Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark; Faculty of Health, Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.
Thromb Res. 2017 Oct;158:86-92. doi: 10.1016/j.thromres.2017.08.009. Epub 2017 Aug 18.
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.
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).
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.
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.
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.
在最近的全基因组关联研究中，冠状动脉疾病（CAD）和心肌梗死（MI）与许多遗传变异有关，但它们在血小板生成中的作用在很大程度上尚不清楚。
我们研究了 CAD 和 MI 相关遗传变异与五个血小板生成相关指标之间的关系：血小板计数（PC）、平均血小板体积（MPV）、未成熟血小板计数（IPC）、未成熟血小板分数（IPF）和血清血小板生成素（TPO）。
我们在 879 名稳定型 CAD 患者中对 45 个全基因组范围内与 CAD/MI 相关的标志物进行了基因分型。计算遗传风险评分以评估与所有遗传变异相关的综合风险。使用希森美康 XE-2100 血液分析仪分析血小板指数。通过 ELISA 测量 TPO。
有两个变异与多个指标有显著关联；对于 rs10947789（KCNK5），每一个 CAD 风险等位基因，MPV 的调整后几何均值增加 2%（95%置信区间：1-2%，p=0.002），IPC 增加 6%（0-12%，p=0.033），IPF 增加 9%（3-16%，p=0.004）。此外，观察到 TPO 降低 11%（3-19%，p=0.010）。rs3184504（SH2B3）与 PC 每一个 CAD 风险等位基因的调整后几何均值增加 3%（1-6%，p=0.003）相关，TPO 降低 11%（5-17%，p<0.001）。此外，PC 每一个 CAD 风险等位基因的调整后 IPC 降低 5%（0-9%，p=0.037），而基因型之间的 IPF 水平没有差异。
作为一项新发现，我们的研究表明 KCNK5 在调节血小板大小和成熟度方面发挥作用。此外，我们的研究结果证实了 SH2B3 基因座与血小板计数之间的关联。
