1) proteins with strong colocalization evidence of shared gene-protein-IHD associations (PPH4 ≥0.8). Comparison with previous MR studies revealed little consistency across studies in the number and identity of target proteins for IHD beyond well-established lipid-related (low-density lipoprotein cholesterol, lipoprotein(a), and triglycerides) or inflammation-related (interleukin-6) protein targets.
CONCLUSIONS
The findings support a role for lipid-driven chronic inflammation in IHD etiology, and treatment strategies simultaneously targeting multiple lipid and inflammation pathways should be prioritized for further research to improve drug treatment of IHD beyond statin therapy.
Mohsen Mazidi, N. Wright, A. Pozarickij et al.· Journal of the American Coll...· 1 citation
