INFLUENCE OF SEX AND HLA ON RHEUMATOID ARTHRITIS

此应用程序是为了支持职业生涯中期研究员奖，该奖项允许继续以患者为导向对类风湿性关节炎(RA)的遗传基础进行调查。近期目标是检验性和人类白细胞抗原如何在类风湿性关节炎遗传中相互作用，而长期目标是详细描述类风湿性关节炎的发病机制，以便有效地预防或治疗。该奖项将提供职业发展支持，以保护以患者为导向的临床研究的时间，发展新的研究技能，并对初级调查人员进行指导。申请者将继续研究风湿性关节炎中性别对人类白细胞抗原外显性的影响。目前的研究表明，RA不仅与DRB1变异体有关，而且与肿瘤坏死因子(TNFpha)变异体独立关联，与人类白细胞抗原区域的几个疾病易感基因座独立相关。未来的研究将确定肿瘤坏死因子变异的功能相关性，方法是确定具有共同人类白细胞抗原基因型别的无关人群，然后检测外周血细胞中可诱导的肿瘤坏死因子产生和MHC II类密度。这些结果将被用来开发多变量模型，以确定这些模型是否解释了人类白细胞抗原外显性的性别差异。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，确定适合进行基因研究的类风湿性关节炎家族。针对这一应用提出了第三个项目。RA家庭将被研究以确定是否存在RA相关的HLA单倍型的分离扭曲，即儿童(无论是否受到影响)是否比预期更有可能从具有HL A单倍型的母亲或父亲那里遗传与RA相关的HL A单倍型。这种原产地效应可能代表了基因组印记。莫克斯利博士已经证明了指导的成功，通过设计、执行、解决问题、分析和发表指导初级调查人员。弗吉尼亚联邦大学拥有丰富的患者群体和强大的项目，以教育研究人员在临床研究和生物统计学。

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.