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)是一种知之甚少的自身免疫综合征，其特征是发病率和死亡率显著。系统性红斑狼疮的临床试验在很大程度上是不成功的，需要更好地了解疾病的异质性和潜在的致病因素，以便有效地干预疾病过程。SLE的发病机制是由遗传危险因素和环境影响共同驱动的，这些因素导致了免疫自我耐受性的不可逆转的破坏。最近对系统性红斑狼疮的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的总体影响不大(优势比1.2-1.3)。这些研究使用了标准的病例对照设计，以高成本研究非常大的队列。随着检测优势比为1.2的基因所需的队列规模呈指数级增长，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，因为我们正在达到病例对照设计的可行性极限。许多证据支持这样的观点，即干扰素α(IFNA)途径信号的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途径的SLE危险基因与SLE患者血清IFNA升高有关。这些数据支持IFNA通路中的功能获得变异是SLE发病机制的基础这一观点。与传统的病例对照研究相比，定量蛋白质水平表型的遗传学研究具有更大的统计发现能力。在这个提案中，我们将使用一些新技术，这些技术使用IFNA作为数量性状来极大地增强遗传分析的能力，使现有的SLE队列中能够发现新的基因。我们将验证来自局部病例-病例设计的SLE患者全基因组筛查的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(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以与SLE患者的血清IFNA关联。IFNA通路是人类系统性红斑狼疮(SLE)中最稳定的失调原因通路之一，确定该通路的遗传学异常将为我们提供最好的机会来确定最初疾病发病机制的分子事件。到目前为止，SLE分子发病机制中未被测量的异质性可能限制了介入药物试验的成功。对特定患者存在的功能性遗传因素的详细了解在个体化治疗中可能非常有用，并可能允许制定预防策略。

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.