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）是一种鲜为人知的自身免疫性综合征，其特点是发病率和死亡率高。SLE的临床试验在很大程度上是不成功的，需要提高对疾病异质性和潜在致病因素的理解，以便有效地干预疾病过程。SLE的发病机制是由遗传风险因素和环境影响共同驱动的，导致免疫自我耐受性的不可逆转的破坏。最近的SLE遗传研究发现了许多新的易感位点，其中大多数对疾病易感性的总体影响不大（优势比1.2-1.3）。这些研究采用了标准的病例对照设计，以高成本研究了非常大的队列。由于检测比值比<1.2的基因所需的队列数量呈指数增长，很容易超过目前可用的SLE样本数量，因此需要新的方法。揭示人类SLE遗传学的下一个主要挑战在于基因发现的新方法，因为我们正在达到病例对照设计可行性的极限。许多证据支持干扰素α (IFNa)信号通路增加是人类狼疮的原因。血清IFNa升高是SLE的遗传危险因素，一些已建立的IFNa通路SLE危险基因与SLE患者血清IFNa升高相关。这些数据支持IFNa通路中的功能获得变异是SLE发病机制的基础。与传统的病例对照研究相比，定量蛋白水平表型的遗传研究具有更大的统计学发现能力。在本提案中，我们将使用一些新技术，将IFNa作为数量性状，大大提高遗传分析的能力，从而在现有的SLE队列中发现新的基因。我们将从SLE患者的局部病例-病例设计全基因组筛选中验证IFNa相关的候选基因，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候选SNP与SLE患者血清IFNa的关联。IFNa通路是人类SLE中最一致失调的因果通路之一，确定该通路失调的遗传学将为我们提供确定初始疾病发病机制的分子事件的最佳机会之一。迄今为止，SLE分子发病机制中未测量的异质性可能限制了介入药物试验的成功。对某一特定患者的功能遗传因素的详细了解可能对个体化治疗有很大的帮助，并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.