POLYMORPHISMSAND SEVERITYIN SICKLE CELL DISEASE

据信，镰状细胞病（SCD）患者的许多临床变异性可能是 基因决定的，由“上位”基因的共同遗传引起，这些基因与基础基因相互作用， 我们最近进行了一项试点研究， 103例SCD患儿几种常见血型多态性遗传分析 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倍有关。目前还没有任何机制 但是我们假设刘易斯红细胞表型和SCD之间的联系 严重性可能是由唾液酸-路易斯a（sLea）的血浆水平差异介导的，sLea是一种高亲和力的 选择素配体。这项拟议的多中心合作研究的目标是：a）确认 从多个中心抽取的较大儿童组中的初步发现; B）确定.-_ 刘易斯（a-b-）表型也与成人疾病的严重程度有关; 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（例如中风、ACS）; d） 确定刘易斯是否独立于HbF、β-珠蛋白单倍型和α地中海贫血而起作用; e） 寻找其他血型多态性之间的任何联系（例如，Duffy，MNS）和SCD疾病严重程度。 刘易斯抗原状态将与其他20种血型抗原沿着进行血清学测定。我们将 用PCR-RFLP法进行Se和Le基因分型，用ELISA法定量血浆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共同数据库。是 预计将从数据库中获得许多患者的回顾性数据。参与 在该项目中，多个中心的合作是必不可少的，因为它需要收集高质量的临床数据， 大量的病人。考虑到在我们的研究中与Le（a-b-）相关的住院率大幅增加， 初步研究，我们认为该标志物可能是SCD严重程度的早期预测因子， 有助于针对高危SCD患者进行积极干预（BMT，慢性输血）。

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.