Genome Wide Association Study of Latent Autoimmune Diabetes in Adults

描述(由申请人提供)：1型和2型糖尿病(T1D和T2D)都是由次优胰岛素作用的代谢后果引起的，具有相似的并发症，但似乎是由于不同的生物机制。这两种疾病的遗传易感性存在重叠，但到目前为止，在这两种疾病中发现的基因都没有被证明与另一种疾病有关。特别是，还没有发现主要的T2D基因TCF7L2在T1D中的作用的证据；然而，TCF7L2与目前的想法有一些不同，TCF7L2与成人潜伏性自身免疫性糖尿病(LADA)密切相关，世界卫生组织认为LADA是T1D的一种缓慢发展的形式。虽然LADA患者的临床表现通常与T2D相似，发病时为成人，确诊时胰岛素独立，但他们的特征是循环中的胰岛自身抗体与T1D中发现的类似。事实上，平均8%-10%的被诊断为T2D的患者实际上是误诊的LADA病例。为了阐明LADA的分类，一种方法是确定与这种特定表型发病相关的离散遗传因素，并利用这两种疾病的公开数据集确定LADA与T1D和T2D在多大程度上具有遗传相似性。这种方法还可能发现T1D和T2D共同的遗传变异。结合招募大量、准确的LADA表型队列(通过靶向策略收集总共10,000例明显的T2D病例，并随后通过高通量GAD65自身抗体分析鉴定LADA)与全基因组SNP基因分型相结合，该项目建议通过对该表型进行基因组全关联(GWA)研究来研究与LADA相关的基因和遗传变异。采用动力研究设计，信号将被识别并随后在另一个队列中复制(所有对照来自费城应用基因组中心儿童医院现有的基因数据库)。这些成功复制的信号随后将在非裔美国人(AA)队列中得到提炼，因为该种族的连锁不平衡(LD)程度较低。在再生障碍性贫血和高加索人中具有相同效果的变异可能代表了更普遍的重要基因和途径，作为一个整体来诊断和预防/治疗糖尿病。

DESCRIPTION (provided by applicant): Type 1 and type 2 diabetes (T1D and T2D) both result from the metabolic consequences of sub-optimal insulin action, with similar complications, but appear to be due to distinct biological mechanisms. An overlap in genetic predisposition to these two diseases has been previously proposed, but none of the genes identified to date in each of these given disorders have been shown to be associated with the other disease. In particular, no evidence has been found for the role of the major T2D gene, TCF7L2, in T1D; however, and somewhat at odds with current thinking, TCF7L2 is strongly associated with latent autoimmune diabetes in the adult (LADA), a disorder considered by the World Health Organization to be a slowly progressing form of T1D. Although LADA patients often present with a clinical picture similar to T2D, with an adult age at onset and insulin independence at diagnosis, they are characterized by circulating islet auto-antibodies similar to those found in T1D. Indeed, on average 8-10% of patients diagnosed with T2D are in fact misdiagnosed LADA cases. One way to shed much needed light on the classification of LADA is to determine the discrete genetic factors conferring risk to the pathogenesis of this specific phenotype and to determine to what extent LADA shares genetic similarities with T1D and T2D, utilizing publically available datasets for these two diseases. Such an approach may also uncover genetic variants that are common to both T1D and T2D. Combining the recruitment of a large, accurately phenotyped LADA cohort (collected through a targeting strategy of a total of 10,000 'apparent' T2D cases, and subsequent LADA identification with high-throughput GAD65 autoantibody assaying) with genome-wide SNP genotyping, this project proposes to study genes and genetic variants that are associated with LADA by conducting a genome wide association (GWA) study of this phenotype. Employing a powered study design, signals will be identified and subsequently replicated in an additional cohort (with all controls being derived from the existing genotype database from the Children's Hospital of Philadelphia's Center for Applied Genomics). Those signals that are successfully replicated will then be refined in an African American (AA) cohort, as the degree of linkage disequilibrium (LD) is lower in this ethnic group. Variants with equal effects in both AA and Caucasians may represent more universally important genes and pathways for diagnosis and prevention/treatment of diabetes as a whole.