POLYMORPHISMSAND SEVERITYIN SICKLE CELL DISEASE

镰状细胞病的多态性和严重程度

• 批准号: 7246524
• 负责人: TIMOTHY C FISHER
• 金额: $ 3.6万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7246524
• 关键词: POLYMORPHISMSAND; SEVERITYIN; SICKLE; CELL; DISEASE

It is believed that much of the clinical variability among patients with sickle cell disease (SCD) may be genetically determined, resultingfrom the co-inheritanceof "epistatic"genes which interact with the basic sicklingdefect to modifythe disease pathophysiology.We recentlyconducted a pilotstudy comparing the inheritanceof several commonbloodgroup polymorphisms with SCD severity in 103 children and found that the Lewisnegative Le(a-b-) phenotype was associatedwith a 2-fold higher hospitalization rate for SCD-related complicationscompared to Le(a+b-) and Le(a-b+) patients. The Le(a-b-) phenotypeis also known be associatedwith a 2-fold increased riskof ischemic heart disease (IHD). No mechanism has yet been identified,but we hypothesize that the association between Lewis RBC phenotype and SCD severitymay be mediated by differencesin the plasmalevels of sialyI-Lewisa (sLea), a high-affinity selectin ligand.The objectives of this proposedmulti-centercollaborativestudy are: a) to confirmour initial findings in a larger group of children drawn from multiple centers; b) to determine whether the .-_ Lewis(a-b-) phenotype is also associated with disease severity in adults; c) to determine whether the Lewis phenotype or plasma sLea level predict specific types of complication (e.g. stroke, ACS); d) to establish whether Lewis acts independently of HbF, beta-globin haplotypes and alpha thalassemia; e) to look for any link between other blood group polymorphisms (e.g., Duffy, MNS) and SCD disease severity. Lewis antigen status will be determined serologically, along with 20 other blood group antigens. We will also perform Se and Le genotyping by PCR-RFLP and quantify plasma sLea by ELISA. Disease severity data will be collected via standardized report forms and entered into the CSCC Common Database. It is anticipated that retrospective data will be available from the Database for many patients. The participation of multiple centers in this project is essential, since it requires the collection of high-quality clinical data on large numbers of patients. Given the large increment in hospitalizations associated with Le(a-b-) in our pilot study, we believe that this marker may be useful as an early predictor of severity in SCD, and may help with the targeting of aggressive interventions (BMT, chronic transfusion) to higher-risk SCD patients.

人们认为，镰状细胞病(SCD)患者的大部分临床变异性可能是 基因决定的，由与基本基因相互作用的上位性基因共同遗传的结果 疾病缺陷以改变疾病的病理生理。我们最近进行了一项初步研究，比较了 103名儿童中几种常见的血型多态与SCD严重程度的遗传 Lewis阴性的Le(a-b-)表型与以下疾病的住院率增加2倍相关 SCD相关并发症与Le(a+b-)和Le(a-b+)患者比较。Le(a-b-)表型也 已知与缺血性心脏病(IHD)风险增加2倍有关。目前还没有任何机制 已经确定，但我们假设Lewis RBC表型与SCD之间的关联 严重程度可能是由唾液酸酶A(SLEA)的血浆水平差异所介导的。 这项提议的多中心合作研究的目的是：a)确认 对来自多个中心的更大一组儿童的初步发现；b)确定是否。 Lewis(a-b-)表型也与成年人的疾病严重程度有关；c)为了确定 Lewis表型或血浆Slea水平预测特定类型的并发症(例如中风、ACS)；d) 确定Lewis的行为是否独立于HBF、β-珠蛋白单倍型和阿尔法地中海贫血；e) 寻找其他血型多态(例如，Duffy，MNS)与SCD疾病严重程度之间的任何联系。 刘易斯抗原状态将与其他20种血型抗原一起进行血清学测定。我们会 用聚合酶链式反应-限制性片段长度多态性方法进行Se、Le基因分型，用ELISA法测定血浆SleA。疾病严重程度 将通过标准化报告表格收集数据，并将其输入CSCC共同数据库。它是 预计许多患者的回溯性数据将从数据库中获得。参与 在这个项目中多个中心的合作是至关重要的，因为它需要收集关于 大量的病人。鉴于与Le(a-b-)相关的住院人数在我们的 先导性研究，我们认为这一标记物可以作为SCD严重程度的早期预测指标，并且可能 帮助针对高危SCD患者的积极干预措施(BMT、慢性输血)。