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风湿性疾病，特别是类风湿性关节炎（RA）遗传学领域的独立资助研究者。为了实现这一目标，申请人提出了一项职业发展计划，重点是通过攻读临床研究公共卫生理学硕士学位课程，进行流行病学和统计遗传学原理的教学培训。此外，她还将获得生物信息学的实践培训。她将精通使用最先进的统计技术，以应对大型遗传数据集带来的独特挑战。该候选人组建了一支强大的跨学科指导团队，在风湿病学、流行病学和统计遗传学方面拥有成功的指导记录和学术成就。这项以患者为导向的研究职业发展奖的研究部分旨在确定非裔美国人与 RA 风险和严重程度的遗传关联，并利用临床和基因组数据建立 RA 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 资助的非裔美国人 RA 纵向评估联盟 (CLEAR) 登记处以及地方和国家合作机构获得。基因分型数据可从免疫芯片中获得，免疫芯片是由免疫芯片联盟开发的约 200,000 个罕见和常见单核苷酸多态性 (SNP) 的定制阵列。该免疫芯片含有从白种人和亚洲人群中通过 GWAS 策略在自身免疫性疾病中发现的最密切相关的标记物中选出的 SNP，这些疾病包括 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 UAB 机构资金进行基因分型（参见 Peter Gregersen 博士的信函），并将在本 K23 申请要求的开始日期之前提供。该研究的科学目的是：1）确定在欧洲和亚洲人群中验证的自身免疫遗传标记是否会影响非裔美国人患 RA 的风险； 2) 确定RA易感性的遗传标记是否在非裔美国人RA的影像学严重程度中发挥作用； 3) 使用非裔美国人的临床和遗传数据开发和测试 RA 风险和结果的预测模型。该项目将极大地提高我们对遗传对 RA 风险和结果影响的理解，并将为 Danila 博士作为独立研究者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.