Genetic analysis of type 1 diabetes susceptibilty

Sammanfattning: Type 1 diabetes (T1D) is a multifactorial disease where the pancreatic beta-cells are destroyed in an autoimmune attack. For the patients, this in turn leads to lifelong daily insulin treatment and increased risk for various kinds of complications. It is thought that both environmental as well as genetic factors act in concert to cause T1D. The HLA region located on chromosome 6 accounts for about 50% of the genetic risk to develop T1D. However, several other genes are also known to contribute to disease risk. Paper I. The programmed cell death 1 (PDCD1) gene (chr 2q37) has previously been seen to be associated to various autoimmune diseases. The PDCD1 gene is believed to be involved in maintaining self tolerance by inhibiting T-cell activation, cellular proliferation and cytokine production. We wanted to test the hypothesis that the PDCD1 gene also was a T1D susceptibility gene. However, no association or linkage was found between T1D and the PDCD1 gene when two separate Swedish cohorts were analyzed. Nor did we observe any association in a meta analysis with a previous study reporting association between PDCD1 and T1D. Paper II. We have previously performed a genome wide linkage study on Scandinavian T1D families where we have detected suggestive linkage on the chromosome 5p13-q13 region. This region showed stronger evidence of linkage, when only the Swedish families were investigated. By typing more than 70 markers in this region in the Swedish families, we identified two associated candidate genes: Ringfinger protein 180 (RNF180) and 5-hydroxytryptamine (serotonin) receptor 1A (HTR1A). We have confirmed the association of these genes in Danish families. These genes are in strong linkage disequilibrium with each other but in preliminary data it appears that HTR1A may be most strongly associated. Further, we report that HTR1A is expressed in human beta-cells. In summary, in this thesis the aim was to identify additional genes which may influence the risk to develop T1D and we report association to two novel T1D susceptibility genes; RNF180 and HTR1A.