INFLUENCE OF SEX AND HLA ON RHEUMATOID ARTHRITIS

性别和 HLA 对类风湿性关节炎的影响

• 批准号: 6374336
• 负责人: GEORGE F MOXLEY
• 金额: $ 9.58万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-27 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6374336
• 关键词: MHC class II antigen; antigen presentation; clinical research; cytokine; enzyme linked immunosorbent assay; family genetics; flow cytometry; gender difference; gene expression; genetic markers; genetic models; genetic screening; genetic susceptibility; genotype; histocompatibility antigens; human genetic material tag; human subject; linkage disequilibriums; major histocompatibility complex; questionnaires; rheumatoid arthritis

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.

该申请旨在支持职业中期研究者奖，允许继续以患者为导向的类风湿性关节炎 (RA) 遗传基础研究。 近期目标是研究性别和 HLA 在 RA 遗传中如何相互作用，而长期目标是详细描述 RA 疾病机制，以便有效预防或治疗成为可能。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，培养新的研究技能，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性关节炎 HLA 外显率的影响。 目前的研究表明，RA与HLA区域的多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（TNFα）变异独立相关。 未来的研究将通过识别具有常见 HLA 基因型的无关人员，然后检查外周血细胞中可诱导的 TNF 产生和 MHC II 类密度来定义 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可以解释 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，以确定适合遗传研究的 RA 家族。 为此应用提出了第三个项目。 将研究 RA 家族，以确定 RA 相关 HLA 单倍型是否存在分离扭曲，即儿童（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 单倍型的父亲遗传 RA 相关 HLA 单倍型。这种亲本效应可能代表基因组印记。莫克斯利博士已经展示了指导初级研究人员的成功，指导初级研究人员完成设计、执行、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临床研究和生物统计学研究人员教育项目。