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）是一种尚不清楚的自身免疫综合征，其特征是显著的发病率和死亡率。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的组合驱动的，这些因素导致免疫自身耐受的不可逆破坏。最近的SLE遗传学研究已经确定了许多新的易感基因座，其中大多数对疾病易感性有适度的总体影响（比值比1.2-1.3）。这些研究采用了标准的病例对照设计，以高成本研究了非常大的队列。需要新的方法，因为检测优势比<1.2的基因所需的队列规模呈指数级增加，很容易超过目前可用的SLE样本数量。解开人类SLE遗传学的下一个主要挑战在于发现基因的新方法，因为我们已经达到病例对照设计的可行性极限。许多证据支持这一观点，即干扰素α（IFNa）途径信号传导增加是人类狼疮的原因。高血清IFNa是SLE的一个可遗传的危险因素，并且一些已确定的IFNa通路SLE危险基因与SLE患者的高血清IFNa相关。这些数据支持IFNa通路中的功能获得性变体是SLE发病机制的基础的观点。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。在这项提议中，我们将使用许多新技术，这些技术采用IFNa作为定量性状，以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相关候选基因，重新分析可用的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来选择和测试候选SNP与SLE患者中的血清IFNa的关联。IFNa通路是人类SLE中最一致的失调因果通路之一，并且定义该通路失调的遗传学将为我们定义初始疾病发病机制下的分子事件提供最佳机会之一。迄今为止，SLE分子发病机制中不可测量的异质性可能限制了干预性药物试验的成功。详细了解功能性遗传因素存在于一个给定的病人可能是非常有用的个性化治疗，并可能允许预防策略的发展。

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.