GENOTYPIC DETERMINANTS OF ASPIRIN RESPONSE IN HIGH RISK FAMILIES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 小剂量阿司匹林(ASA)是预防和治疗冠心病(CHD)的经济有效的药物。ASA的益处被认为与血小板环氧合酶-1(COX-1)的不可逆乙酰化有关，从而减少了血小板聚集和血小板介导的炎症。ASA对血小板功能的影响存在相当大的个体间差异，这种差异可能与个体间的遗传差异有关。本研究将研究ASA对400个多世代家庭的3200名受试者(非洲裔美国人和白人各一半)的血小板聚集、血栓素和ATP释放、切变条件下的聚集以及P-选择素和CD40配体的表面表达的抑制作用。参与者将是早产儿冠心病患者的高危兄弟姐妹(之前在约翰·霍普金斯兄弟姐妹研究中确定)，以及他们的成年子女。在服用阿司匹林14天后，每天81毫克，检测血小板功能和血浆炎症标志物(C-反应蛋白、白介素1β、白介素6、单核细胞趋化蛋白-1和基质金属蛋白酶-9)，以表征阿司匹林的反应表型。从已知的参与血小板聚集和血小板介导的炎症的生化途径的候选基因列表中，将根据生物学重要性和编码和/或调节区是否存在足够的已知SNP，初步选择20个基因用于每个基因的15-20个单核苷酸多态(SNPs)的基因分型。在第一批1600名参与者完成表型鉴定后，将使用SNP簇对短串联重复(STR)标记进行全基因组互补扫描，并对多达5个感兴趣的区域进行精细定位。根据连锁分析，候选基因名单将重新排序，并将进行额外的基因分型。将进行分析，以确定ASA反应性是否可遗传，以及它是否与候选基因或已定义单倍型的特定变异有关。这一结果将有助于更好地了解个体之间在ASA反应性方面的差异，包括可能的种族差异，并应能够为高危个体的CHD预防治疗提供基因定制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Low dose aspirin (ASA) is cost effective and efficacious for the prevention and treatment of coronary heart disease (CHD). The benefit of ASA is thought to be related to the irreversible acetylation of platelet cyclo-oxygenase-1 (COX-1), resulting in a reduction in platelet aggregation and platelet-mediated inflammation. Considerable inter-individual variation exists in the effect of ASA on platelet function, and this variability may be related to genetic variations across individuals. This study will characterize the inhibitory effect of ASA on agonist-induced platelet aggregation, thromboxane and ATP release, aggregation under shear conditions, and surface expression of P-selectin and CD40 ligand in 3200 subjects from 400 multi-generational families, half African American and half white. Participants will be high-risk siblings of patients with premature CHD (previously identified in the Johns Hopkins Sibling Study), along with their adult offspring. Platelet function and plasma inflammatory markers (C-reactive protein, interleukin-1beta, interleukin-6, monocyte chemotactic protein-1, and matrix metalloproteinase-9) will be measured at baseline and after 14 days of ASA, 81 mg/day to characterize ASA-response phenotypes. From a list of candidate genes involved in the known biochemical pathways of platelet aggregation and platelet-mediated inflammation, 20 genes will be initially selected for genotyping of 15-20 single nucleotide polymorphisms (SNPs) per gene, based on biological importance and the presence of sufficient known SNPs in coding and/or regulatory regions. After the first 1600 participants have been phenotyped, a complementary genome wide scan of short tandem repeat (STR) markers and fine mapping of up to 5 regions of interest will be done using SNP clusters. Based on linkage analysis, the list of candidate genes will be re-prioritized and additional genotyping will be performed. Analyses will be performed to determine whether ASA responsiveness is heritable and whether it is associated with specific variations in candidate genes or defined haplotypes. The results should lead to a better understanding of the variability among individuals in ASA responsiveness, including possible racial differences, and should enable genotypic tailoring of preventive therapy for CHD in high-risk individuals.