Characterizing the Takayasu arteritis genetic risk in RPS9/LILRB3

摘要 大动脉炎是大动脉及其主要分支的全身性炎症性疾病。这个 大动脉炎的病因和发病机制目前知之甚少，然而，遗传因素对大动脉炎 已建立的与人类白细胞抗原B*52的遗传关联提示了疾病的发生。我们最近的工作确定了 证实了人类白细胞抗原区域外的多个遗传易感基因对大动脉炎易感。这些 在染色体19q13.4上的白细胞受体复合体(LRC)区域包括一个遗传风险基因。我们 将该区域的遗传信号定位为RPS9/LILRB3，并将该基因座的因果变异(S)标记为 SNP rs11666543影响该区域内多个转录本的表达水平 因果变异位于受调控的遗传因素内。实际上，rs11666543位于 原代单核细胞中的活性增强子区域，并且疾病风险变量与显著相关 降低LILRB3mRNA的表达。LILRB3是一种抑制性免疫调节受体，表达于 抗原提呈细胞，其缺陷与单核/巨噬细胞的激活有关。我们建议 使用创新的最先进的基因组和表观基因组学方法，然后进行功能研究 鉴定和鉴定该基因座上的致病遗传变异，以及它们的致病作用。 疾病易感性。

Abstract Takayasu arteritis is a systemic inflammatory disease of the large arteries and their major branches. The etiology and pathogenesis of Takayasu arteritis are poorly understood, however, a genetic contribution to the disease has been suggested by the established genetic association with HLA-B*52. Our recent work identified and confirmed multiple genetic susceptibility loci for Takayasu arteritis outside of the HLA region. These include a genetic risk locus on the leukocyte receptor complex (LRC) region on chromosome 19q13.4. We localized the genetic signal in this region to RPS9/LILRB3, and the causal variant(s) in this locus is tagged by the SNP rs11666543 which influences the expression levels of multiple transcripts within this region suggesting that the causal variant is located within a regulatory genetic element. Indeed, rs11666543 is located within an active enhancer region in primary monocytes, and the disease risk variant is associated with significant reduction of LILRB3 mRNA expression. LILRB3 is an inhibitory immunoregulatory receptor expressed on antigen presenting cells, and its deficiency has been linked to monocyte/macrophage activation. We propose to use innovative state-of-the-art genomic and epigenomic approaches, followed by functional studies to identify and characterize the causal genetic variants in this locus, and their functional pathogenic effect upon disease susceptibility.