Innate immune gene SNPS in African-Americans with RA

患有 RA 的非洲裔美国人的先天免疫基因 SNPS

• 批准号: 6704095
• 负责人: PATRICIA Ann FRASER
• 金额: $ 28.35万
• 依托单位: IMMUNE DISEASE INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-15 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6704095
• 关键词: African American; CD16 molecule; clinical research; computer assisted sequence analysis; cytokine; disease /disorder etiology; epidemiology; genetic library; genetic markers; genetic regulatory element; genetic screening; genetic susceptibility; genotype; high throughput technology; histocompatibility gene; human subject; immunogenetics; immunoregulation; phlebotomy; protein protein interaction; regulatory gene; rheumatoid arthritis; single nucleotide polymorphism; statistics /biometry

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a chronic inflammatory erosive polyarthritis of unknown etiology. Predisposition to RA is inherited as a complex trait. Although specific HLA-DRB1 alleles show statistically significant increased frequencies among patients with RA that vary with race and ethnicity, this genetic association does not adequately explain susceptibility to RA in African-Americans. We hypothesize that other genes modulate RA risk in African-Americans. The HLA-DRB1 association with RA risk is consistent with the role of adaptive immunity in predisposition to RA. Molecular mechanisms that govern innate immune responses are also hypothesized to participate in the pathogenesis of RA . MICA and Fc gammaRIllA (FcgammaRIIIA; CD16) allelic associations with RA susceptibility provide evidence for the involvement of two different pathways of innate immune function. Molecular interactions in other activation and signaling pathways of innate immunity, involving LBP, CD14, MD2, MYD88, IKBL and pattern recognition receptors (PRR) for microbial pathogens, such as Toll-like receptor 4 (TLR-4), as well as those affected by the TH1 enhancer interleukin 18 (IL-18), may also modulate RA risk. There are gaps in our knowledge about MICA and FcgammaRIIIA polymorphisms, known determinants of RA susceptibility, or whether molecules involved in microbial signaling pathways or IL-18 modulate the risk of RA in African-Americans. We hypothesize: HLA-DRB1 alleles encoding the shared epitope interact with genetic determinants of IL-18 and molecules involved in pathways of innate immune function (MICA, Fc(RIIIA, LBP, CD14, TLR4, MD2, MYD88, IKBL) to modulate RA risk in African-Americans. DNA from well-characterized samples of African-Americans with RA in Boston and Atlanta, healthy African-American controls from Boston and the African-American national repository will be used in high-throughput molecular techniques for the determination of microsatellites and to construct single nucleotide polymorphism (SNP) haplotypes and multi-locus genotypes to test this hypothesis. Our specific aim is to determine the multi-locus genotype that best predicts predisposition to RA in African-Americans.

描述（由申请人提供）：类风湿关节炎（RA）是一种未知病因的慢性炎性侵蚀性多性关节炎。 RA的易感性被遗传为一个复杂的性状。尽管特定的HLA-DRB1等位基因在RA患者中显示出随着种族和种族而变化的统计学意义，但这种遗传关联并不能充分解释非裔美国人对RA的易感性。我们假设其他基因调节非裔美国人的RA风险。 HLA-DRB1与RA风险的关联与适应性免疫在RA倾向中的作用一致。还假设控制先天免疫反应的分子机制参与RA的发病机理。云母和FC Gammarilla（Fcgammariiia; CD16）与RA敏感性的等位基因关联为参与两种先天免疫功能途径的参与提供了证据。用于微生物病原体的LBP，CD14，MD2，MYD88，IKBL和模式识别受体（PRR）的其他激活和信号传导途径的分子相互作用，例如Toll样受体4（TLR-4），以及受TH1增强器Interleeukin InterLeukin InterLeukin 18（i-il-bir）的影响，例如TOLL样受体4（TLR-4）（TLR-4），也是如此。 我们关于云母和fcmariiia多态性的知识，已知的RA易感性决定因素，或者是否涉及微生物信号通路或IL-18的分子调节非裔美国人RA的风险。我们假设：编码共享表位的HLA-DRB1等位基因与IL-18的遗传决定因素以及参与先天免疫功能途径（MICA，FC（RIIIIA，LBP，CD14，TLR4，TLR4，MD2，MD2，MYD88，IKBL，IKBL））的分子相互作用。 来自波士顿和亚特兰大的非裔美国人的特征良好样本的DNA，来自波士顿的健康非裔美国人对照组和非裔美国人国家存储库将用于高通量分子技术，以确定微卫星的确定，并用于构建单核苷酸多孔（SNP）和跨性别的单核（snp）和跨性别型。 我们的具体目的是确定最能预测非裔美国人RA易感性的多层次基因型。