Innate immune gene SNPS in African-Americans with RA

描述（由申请人提供）：类风湿性关节炎（RA）是一种病因不明的慢性炎症性糜烂性多关节炎。RA的易感性是作为一种复杂的性状遗传的。虽然特定的HLA-DRB 1等位基因在RA患者中的频率随种族和民族而变化，但这种遗传相关性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-DRB 1与RA风险的相关性与获得性免疫在RA易感性中的作用一致。先天性免疫反应的分子机制也被假设参与RA的发病机制。云母和Fc γ RIIIA（Fc γ RIIIA; CD 16）等位基因与RA易感性的相关性为参与先天免疫功能的两种不同途径提供了证据。先天免疫的其他激活和信号传导途径中的分子相互作用，包括LBP、CD 14、MD 2、MYD 88、IKBL和微生物病原体的模式识别受体（PRR），如Toll样受体4（TLR-4），以及受TH 1增强子白细胞介素18（IL-18）影响的受体，也可能调节RA风险。 我们对云母和Fc γ RIIIA多态性、RA易感性的已知决定因素，以及参与微生物信号通路的分子或IL-18是否调节非裔美国人的RA风险的认识存在差距。我们假设：编码共享表位的HLA-DRB 1等位基因与IL-18的遗传决定簇和参与先天免疫功能途径的分子（云母、Fc（RIIIA、LBP、CD 14、TLR 4、MD 2、MYD 88、IKBL）相互作用，以调节非裔美国人的RA风险。 来自波士顿和亚特兰大患有RA的非洲裔美国人，来自波士顿的健康非洲裔美国人对照和非洲裔美国人国家储存库的良好表征的样本的DNA将用于高通量分子技术，用于确定微卫星，并构建单核苷酸多态性（SNP）单倍型和多位点基因型来验证这一假设。 我们的具体目标是确定多位点基因型，最好的预测易感性RA在非洲裔美国人。

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.