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.
The pathophysiology of latent autoimmune diabetes in adults (LADA) is considered less understood than its much better characterized counterparts of type 1 and type 2 diabetes (T1D and T2D), where its clinical presentation exhibits some features of each of these two main diseases, earning it a reputation as being Type 1.5 Diabetes. The etiology of LADA remains unknown but a genetic component has been implicated from recent reports of T1D and T2D genes playing a role in its pathogenesis. This project proposes to study genetic variants that are associated with LADA, and perhaps also help shed light on diabetes genetics generally, in large cohorts of LADA patients by conducting a genome-wide association study using a high density tag-SNP platform.
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|Redondo, Maria J; Muniz, Jesse; Rodriguez, Luisa M et al. (2014) Association of TCF7L2 variation with single islet autoantibody expression in children with type 1 diabetes. BMJ Open Diabetes Res Care 2:e000008|