Sickle Cell Trait: An overlooked genetic modifier of disease in African-Americans

 描述（由申请人提供）：镰状细胞性状（SCT）影响超过1/12的非裔美国人在美国和全球近3亿人。虽然SCT在很大程度上被认为是一种良性疾病，但新出现的证据表明，在低氧张力或压力的情况下，急性和慢性镰状化可能导致受影响的携带者出现临床并发症。特别是，肾髓质的缺氧环境似乎诱导局部红细胞镰状化，最终导致血管损伤和慢性肾病（CKD）。类似的过程也可能发生在身体的缺氧静脉系统中，导致凝血激活和静脉血栓栓塞（VTE）的风险增加。与其他人群相比，非裔美国人的CKD和VTE风险似乎更高;因此SCT可能是该人群中重要且未被识别的疾病遗传修饰因子。Naik博士是约翰霍普金斯大学血液学系的助理教授，他的长期愿望是成为镰状细胞性状的独立研究者，目标是为受影响的个体制定循证筛查，遗传咨询和治疗指南。她的建议的总体目标是阐明潜在的并发症 并确定SCT对非裔美国人CKD和VTE风险的影响。她将首先对已发表的文献进行严格的系统综述，以确定与SCT相关的重要临床并发症，确定现有文献的优势，并确定当前知识的差距。使用先进的流行病学技术，她将分析来自具有大量非洲裔美国人参与者的特征良好的队列的数据，以描述SCT患者中CKD和VTE的风险。这项研究将有助于关键知识的并发症SCT，并将提供框架，为未来的流行病学，转化和治疗研究SCT。此外，在K 08导师职业发展奖的支持下，Naik博士将整合一个全面的多学科导师团队，一个有针对性的培训计划和一个创新的研究策略，以确保她成功过渡到一名独立的研究者。

 DESCRIPTION (provided by applicant): Sickle cell trait (SCT) affects over 1 in 12 African Americans in the United States and nearly 300 million people worldwide. Although SCT has largely been considered a benign condition, emerging evidence suggests that acute and chronic sickling in the setting of low oxygen tension or stress may lead to clinical complications in affected carriers. In particular, the hypoxic environment of the renal medulla appears to induce local red blood cell sickling, ultimately resulting in vascular damage and chronic kidney disease (CKD). A similar process may also occur in the hypoxic venous system of the body, leading to coagulation activation and an increased risk of venous thromboembolism (VTE). The risk of both CKD and VTE appears to be higher in African Americans compared to other populations; therefore SCT may be an important and unrecognized genetic modifier of disease in this population. Dr. Naik is an Assistant Professor in the Division of Hematology at Johns Hopkins whose long-term aspiration is to become an independent investigator in sickle cell trait with the goal of developing evidence-based screening, genetic counseling, and treatment guidelines for affected individuals. The overall aims of her proposal are to elucidate the potential complications of SCT and to determine the impact of SCT on CKD and VTE risk in African Americans. She will first perform a rigorous systematic review of the published literature to identify important clinicl complications related to SCT, determine the strength of the existing literature, and identify gaps in current knowledge. Using advanced epidemiologic techniques, she will then analyze data from well-characterized cohorts with large numbers of African-American participants to characterize the risk of CKD and VTE in individuals with SCT. This research will contribute critical knowledge about the complications of SCT and will provide framework for future epidemiologic, translational, and treatment studies in SCT. In addition, with the support of this K08 Mentored Career Development Award, Dr. Naik will integrate a well-rounded, multi-disciplinary mentorship team, a focused training plan, and an innovative research strategy to ensure her successful transition to an independent investigator.