Genetic analysis of type 1 diabetes

Abstract

Type 1 diabetes is one of the most common chronic diseases among children and young adults in Sweden today. Type 1 diabetes is classified as an autoimmune disease caused by a destruction of the beta-cells in the endocrine pancreas. The disease is thought to be caused by interaction between genetic and environmental factors. The HLA region on chromosome 6 accounts for about 40-50% of the genetic risk to develop type 1 diabetes but other genes also contribute to the risk.

In paper I I have, through a questionnaire sent to almost 4000 individuals been able to show that women developing type 1 diabetes between 15-34 years of age have more first degree relatives with the disease than men developing type 1 diabetes in the same age group. This suggests that more genetic risk factors are needed when a woman, compared to when a man develops type 1 diabetes. This finding is consistent with the fact that in this age group 60% of the persons developing type 1 diabetes are men and only 40% are women.

In paper II we performed a genome-wide linkage analysis of families with two or more siblings with type 1 diabetes from Scandinavia, France and USA. We scanned for regions where risk genes for type 1 diabetes are located. Apart from verifying the HLA and Insulin regions, we could confirm a locus on chromosome 6q21. Suggestive linkage was also seen on chromosome 2p, 5q, and 16p.

There is an increased risk for a child to develop type 1 diabetes if the father rather than the mother has the disease. We have tried to find explanations for this.

In paper III we examined whether the HLA type that the child does not inherit from the mother affects the risk for the child to develop type 1 diabetes. In children that have inherited one high risk HLA type and one neutral HLA type, it seems to be protective if the HLA haplotype not inherited from the mother is a high risk haplotype. The mechanism for this could be the shaping of the immune repertoire during fetal life and we speculate that the child might be partly protected against the disease later in life when he/she is predisposed to the mother’s high risk HLA haplotype intrauterine.

In paper IV, the hypothesis that the difference in risk to develop type 1 diabetes between children to mothers and fathers with type 1 diabetes is due to imprinting mechanisms is tested. The hypothesis is that the genes are expressed in a parent of origin specific manner and that there is an increased risk to develop disease if the risk gene is inherited from one of the parents. We show in this study that the risk to develop type 1 diabetes seems to be influenced by imprinting mechanisms in two regions. One is located on chromosome 6q (IDDM15) and here we see an increased risk for the child to develop type 1 diabetes if the risk allele is inherited from the father. This is consistent with the finding that there is a greater risk for children to develop type 1 diabetes if the father rather than the mother has the disease. The other region is on chromosome 13q12 and this region shows a maternal effect. The maternal effect might also be explained by the fact that a woman need more risk genes to develop type 1 diabetes. This increases the risk for the child to inherit a risk gene from the mother than from the father.

In summary, the overall aim of this thesis was to identify genetic factors that influence the risk to develop type 1 diabetes. By identifying genetic risk factors these studies hopefully will contribute to the understanding of the genesis of type 1 diabetes.