Identification of Shared and Asian-Specific Loci for Systemic Lupus Erythematosus and Evidence for Roles of Type III Interferon Signaling and Lysosomal Function in the Disease: A Multi-Ancestral Genome-Wide Association Study
Identification of Shared and Asian-Specific Loci for Systemic Lupus Erythematosus and Evidence for Roles of Type III Interferon Signaling and Lysosomal Function in the Disease: A Multi-Ancestral Genome-Wide Association Study
复制标题
多祖先 GWAS 确定了 SLE 的共享和亚洲特异性位点，并将 III 型干扰素信号传导和溶酶体功能与该疾病联系起来
DOI：
10.1002/art.42021
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发表时间：
2022-03-29
影响因子：
13.3
通讯作者：
Yang, Wanling
中科院分区：
文献类型：
--
作者：
Wang, Yong-Fei;Wei, Wei;Yang, Wanling
目的系统性红斑狼疮（SLE）是一种典型的自身免疫性疾病，其患病率和严重程度在不同的祖先群体中存在差异。这项研究旨在确定亚洲和欧洲人群之间共享或不同的新遗传成分。方法对SLE全基因组关联研究（GWAS）进行跨祖先和祖先特异性荟萃分析，涉及30，604名欧洲、中国或泰国血统的参与者。使用公开的表观基因组数据和表达数量性状基因座，进行精细作图分析以鉴定新鉴定的基因座的推定的致病变体和基因。通过比较不同的训练数据，对泰国队列的多基因风险评分的性能进行了评估。结果IFNLR 1基因上游1bp缺失与SLE的发生相关，IFNLR 1基因表达增高与SLE的危险等位基因相关。该基因编码干扰素-λ（IFN λ）受体1，提供了SLE中III型IFN信号作用的证据。发现SLC 29 A3的内含子变异仅与亚洲人的SLE相关。推测的风险变异可能以单核细胞特异性方式调节SLC 29 A3表达。SLC 29 A3编码溶酶体核苷转运蛋白，随后的分析表明，溶酶体功能和吞噬作用的降低可能是这种关联的机制。TAOK 3、CHD 9、CAMK 1D、ATXN 1和TARBP 1中或附近的亚洲人共享位点以及靠近PEX 2、FCHSD 2和TMEM 116的亚洲人特异性位点也达到了全基因组范围内与SLE显著相关。此外，跨祖先荟萃分析被证明是有价值的风险预测个人没有祖先匹配的数据。结论在本研究中，SLE的共同和亚洲特有的位点被确定，和功能注释提供了证据，参与增加的III型IFN信号和降低的溶酶体功能在SLE。
Objective Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease with differences in prevalence and severity among ancestral groups. This study was undertaken to identify novel genetic components, either shared by or distinct between Asian and European populations. Methods Both trans-ancestral and ancestry-specific meta-analyses of genome-wide association studies (GWAS) for SLE were performed, involving 30,604 participants of European, Chinese, or Thai origin. Using public epigenomic data and expression quantitative trait loci, fine-mapping analyses were conducted to identify putative causal variants and genes for the newly identified loci. Performance of polygenic risk scores for the Thai cohort was evaluated by comparing different training data. Results A 1-bp deletion upstream of IFNLR1 was found to be associated with SLE, with the risk allele correlated with increased expression of IFNLR1. This gene encodes interferon-lambda (IFN lambda) receptor 1, providing evidence of a role of type III IFN signaling in SLE. An intronic variant in SLC29A3 was found to be associated with SLE in Asians only. The putative risk variant may modulate SLC29A3 expression in a monocyte-specific manner. SLC29A3 encodes a lysosomal nucleoside transporter, and subsequent analyses suggested that reduced lysosomal function and phagocytosis might be the mechanism underlying this association. Ancestry-shared loci in or near TAOK3, CHD9, CAMK1D, ATXN1, and TARBP1 and Asian-specific loci close to PEX2, FCHSD2, and TMEM116 also reached the genome-wide significant association with SLE. In addition, trans-ancestral meta-analysis was shown to be valuable in risk prediction for individuals without ancestry-matched data. Conclusion In this study both shared and Asian-specific loci for SLE were identified, and functional annotation provided evidence of the involvement of increased type III IFN signaling and reduced lysosomal function in SLE.