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Integrative Genomic Analysis Reveals Four Protein Biomarkers for Platelet Traits
Dong Heon Lee1,2, Chen Yao1,2, Arunoday Bhan3
1The Framingham Heart Study, Framingham, MA (D.H.L., C.Y., J.K., B.A.T.R., S,-J.H., M.-H.C., D.L., A.D.J.).
Insights
Researchers identified four proteins causally linked to platelet count (PLT) and mean platelet volume (MPV). These findings offer insights into cardiovascular disease (CVD) mechanisms involving platelet function and blood coagulation.
Area of Science:
- Biochemistry and Molecular Biology
- Cardiovascular Disease Research
- Genetics and Genomics
Background:
- Mean platelet volume (MPV) and platelet count (PLT) are established risk factors for cardiovascular disease (CVD) and mortality.
- Identifying underlying protein biomarkers can elucidate CVD pathogenesis and inform therapeutic strategies.
Purpose of the Study:
- To identify causal protein biomarkers associated with MPV and PLT using a multi-omics approach.
- To investigate the role of these proteins in platelet production and their potential link to CVD risk.
Main Methods:
- Integrative analysis of genetic variants, protein quantitative trait loci (pQTLs), and Mendelian randomization (MR) to infer causality.
- Association analyses in Framingham Heart Study (FHS) participants.
- RNA-sequencing of megakaryocyte clones and siRNA gene knockdown experiments to validate protein function.
Main Results:
- Ten proteins associated with MPV and 31 with PLT were identified.
- MR revealed 4 putatively causal proteins for MPV and 4 for PLT.
- GP-5, GRN, and MCAM were linked to PLT, while MPO showed association with MPV. Silencing GP-5, GRN, and MPO reduced platelet production.
Conclusions:
- Four proteins were causally linked to platelet count and volume.
- These proteins may contribute to CVD pathogenesis through platelet and blood coagulation pathways.
- Findings highlight potential novel therapeutic targets for CVD prevention and treatment.
Rationale:
Mean platelet volume (MPV) and platelet count (PLT) are platelet measures that have been linked to cardiovascular disease (CVD) and mortality risk. Identifying protein biomarkers for these measures may yield insights into CVD mechanisms.
Objective:
We aimed to identify causal protein biomarkers for MPV and PLT among 71 CVD-related plasma proteins measured in FHS (Framingham Heart Study) participants.
Methods And Results:
We conducted integrative analyses of genetic variants associated with PLT/MPV with protein quantitative trait locus variants associated with plasma proteins followed by Mendelian randomization to infer causal relations of proteins for PLT/MPV. We also tested protein-PLT/MPV association in FHS participants. Using induced pluripotent stem cell-derived megakaryocyte clones that produce functional platelets, we conducted RNA-sequencing and analyzed expression differences between low- and high-platelet producing clones. We then performed small interfering RNA gene knockdown experiments targeting genes encoding proteins with putatively causal platelet effects in megakaryocyte clones to examine effects on platelet production. In protein-trait association analyses, ten proteins were associated with MPV and 31 with PLT. Mendelian randomization identified 4 putatively causal proteins for MPV and 4 for PLT. GP-5 (Glycoprotein V), GRN (granulin), and MCAM (melanoma cell adhesion molecule) were associated with PLT, while MPO (myeloperoxidase) showed significant association with MPV in both analyses. RNA-sequencing analysis results were directionally concordant with observed and Mendelian randomization-inferred associations for GP-5, GRN, and MCAM. In siRNA gene knockdown experiments, silencing GP-5, GRN, and MPO decreased PLTs. Genome-wide association study results suggest several of these may be linked to CVD risk.
Conclusions:
We identified 4 proteins that are causally linked to PLTs. These proteins may also have roles in the pathogenesis of CVD via a platelet/blood coagulation-based mechanism.
