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学机制。以前曾提出这两种疾病的遗传易感性存在重叠，但迄今为止，在这两种疾病中发现的基因都没有被证明与另一种疾病相关。特别是，没有证据表明T2D主要基因TCF7L2在T1D中的作用；然而，TCF7L2与成人潜伏性自身免疫性糖尿病（LADA）密切相关，世界卫生组织认为这种疾病是一种进展缓慢的T1D，这与目前的观点有些不同。虽然LADA患者通常表现出与T2D相似的临床表现，发病年龄为成人，诊断时胰岛素独立，但其特点是循环胰岛自身抗体与T1D相似。事实上，平均有8-10%的T2D患者实际上是误诊的LADA病例。阐明LADA分类急需的一种方法是确定赋予这种特定表型发病风险的离散遗传因素，并确定LADA与T1D和T2D在多大程度上具有遗传相似性，利用这两种疾病的公开数据集。这种方法也可能发现T1D和T2D共同的遗传变异。结合招募大量准确表型的LADA队列（通过总共10,000例“明显”T2D病例的靶向策略收集，随后使用高通量GAD65自身抗体检测LADA）和全基因组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。采用动力研究设计，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现有的基因型数据库）。这些成功复制的信号随后将在非裔美国人（AA）队列中进行细化，因为该种族群体的连锁不平衡程度（LD）较低。在AA和白种人中具有相同作用的变异可能代表了更普遍的重要基因和诊断和预防/治疗糖尿病的途径。

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.