POLYMORPHISMSAND SEVERITYIN SICKLE CELL DISEASE

镰状细胞病的多态性和严重程度

• 批准号: 7446745
• 负责人: TIMOTHY C FISHER
• 金额: $ 2.9万
• 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/7446745
• 关键词: Adult; Affinity; Antibodies; Antigens; Biological Assay; Blood; Blood Group Antigens; Blood typing procedure; CA-19-9 Antigen; Cancer Patient; Child; Chronic; Clinical; Clinical Data; Collection; Complication; Data; Databases; Disease; Enzyme-Linked Immunosorbent Assay; Epistatic Gene; Event; Frequencies; GYPA gene; Genes; Genetic Polymorphism; Genotype; Globin; Haplotypes; Hematocrit procedure; Hospitalization; Inflammatory Response; Intervention; Ligands; Link; Lipids; Mediating; Mucins; Myocardial Ischemia; Numbers; Odds Ratio; Outcome; Pain; Patients; Phenotype; Pilot Projects; Plasma; Prevalence; Range; Rate; Reporting; Risk; Risk Factors; Selectins; Serologic tests; Severities; Severity of illness; Sickle Cell Anemia; Stroke; Study of serum; Surface; Testing; Transfusion; Tumor Markers; acute chest syndrome; alpha-Thalassemia; beta Globin; blood group; carbohydrate structure; indium arsenide; novel; sickling

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.

据信，镰状细胞病（SCD）患者的临床变异性很大可能是 基因确定的，从与基本相互作用的“同志”基因的共同启示中产生 SicklingDefect修改病理生理学。 在103名儿童中遗传了具有SCD严重程度的几种普通小组多态性的遗传，发现 Lewisnegativate LE（A-B-）表型与住院率高2倍 与LE（A+B-）和LE（A-B+）患者相比，SCD相关的并发症。 LE（A-B-）表型也 已知与缺血性心脏病（IHD）的风险增加2倍。还没有机制 已被确定，但我们假设刘易斯RBC表型与SCD之间的关联 严重程度是由sialyi-lewisa（SLEA）的浆层差异介导的，这是一种高亲和力 Selectin配体。此提议的Multi-CenterCollaBoraBoraBoraTudy的目标是：a）确认 从多个中心汲取的较大儿童中的初步发现； b）确定。-_是否 刘易斯（A-B-）表型也与成年人的疾病严重程度有关。 c）确定是否 刘易斯表型或血浆SLEA水平预测特定类型的并发症类型（例如中风，ACS）； d）到 确定刘易斯是否独立于HBF，β-珠蛋白单倍型和阿尔法thalassysymia行为； e）到 寻找其他血型多态性（例如Duffy，MNS）和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种血液组抗原一起在血清学上确定。我们将 还通过PCR-RFLP执行SE和LE基因分型，并通过ELISA量化血浆SLEA。疾病的严重程度 数据将通过标准化报告表格收集，并输入CSCC公共数据库。这是 预计将为许多患者提供回顾性数据。参与 该项目中的多个中心是必不可少的，因为它需要收集高质量的临床数据 大量患者。鉴于我们与LE（A-B-）相关的住院时间大幅增加 试点研究，我们认为该标记物可能是SCD严重程度的早期预测指标，并且可以 帮助针对高风险SCD患者的侵略性干预措施（BMT，慢性输血）。