Differences in the Platelet mRNA Landscape Portend Racial Disparities in Platelet Function and Suggest Novel Therapeutic Targets.
Differences in the Platelet mRNA Landscape Portend Racial Disparities in Platelet Function and Suggest Novel Therapeutic Targets.
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血小板mRNA景观的差异预示着血小板功能的种族差异，并提出新的治疗靶点。
DOI：
10.1002/cpt.2363
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发表时间：
2021-09
影响因子：
6.7
通讯作者：
Lee, Norman H.
中科院分区：
文献类型：
--
作者：
Garofano, Kaitlin;Park, C. Sehwan;Alarcon, Cristina;Avitia, Juan;Barbour, April;Diemert, David;Fraser, Claire M.;Friedman, Paula N.;Horvath, Anelia;Rashid, Kameron;Shaazuddin, Mohammed;Sidahmed, Alfateh;O'Brien, Travis J.;Perera, Minoli A.;Lee, Norman H.
与欧洲裔美国人相比，非洲裔美国人（AA）的血栓和中风死亡率高出1.6至3倍。目前的抗血小板治疗靶向adp介导的信号通路，这对血小板反应性显示出显着的药物遗传变异。本研究的重点是确定血小板功能的潜在人群差异，以确定未来抗血小板治疗的新分子靶点。我们进行了深度覆盖RNA-Seq来比较来自一组健康志愿者的血小板中的基因表达水平。我们鉴定了13000个表达的血小板基因，其中480个是aa和ea之间显著差异表达的基因（DEGs）。编码已知或预测调节血小板聚集、形态或血小板计数的蛋白的DEGs在AA血小板中上调。许多g蛋白偶联受体（gpcr）、离子通道和促炎细胞因子先前与血小板功能无关，同样也存在差异表达。许多信号蛋白是干预的潜在药理学靶点。值得注意的是，我们通过qRT-PCR证实了独立队列中细胞因子IL32和PROK2的差异表达，并提供了这两种细胞因子对胶原诱导的AA血小板聚集的相反作用的功能验证。利用GTEx全血数据，我们鉴定出516个Fst值为>0.25的eqtl，表明群体分化等位基因可能导致基因表达差异。本研究确定了人群水平上可能影响血小板功能的基因表达差异，并将其作为识别心血管疾病风险的潜在生物标志物。此外，我们的分析揭示了未来抗血小板治疗的候选新药物靶点。
The African American (AA) population displays a 1.6 to 3-fold higher incidence of thrombosis and stroke mortality compared to European Americans (EA). Current anti-platelet therapies target the ADP-mediated signaling pathway, which displays significant pharmacogenetic variation for platelet reactivity. The focus of this study was to define underlying population differences in platelet function in an effort to identify novel molecular targets for future anti-platelet therapy. We performed deep coverage RNA-Seq to compare gene expression levels in platelets derived from a cohort of healthy volunteers defined by ancestry determination. We identified >13,000 expressed platelet genes of which 480 were significantly differentially expressed genes (DEGs) between AAs and EAs. DEGs encoding proteins known or predicted to modulate platelet aggregation, morphology or platelet count were up-regulated in AA platelets. Numerous G-protein coupled receptors (GPCRs), ion channels, and pro-inflammatory cytokines not previously associated with platelet function were likewise differentially expressed. Many of the signaling proteins represent potential pharmacologic targets of intervention. Notably, we confirmed the differential expression of cytokines IL32 and PROK2 in an independent cohort by qRT-PCR, and provide functional validation of the opposing actions of these two cytokines on collagen-induced AA platelet aggregation. Using GTEx whole blood data, we identified 516 eQTLs with Fst values >0.25, suggesting that population-differentiated alleles may contribute to differences in gene expression. This study identifies gene expression differences at the population level that may affect platelet function and serve as potential biomarkers to identify CVD risk. Additionally, our analysis uncovers candidate novel druggable targets for future anti-platelet therapies.
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影响因子：
20.3
作者：
Nagalla, Srikanth;Shaw, Chad;Bray, Paul F.
通讯作者：
Bray, Paul F.
遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
37.8
作者：
Mao G;Songdej N;Voora D;Goldfinger LE;Del Carpio-Cano FE;Myers RA;Rao AK
通讯作者：
Rao AK
影响因子：
3.3
作者：
GURDOL, F;NWOSE, OM;MIKHAILIDIS, DP
通讯作者：
MIKHAILIDIS, DP
影响因子：
3.7
作者：
Bernal-Quirós M;Wu YY;Alarcón-Riquelme ME;Castillejo-López C
通讯作者：
Castillejo-López C