Analysis of Trans-Ancestral SLE Risk Loci Identifies Unique Biologic Networks and Drug Targets in African and European Ancestries
Analysis of Trans-Ancestral SLE Risk Loci Identifies Unique Biologic Networks and Drug Targets in African and European Ancestries
复制标题
DOI：
10.1016/j.ajhg.2020.09.007
复制
发表时间：
2020-11-05
影响因子：
9.8
通讯作者：
Lipsky, Peter E.
中科院分区：
文献类型：
--
作者：
Owen, Katherine A.;Price, Andrew;Lipsky, Peter E.
系统性红斑狼疮（SLE）是一种多器官自身免疫性疾病，具有突出的遗传成分。与欧洲血统（EA）人群相比，非洲血统（AA）的个体更严重地经历该病，并且伴随发病率负担增加。我们假设AA和EA人群在疾病患病率、活动性和对标准药物反应方面的差异部分归因于基因组对生物学途径的影响。为了解决这个问题，我们采用了一种综合的方法来鉴定免疫芯片检测到的snp相关风险位点预测的所有基因。通过结合通过eQTL分析预测的基因，以及从基因间增强子位点的碱基对变化、编码区变异和snp基因接近性预测的基因，我们能够确定1731个潜在的SLE祖先特异性和跨祖先遗传驱动因素。使用连接图谱将基因关联与上游和下游调节因子联系起来，并为候选药物靶点挖掘预测的生物学途径。对跨祖先通路的检查反映了干扰素在SLE中的明确作用，并揭示了与组织修复和重塑相关的通路。ea显性遗传驱动因素更多地与先天免疫和髓细胞功能途径相关，而AA显性途径反映了AA受试者的临床发现，表明疾病进展是由异常B细胞活性伴随内质网应激和代谢功能障碍驱动的。最后，确定了潜在的祖先特异性和非特异性候选药物。将所有SLE snp预测基因整合到功能通路中，揭示了代表每个人群的关键分子通路，强调了祖先对疾病机制的影响，也为治疗选择提供了关键见解。
Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disorder with a prominent genetic component. Individuals of African ancestry (AA) experience the disease more severely and with an increased co-morbidity burden compared to European ancestry (EA) populations. We hypothesize that the disparities in disease prevalence, activity, and response to standard medications between AA and EA populations is partially conferred by genomic influences on biological pathways. To address this, we applied a comprehensive approach to identify all genes predicted from SNP-associated risk loci detected with the Immunochip. By combining genes predicted via eQTL analysis, as well as those predicted from base-pair changes in intergenic enhancer sites, coding-region variants, and SNP-gene proximity, we were able to identify 1,731 potential ancestry-specific and trans-ancestry genetic drivers of SLE. Gene associations were linked to upstream and downstream regulators using connectivity mapping, and predicted biological pathways were mined for candidate drug targets. Examination of trans-ancestral pathways reflect the well-defined role for interferons in SLE and revealed pathways associated with tissue repair and remodeling. EA-dominant genetic drivers were more often associated with innate immune and myeloid cell function pathways, whereas AA-dominant pathways mirror clinical findings in AA subjects, suggesting disease progression is driven by aberrant B cell activity accompanied by ER stress and metabolic dysfunction. Finally, potential ancestry-specific and non-specific drug candidates were identified. The integration of all SLE SNP-predicted genes into functional pathways revealed critical molecular pathways representative of each population, underscoring the influence of ancestry on disease mechanism and also providing key insight for therapeutic selection.