Characterizing the Takayasu arteritis genetic risk in RPS9/LILRB3

摘要 多发性大动脉炎是一种大动脉及其主要分支的全身性炎症性疾病。的 高安动脉炎的病因和发病机制知之甚少，然而，遗传因素对高安动脉炎的发病机制的贡献是有限的。 疾病已被证实与HLA-B*52的遗传关联。我们最近的研究发现 并证实了HLA区域外的多发性大动脉炎的遗传易感性位点。这些 包括染色体19q13.4上白细胞受体复合物（LRC）区域上的遗传风险基因座。我们 将该区域中的遗传信号定位于RPS 9/LILRB 3，并且该基因座中的致病变体通过以下标记： SNP rs 11666543影响该区域内多种转录本的表达水平，这表明 致病变异体位于调节遗传元件内。事实上，RS 11666543位于 在初级单核细胞中的活性增强子区域，并且疾病风险变体与显著的 LILRB 3 mRNA表达的降低。LILRB 3是一种抑制性免疫调节受体，表达于 抗原呈递细胞，其缺陷与单核细胞/巨噬细胞活化有关。我们提出 使用创新的最先进的基因组和表观基因组方法，然后进行功能研究， 鉴定和表征该基因座中的致病性遗传变异，以及它们对 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.