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（T1 D和T2 D）均由次优胰岛素作用的代谢后果引起，具有相似的并发症，但似乎是由于不同的生物学机制。先前已经提出了这两种疾病的遗传易感性的重叠，但是迄今为止在这些给定疾病中的每一种中鉴定的基因都没有显示出与另一种疾病相关。特别是，没有证据表明主要的T2 D基因TCF 7 L2在T1 D中的作用;然而，与目前的想法有些不一致，TCF 7 L2与成人隐匿性自身免疫性糖尿病（LADA）密切相关，LADA是世界卫生组织认为是T1 D的缓慢进展形式的一种疾病。 虽然LADA患者通常表现出与T2 D相似的临床表现，发病时为成年人，诊断时不依赖胰岛素，但其特征是循环胰岛自身抗体与T1 D相似。事实上，平均8-10%的诊断为T2 D的患者实际上是误诊的LADA病例。 揭示LADA分类的一种方法是确定赋予这种特定表型发病机制风险的离散遗传因素，并确定LADA与T1 D和T2 D在多大程度上具有遗传相似性，利用这两种疾病的实验室可用数据集。这种方法还可以发现T1 D和T2 D共同的遗传变异。 结合招募一个大的，准确的表型LADA队列（通过总共10，000个“明显的”T2 D病例的靶向策略收集，随后用高通量GAD 65自身抗体测定进行LADA鉴定）与全基因组SNP基因分型，该项目提出通过对该表型进行全基因组关联（GWA）研究来研究与LADA相关的基因和遗传变异。采用有把握的研究设计，将识别信号并随后在另一个队列中复制（所有对照均来自费城儿童医院应用基因组学中心的现有基因型数据库）。这些成功复制的信号将在非裔美国人（AA）队列中进行细化，因为该种族群体的连锁不平衡（LD）程度较低。在AA和高加索人中具有同等作用的变异体可能代表了更普遍的重要基因和途径，用于糖尿病的诊断和预防/治疗。

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.