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) 患者的大部分临床变异可能是由于 遗传决定的，源于与基本相互作用的“上位”基因的共同遗传 镰状缺陷来改变疾病的病理生理学。我们最近进行了一项初步研究，比较了 对 103 名儿童中几种常见血型多态性与 SCD 严重程度的遗传情况进行了研究，发现 Lewis 阴性 Le(a-b-) 表型与 2 倍高的住院率相关 与 Le(a+b-) 和 Le(a-b+) 患者相比，SCD 相关并发症。 Le(a-b-) 表型也 已知与缺血性心脏病 (IHD) 风险增加 2 倍相关。目前还没有机制 已被确定，但我们假设 Lewis RBC 表型与 SCD 之间的关联 严重程度可能是由血浆唾液酸 I-Lewisa (sLea) 水平的差异介导的，唾液酸 I-Lewisa 是一种高亲和力 选择素配体。这项多中心合作研究的目标是：a) 确认我们的 对来自多个中心的较大儿童群体的初步研究结果； b) 判断是否.-_ Lewis(a-b-) 表型也与成人疾病的严重程度相关； c) 确定是否 Lewis 表型或血浆 sLea 水平可预测特定类型的并发症（例如中风、ACS）； d) 至 确定 Lewis 的作用是否独立于 HbF、β-珠蛋白单倍型和 α 地中海贫血； e) 至 寻找其他血型多态性（例如 Duffy、MNS）与 SCD 疾病严重程度之间的联系。 Lewis 抗原状态将与其他 20 种血型抗原一起通过血清学方法确定。我们将 还通过 PCR-RFLP 进行 Se 和 Le 基因分型，并通过 ELISA 定量血浆 sLea。疾病严重程度 数据将通过标准化报告表格收集并输入 CSCC 通用数据库。这是 预计将从数据库中获得许多患者的回顾性数据。参与情况 该项目中的多个中心至关重要，因为它需要收集高质量的临床数据 大量患者。鉴于我们的地区与 Le(a-b-) 相关的住院人数大幅增加 初步研究中，我们相信该标记物可能有助于作为 SCD 严重程度的早期预测因子，并且可能 帮助针对高危 SCD 患者采取积极干预措施（BMT、慢性输血）。