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The SH2B3 and KCNK5 loci may be implicated in regulation of platelet count, volume, and maturity
Morten K Christiansen1, Sanne B Larsen2, Mette Nyegaard3
1Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark; Faculty of Health, Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Insights
Genetic variants linked to coronary artery disease influence platelet production and size. KCNK5 impacts platelet volume and maturity, while SH2B3 affects platelet count and thrombopoietin levels.
Area of Science:
- Cardiovascular Genetics
- Hematology
- Thrombopoiesis Research
Background:
- Genome-wide association studies (GWAS) have identified genetic variants associated with coronary artery disease (CAD) and myocardial infarction (MI).
- The functional role of these CAD/MI-associated variants in thrombopoiesis remains largely unexplored.
- Understanding genetic links to platelet function is crucial for cardiovascular health.
Purpose of the Study:
- To investigate the association between genetic variants implicated in CAD/MI and key thrombopoiesis indices.
- To examine the relationship between CAD/MI genetic markers and platelet count (PC), mean platelet volume (MPV), immature platelet count (IPC), immature platelet fraction (IPF), and serum thrombopoietin (TPO).
Main Methods:
- Genotyping of 45 genome-wide significant CAD/MI markers in 879 stable CAD patients.
- Calculation of a genetic risk score to evaluate combined risk from identified variants.
- Analysis of platelet indices using the Sysmex XE-2100 haematology analyser and TPO levels via ELISA.
Main Results:
- The variant rs10947789 (KCNK5) showed associations with increased MPV, IPC, and IPF, and decreased TPO.
- The variant rs3184504 (SH2B3) was linked to higher PC and lower TPO.
- A significant association was found between SH2B3 and decreased IPC, but not IPF.
Conclusions:
- KCNK5 plays a novel role in regulating platelet size and maturity.
- The SH2B3 locus is confirmed to be associated with platelet count.
- These findings link CAD/MI genetic risk factors to specific mechanisms of platelet production and function.
Introduction:
In recent genome-wide association studies, coronary artery disease (CAD) and myocardial infarction (MI) have been linked to a number of genetic variants, but their role in thrombopoiesis is largely unknown.
Aim:
We investigated the association between CAD and MI-associated genetic variants and five thrombopoiesis-related indices: platelet count (PC), mean platelet volume (MPV), immature platelet count (IPC), immature platelet fraction (IPF), and serum thrombopoietin (TPO).
Methods:
We genotyped 45 genome-wide significant CAD/MI-markers in 879 stable CAD patients. A genetic risk score was calculated to assess the combined risk associated with all the genetic variants. Platelet indices were analysed using the Sysmex XE-2100 haematology analyser. TPO was measured by ELISA.
Results:
Two variants were nominally associated with several indices; for rs10947789 (KCNK5), the adjusted geometric mean was 2% higher for MPV (95% confidence interval: 1-2%, p=0.002), 6% for IPC (0-12%, p=0.033), and 9% for IPF (3-16%, p=0.004) per CAD risk allele. Moreover, an 11% lower TPO (3-19%, p=0.010) was observed. Rs3184504 (SH2B3) was associated with a higher adjusted geometric mean of 3% (1-6%, p=0.003) per CAD risk allele for PC, and an 11% (5-17%, p<0.001) lower TPO. Furthermore, the adjusted IPC was 5% (0-9%, p=0.037) lower per CAD risk allele for PC, whereas IPF levels did not vary across genotypes.
Conclusion:
As a novel finding, our study suggests a role for KCNK5 in the regulation of platelet size and maturity. Furthermore, our findings confirm an association between the SH2B3-locus and platelet count.
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