INFLUENCE OF SEX AND HLA ON RHEUMATOID ARTHRITIS

本申请是为了支持一个职业中期研究者奖，允许继续以患者为导向的研究类风湿关节炎（RA）的遗传基础。近期目标是研究性别和HLA在类风湿关节炎遗传中的相互作用，而长期目标是详细描述类风湿关节炎的发病机制，从而使有效的预防或治疗成为可能。该奖项将提供职业发展支持，以保护这种以患者为导向的临床研究的时间，开发新的研究技能，并对初级研究人员进行指导。申请人将继续研究性别对类风湿关节炎患者HLA外显率的影响。目前的研究表明，RA与HLA区域的几个疾病易感位点独立相关，不仅与DRB1变异相关，还与肿瘤坏死因子（TNFalpha）变异独立相关。未来的研究将通过鉴定具有共同HLA基因型的不相关人群，然后检查外周血细胞中诱导的TNF生成和MHC II类密度，来确定TNF变异的功能相关性。这些结果将用于开发多变量模型，以确定这些模型是否解释了HLA外显率的性别差异。第二个正在进行的项目是与凯斯西储大学的研究人员合作，确定适合进行遗传研究的类风湿性关节炎家族。为此应用程序提出了第三个项目。将对RA家族进行研究，以确定RA相关HLA单倍型是否存在分离扭曲，也就是说，儿童（无论是否受影响）是否比预期更有可能从具有HLA单倍型的母亲或具有HLA单倍型的父亲那里继承RA相关HLA单倍型。这种亲本效应可能代表了基因组印记。Moxley博士已经证明了指导的成功，通过设计，性能，解决问题，分析和发表指导初级研究人员。弗吉尼亚联邦大学有丰富的患者群体和强大的项目来教育临床研究和生物统计学的研究人员。

This application is to support a Midcareer Investigator Award allowing continued patient-oriented investigation into the genetic basis of rheumatoid arthritis (RA). The immediate goal is to examine how sex and HLA interact in RA heredity, while the long-term goal is to describe RA disease mechanisms in such detail that effective prevention or therapy will be possible. This award will provide career development support to protect time for this patient-oriented clinical research, develop new research skills, and do mentoring of junior investigators. The applicant will continue studies of sex influence on HLA penetrance in rheumatoid arthritis. The current studies have shown that RA is independently associated with several disease susceptibility loci in the HLA region, not just DRB1 variants but also independently with tumor necrosis factor (TNFalpha) variants. The future studies will define the functional correlates of TNF variants by identifying unrelated persons with common HLA genotypes and then examining inducible TNF production and MHC class II density in peripheral blood cells. Such results will be used to develop multivariate models to determine whether these explain sex differences in HLA penetrance. A second ongoing project, in cooperation with investigators at Case Western Reserve University, is to identify RA families suitable for genetic studies. A third project is proposed for this application. RA families will be studied to determine whether there is segregation distortion of RA-associated HLA haplotypes, that is, whether a child (either affected or not) is more likely than expected to inherit a RA-associated HLA haplotype from a mother with the HLA haplotype or a father with the HLA haplotype. Such parent-of-origin effects might represent genomic imprinting. Dr. Moxley has already demonstrated mentoring success, guiding junior investigators through design, performance, problem- solving, analysis, and publication. Virginia Commonwealth University has a rich patient population and strong programs to educate investigators in clinical research and biostatistics.