INFLUENCE OF SEX AND HLA ON RHEUMATOID ARTHRITIS

这项申请是为了支持中期职业研究者奖，允许继续以患者为导向的调查类风湿关节炎（RA）的遗传基础。 近期目标是研究性别和HLA在RA遗传中的相互作用，而长期目标是详细描述RA疾病机制，以便有效预防或治疗。该奖项将提供职业发展支持，以保护这项以患者为导向的临床研究的时间，开发新的研究技能，并指导初级研究人员。 申请人将继续研究性别对类风湿性关节炎中HLA多态性的影响。 目前的研究表明，RA与HLA区域的几个疾病易感性位点独立相关，不仅是DRB 1变异，而且与肿瘤坏死因子（TNF α）变异也独立相关。 未来的研究将通过识别具有共同HLA基因型的无关人员，然后检查外周血细胞中诱导型TNF产生和MHC II类密度来确定TNF变体的功能相关性。 这些结果将被用于建立多变量模型，以确定这些是否解释了HLA等位基因频率的性别差异。 第二个正在进行的项目，与凯斯西储大学的研究人员合作，是确定适合遗传研究的RA家族。 第三个项目是针对这一应用提出的。 将对RA家族进行研究，以确定是否存在RA相关HLA单倍型的分离畸变，即儿童（受影响或未受影响）是否比预期更可能从具有HLA单倍型的母亲或具有HLA单倍型的父亲遗传RA相关HLA单倍型。这种亲本效应可能代表基因组印记。Moxley博士已经展示了指导的成功，指导初级研究人员通过设计，性能，解决问题，分析和出版。 弗吉尼亚联邦大学拥有丰富的患者群体和强大的项目，以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.