Title: Genetic contribution to type 1 diabetes microvascular complications
Description: Type 1 diabetes (T1D) is an autoimmune disease characterized by destruction of beta cells in the pancreas resulting in insulin deficiency, which leads to hyperglycemia and organ damage. T1D patients experience an increased risk of morbidity and mortality due to long-term complications, specifically retinopathy, nephropathy, and neuropathy. Studies demonstrating familial aggregation support the claim that a genetic contribution may influence the development of complications. This dissertation aims to identify genes/chromosomal regions that predispose T1D patients to, or protect them from, the expression of the chronic microvascular complications: retinopathy, neuropathy and nephropathy. In my first chapter, I introduce the history of type 1 diabetes and microvascular complications and their importance as a public health concern. Data show that the prevalence for T1D is increasing, and thus it is likely that the prevalence for the associated complications will also increase. Further, a large proportion of T1D patients develop at least one microvascular complication within 15 years of T1D diagnosis.

By identifying risk alleles for the microvascular complications of T1D, the findings of this study could allow physicians to determine which patients are at greater/lesser risk for developing complications, help to develop interventions to delay or protect against the development of complications and thus reduce medical expenditure and suffering due to diabetes. In the second chapter, I provide the background for, and review the literature on, the genetics of T1D and microvascular complications. The genetic risk factors for T1D are well-established, but there is conflicting research on the question of whether T1D-predisposing HLA alleles may also be in part responsible for the occurrence of microvascular complications seen in T1D patients. We also investigate whether T1D HLA risk alleles are associated with all forms of microvascular complications or whether there are HLA alleles specifically associated with a given complication. In the work described, I address these questions by examining the relationship of HLA alleles to the risk for any complication and to the risk for some specific complication.

In the third chapter, I perform case-control analysis and evaluate known type 1 diabetes HLA susceptibility alleles and their association with microvascular complications. I used data from the Human Biological Data Interchange (HBDI), which includes 425 Caucasian families (2,506 family members) with cases diagnosed with type 1 diabetes. Using a case-control study design nested on the cohort of the HBDI type 1 diabetes patients and their families, probands with at least one microvascular complication were considered cases, and the probands with T1D without microvascular complications (T1D only) were considered controls. Our findings suggest that the HLA class II DRB1*03:01 allele is a protective factor for complications, specifically for retinopathy, as is the DQA1*05:01-DQB1*02:01 haplotype. The DRB1*04:01 allele showed no evidence of association, except when the carriers of the protective DRB1*03:01 were removed from the analysis. Findings also showed a strong positive association between the HLA class I allele B*39:06 and complications.

In the fourth chapter, using the same sample of HBDI type 1 diabetes families that I used in Chapter 3, I perform linkage analysis and test markers along chromosome 6 for co-segregation with microvascular complications. Using SNP data that were genotyped by the Center for Inherited Disease Research (CIDR), I performed linkage analysis examining 1) the phenotype of T1D itself, 2) the presence of any microvascular complication, 3) retinopathy alone, 4) nephropathy alone, and 5) neuropathy alone. Initially, we confirmed the linkage of the HLA locus to T1D. In subsequent analyses, using all complications as well as retinopathy alone as the phenotypes, we identified two linkage peaks; a linkage peak located at the HLA locus and another novel locus was telomeric to HLA. We did not find evidence for linkage for nephropathy alone or neuropathy alone. Findings from this dissertation show that both HLA and non-HLA regions are involved in the expression of complications with strong evidence of genetic influences specifically for retinopathy.