Genetic aspects of type 1 diabetes and its complications

Type 1 diabetes (T1D) is an autoimmune form of diabetes with a high incidence in Finland. The typical onset age of T1D is in childhood, but the disease may also manifest in adults. The late complications of diabetes in the kidneys (diabetic nephropathy) and in the eyes (diabetic retinopathy), however, appear only after living for years with diabetes. High blood glucose levels are a major risk factor for these microvascular complications. Glycated hemoglobin (HbA1c), a measure of long-term hyperglycemia, constantly forms when free glucose attaches to hemoglobin in the red blood cells. Earlier genetic and heritability analyses have shown that all these phenotypes, T1D, HbA1c, and complications of diabetes are affected by the genome. The studies included in this thesis had four specific aims: 1) to examine the relationship between leukocyte telomere length and diabetic nephropathy, 2) to study genetic variability in three histone methyltransferases and the risk of diabetes complications, 3) to find genetic factors associated with HbA1c in type 1 diabetes in a genome-wide association study, and 4) to look for genetic variants and genes associated with age at diagnosis of type 1 diabetes (Study IV). The Finnish Diabetic Nephropathy (FinnDiane) Study was the primary study cohort. Several other diabetes cohorts served as replication cohorts (Studies II and III) or were included together with the FinnDiane in a genome-wide association study meta-analysis as in Study IV. As commonly shown, telomere length shortened with age in our cohort. Most importantly, short telomere length and a higher proportion of short telomeres predicted diabetic nephropathy progression. In the candidate gene study, an exonic SNP in SUV39H2 was associated with diabetic retinopathy. Study III showed that HbA1c is partly an inherited trait in diabetes. A locus on chromosome 13 closest to the gene RXFP2 was associated with HbA1c with genome-wide significance. Additionally, many variants known to be associated with HbA1c in the general population had a similar direction in our diabetes cohort. In Study IV, our top associations for T1D diagnosis age were in known T1D risk loci in the HLA region on chromosome 6 and chromosome 17q12, a known risk locus for childhood-onset asthma as well. However, most of the suggestive associations were at genomic regions not previously implicated in T1D. A transcriptome-wide association study highlighted genes such as IKZF3, GSDMB, ORMDL3, and ZBPB2 in the chr17q12 locus. To conclude, the four studies included in this thesis utilized various genetic study approaches and found significant associations between genetic variants and age of diagnosis of T1D, HbA1c, and diabetes complications. More importantly, the HbA1c values are surprisingly stable over time and are affected by genetic variants. An analysis integrating the information from genetic variants and gene expression suggested genes that have potential age-related effects in the pathogenesis of T1D.