Background Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease characterized by the development of anti-nuclear antibodies. Susceptibility to SLE is multifactorial, with a combination of genetic and environmental risk factors contributing to disease development. Like other polygenic diseases, a significant proportion of estimated SLE heritability is not accounted for by common disease alleles analyzed by SNP array-based GWASs. Death-associated protein 1 (DAP1) was implicated as a candidate gene in a previous familial linkage study of SLE and rheumatoid arthritis, but the association has not been explored further. Results We perform deep sequencing across the DAP1 genomic segment in 2032 SLE patients, and healthy controls, and discover a low-frequency functional haplotype strongly associated with SLE risk in multiple ethnicities. We find multiple cis-eQTLs embedded in a risk haplotype that progressively downregulates DAP1 transcription in immune cells. Decreased DAP1 transcription results in reduced DAP1 protein in peripheral blood mononuclear cells, monocytes, and lymphoblastoid cell lines, leading to enhanced autophagic flux in immune cells expressing the DAP1 risk haplotype. Patients with DAP1 risk allele exhibit significantly higher autoantibody titers and altered expression of the immune system, autophagy, and apoptosis pathway transcripts, indicating that the DAP1 risk allele mediates enhanced autophagy, leading to the survival of autoreactive lymphocytes and increased autoantibody. Conclusions We demonstrate how targeted sequencing captures low-frequency functional risk alleles that are missed by SNP array-based studies. SLE patients with the DAP1 genotype have distinct autoantibody and transcription profiles, supporting the dissection of SLE heterogeneity by genetic analysis.

中文翻译：

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深度测序揭示了增强系统性红斑狼疮自身免疫的 DAP1 调节单倍型


背景系统性红斑狼疮（SLE）是一种临床异质性自身免疫性疾病，其特征是抗核抗体的产生。系统性红斑狼疮的易感性是多因素的，遗传和环境风险因素共同促进疾病的发展。与其他多基因疾病一样，基于 SNP 阵列的 GWAS 分析的常见疾病等位基因无法解释估计的 SLE 遗传力的很大一部分。死亡相关蛋白 1 (DAP1) 在之前的 SLE 和类风湿性关节炎家族连锁研究中被认为是候选基因，但这种关联尚未得到进一步探讨。结果我们对 2032 名 SLE 患者和健康对照的 DAP1 基因组片段进行了深度测序，发现了与多个种族的 SLE 风险密切相关的低频功能单倍型。我们发现多个 cis-eQTL 嵌入风险单倍型中，逐渐下调免疫细胞中的 DAP1 转录。 DAP1 转录减少导致外周血单核细胞、单核细胞和类淋巴母细胞系中的 DAP1 蛋白减少，从而导致表达 DAP1 风险单倍型的免疫细胞的自噬通量增强。具有 DAP1 风险等位基因的患者表现出显着较高的自身抗体滴度以及免疫系统、自噬和凋亡途径转录物表达的改变，表明 DAP1 风险等位基因介导增强的自噬，导致自身反应性淋巴细胞的存活和自身抗体的增加。结论 我们展示了靶向测序如何捕获基于 SNP 阵列的研究遗漏的低频功能风险等位基因。 具有 DAP1 基因型的 SLE 患者具有独特的自身抗体和转录谱，支持通过遗传分析来剖析 SLE 异质性。