Genetic studies of susceptibility to diabetes mellitus with emphasis on type 1 diabetes

Abstract

Diabetes mellitus is a common multifactorial disease that needs lifelong treatment of insulin and/or oral treatment to prevent hyperglycaemia. Despite treatment, patients with diabetes, still suffer from severe complications later in life. There are two main types of diabetes: the autoimmune type 1 diabetes mellitus (T1DM) and the metabolic type 2 diabetes mellitus (T2DM). The genetic background of T1DM has been shown in twin studies and two genes, HLA and insulin, have so far been repeatedly implicated to be involved in the disease pathogenesis. In addition several other susceptibility loci for T1DM have been identified in genome scans, however, replication of these loci has been difficult partly due to the lack of independent families but also because of low power.

T2DM mellitus is a genetically heterogeneous group of metabolic disorders sharing glucose intolerance. The precise underlying biochemical defects are unknown and almost certainly include impairments both of insulin secretion and action, as well as limited b‑cell reserve. Genome-wide scans in T2DM have revealed linkage to a number of chromosome regions. One of this implicate a chromosome 2 region, where the calpain-10 gene is located. This gene is also one of the several genes that have been associated with T2DM.

In a genome scan of 408 Scandinavian T1DM families, I confirmed linkage of HLA (IDDM1) (p = 7 x 10-45), INS (IDDM2) (p = 10-6) and the IDDM 15 (p = 1 x 10-6) loci. Suggestive evidence of linkage was shown to chromosome 2p (p = 9 x 10-4), 5p11-q13 (p = 8 x 10-4), and 16p (p = 2 x 10-4). The region on chromosome 2p includes the EIF2AK3 gene, which has been implicated in a rare form of very early onset insulin-dependent diabetes. However, association to T1DM was not observed for markers close to the EIF2AK3 gene in our Scandinavian families. Stratification for HLA and INS in T1DM families, suggested that an extended region on chromosome 16p contain more than one T1DM susceptibility locus. On chromosome 5, stratification according to population of origin resulted in increased evidence of linkage in the Swedish families to LOD = 2.7. This region on chromosome 5p11-q13 has not previously been linked to T1DM. A candidate gene, ISL1, located in the linked chromosome 5p11-q13 region was selected for sequencing and the variations found were analysed.

Two haplotypes formed by SNPs in ISL1 were negatively associated with T1DM in Swedish families (p<0.02). Since the genetic risk to T1DM is likely due to interaction between several susceptibility genes in the same functional pathway, a pathway restricted linkage analysis was performed. This resulted in an increase of the LOD from 2.2 to 5.3 (p <0.001) when linkage analysis allowed interaction between 5q11-q13 and 7q32. Two haplotypes formed from SNPs in the PAX4 gene, a transcription factor in the chromosome 7q32 region, showed association to T1DM using TDT (p <0.05).

In fine-mapping of the chromosome 5 region, the 1-LOD support interval was reduced to 6 cM in the Swedish T1DM families and, in all the Scandinavian families one marker reaches the level of significant linkage of 3.59 (p <2.4 x 10-5). As an initial step to perform a genome-wide scan in T2DM families from Sardinia, chromosome 2 was studied in an attempt to confirm the previously detected NIDDM1 susceptibility locus. We did not detect any evidence of linkage between NIDDM1 and T2DM and could excluded a gene with ls = 1.3 in the NIDDM1 region.

T1DM and T2DM are according to the "Accelerator Hypothesis" thought to be the same disease. The difference between them is thought to be the rate by which the b-cells are destroyed and the factors triggering this destruction. However, no common gene has yet been revealed between T1DM and T2DM. I have identified several loci showing linkage to the T1DM and then focused on trying to identify susceptibility gene(s) in one of these loci. In order to conclude which susceptibility genes are involved in the 5p11-q13 region additional markers will need to be typed and replication of identified association(s) have to be performed in independent T1DM samples.