Interferon Alpha as a Tool for Gene Discovery in Human Lupus

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种人们知之甚少的自身免疫综合征，其特征是发病率和死亡率显着。 SLE 的临床试验基本上不成功，需要提高对疾病异质性和潜在致病因素的了解，才能有效干预疾病过程。 SLE 的发病机制是由遗传风险因素和环境影响共同驱动的，导致免疫自我耐受的不可逆转的破坏。最近的 SLE 遗传学研究已经发现了许多新的易感性位点，其中大多数对疾病易感性具有适度的总体影响（比值比 1.2-1.3）。这些研究采用了标准的病例对照设计，以高成本研究非常大的队列。需要新的方法，因为检测比值比 <1.2 的基因所需的队列规模呈指数增长，很容易超过当前可用的 SLE 样本数量。解开人类系统性红斑狼疮遗传学的下一个主要挑战在于基因发现的新方法，因为我们已经达到了病例对照设计的可行性极限。许多证据支持这样的观点：干扰素 α (IFNa) 通路信号传导的增加与人类狼疮有关。高血清 IFNa 是 SLE 的遗传危险因素，一些已确定的 IFNa 途径 SLE 风险基因与 SLE 患者血清 IFNa 升高相关。这些数据支持这样的观点，即 IFNa 通路中的功能获得变异是 SLE 发病机制的基础。定量蛋白质水平表型的遗传学研究的特点是比传统的病例对照研究具有更大的发现统计能力。在本提案中，我们将使用许多采用 IFNa 作为数量性状的新技术，以大大提高遗传分析的能力，从而在现有 SLE 队列中发现新的基因。我们将通过本地病例设计对 SLE 患者进行全基因组筛查来验证 IFNa 相关候选基因，重新分析现有的 SLE 全基因组单核苷酸多态性 (SNP) 数据以检测与血清 IFNa 的关联，并使用基因表达数据库选择和测试与 SLE 患者血清 IFNa 关联的候选 SNP。 IFNα途径是人类SLE中最一致失调的因果途径之一，定义该途径失调的遗传学将为我们提供定义初始疾病发病机制背后的分子事件的最佳机会之一。 SLE 分子发病机制中未测量的异质性可能限制了迄今为止介入药物试验的成功。对特定患者中存在的功能性遗传因素的详细了解对于个体化治疗非常有用，并且可能有助于制定预防策略。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a poorly understood autoimmune syndrome characterized by significant morbidity and mortality. Clinical trials in SLE have largely been unsuccessful, and improved understanding of disease heterogeneity and underlying pathogenic factors will be required for efficient intervention in the disease process. The pathogenesis of SLE is driven by a combination of genetic risk factors and environmental influences which lead to an irreversible break in immunologic self-tolerance. Recent genetic studies in SLE have identified numerous novel susceptibility loci, most of which have a modest overall effect on disease susceptibility (odds ratios 1.2-1.3). These studies have used a standard case-control design, studying very large cohorts at high cost. New approaches are needed, as the cohort size required to detect genes with odds ratios <1.2 increases exponentially, easily exceeding the current number of SLE samples available. The next major challenge in unraveling human SLE genetics lies in novel methods for gene discovery, as we are reaching the limit of feasibility with case-control designs. Many lines of evidence support the idea that increased interferon alpha (IFNa) pathway signaling is causal in human lupus. High serum IFNa is a heritable risk factor for SLE, and some established IFNa pathway SLE-risk genes are associated with higher serum IFNa in SLE patients. These data support the idea that gain-of-function variants in the IFNa pathway underlie SLE pathogenesis. Genetic studies of quantitative protein-level phenotypes are characterized by much greater statistical power for discovery than traditional case-control studies. In this proposal, we will use a number of novel techniques which employ IFNa as a quantitative trait to greatly increase the power of genetic analyses, enabling novel gene discovery in existing SLE cohorts. We will validate IFNa-associated candidate genes from a local case-case design genome- wide screen of SLE patients, re-analyze available SLE genome-wide single nucleotide polymorphism (SNP) data to detect associations with serum IFNa, and use gene expression databases to select and test candidate SNPs for association with serum IFNa in SLE patients. The IFNa pathway is one of the most consistently dysregulated causal pathways in human SLE, and defining the genetics of this pathway dysregulation will provide one of our best chances to define the molecular events underlying initial disease pathogenesis. Unmeasured heterogeneity in the molecular pathogenesis in SLE has likely limited the success of interventional drug trials to date. Detailed knowledge of the functional genetic factors present in a given patient could be of great utility in individualizing therapy, and may allow for the development of preventive strategies.