Genetic Architecture of Rheumatoid Arthritis in African-Americans

描述(由申请人提供)：申请人的职业目标是成为一名独立资助的风湿性疾病遗传学研究人员，特别是类风湿性关节炎(RA)。为了实现这一目标，申请者提出了一项职业发展计划，重点是通过追求临床研究公共卫生理学硕士课程，进行流行病学原理和统计遗传学方法的教学培训。此外，她还将接受生物信息学方面的实践培训。她将精通使用最先进的统计技术，这些技术可以应对大型遗传数据集带来的独特挑战。应聘者组建了一支强大的跨学科指导团队，在风湿学、流行病学和统计遗传学方面拥有成功的指导和学术成就的成功记录。这项以患者为导向的研究职业发展奖的研究部分建议确定与非裔美国人类风湿性关节炎风险和严重性的遗传关联，并使用临床和基因组数据建立类风湿性关节炎风险和结果的预测模型。来自约1000名非裔美国人RA参与者和约1700名非裔美国人对照的数据可从NIH资助的具有RA(CLEAR)登记的非裔美国人纵向评估联盟以及地方和国家合作中获得。基因分型数据将从免疫芯片获得，这是一个由免疫芯片联盟开发的约20万个罕见和常见的单核苷酸多态(SNPs)的定制阵列。该免疫芯片包含从高加索和亚洲人群中发现的最强相关标志物中选择的SNPs，这些标记物通过Gwas策略在自身免疫性疾病中被发现，包括RA、1型糖尿病、狼疮、乳糜泻、自身免疫性甲状腺疾病、炎症性肠道疾病、强直性脊柱炎、牛皮癣和其他疾病。目前正在使用Lou Bridges博士提供的来自UAB的机构资金进行基因分型(见Peter Gregersen博士的信函)，并将在要求的K23申请开始日期之前提供。这项研究的科学目的是：1)确定在欧洲和亚洲人群中验证的自身免疫的遗传标记是否影响非裔美国人患类风湿性关节炎的风险；2)确定类风湿性关节炎易感性的遗传标记是否在非裔美国人的类风湿性关节炎的放射学严重程度中发挥作用；3)利用非裔美国人的临床和遗传数据开发和测试类风湿关节炎风险和预后的预测模型。该项目将极大地提高我们对遗传对类风湿性关节炎风险和结果的影响的理解，并将为Danila博士作为独立研究员的发展提供必要的培训。

DESCRIPTION (provided by applicant): The applicant's career goal is to become an independently funded investigator in the genetics of rheumatic diseases, particularly rheumatoid arthritis (RA). To meet this goal, the applicant proposes a career development plan with emphasis on didactic training in the principles of epidemiology and statistical genetics methods by pursing courses towards a Masters of Science in Public Health in Clinical Research. In addition, she will obtain hands-on training in bioinformatics. She will become well versed in using state-of-the-art statistical techniques that can accommodate the unique challenges posed by large genetic data sets. The candidate has assembled a strong interdisciplinary mentoring team with proven track record of successful mentorship and academic accomplishment in rheumatology, epidemiology and statistical genetics. The research component of this mentored patient-oriented research career development award proposes to identify genetic associations with risk and severity of RA in African Americans and to build predictive models for RA risk and outcome using clinical and genomic data. Data from ~ 1000 African Americans RA participants and ~1700 African American controls is available from the NIH-funded Consortium for the Longitudinal Evaluation of African Americans with RA (CLEAR) Registry and from local and national collaborations. Genotyping data will be available from the ImmunoChip, a custom array of ~200,000 rare and common single nucleotide polymorphisms (SNPs) developed by the ImmunoChip Consortium. The ImmunoChip contains SNPs selected from the most strongly associated makers discovered in Caucasian and Asian populations through GWAS strategy in autoimmune diseases including RA, type 1 diabetes, lupus, celiac disease, autoimmune thyroid disease, inflammatory bowel disease, ankylosing spondylitis, psoriasis and other diseases. Genotyping is currently underway (see letter from Dr. Peter Gregersen) using institutional funds from UAB provided by Dr. Lou Bridges and will be available by the requested start date of this K23 application. The scientific aims of the study are: 1) to determine whether genetic markers of autoimmunity validated in European and Asian populations influence the risk of developing RA in African Americans; 2) to determine whether the genetic markers of susceptibility to RA play a role in radiographic severity of RA in African Americans; 3) to develop and test predictive models for RA risk and outcome using clinical and genetic data in African Americans. This project will greatly improve our understanding of the genetic influences on the RA risk and outcome and will provide essential training for Dr. Danila' development as an independent investigator.