Susceptibility to type 1 diabetes (T1D) is determined by an interaction between genes and the environment. The major genetic susceptibility so far found is conferred by genes in the HLM region on chromosome 6. Despite this progress, our understanding of the genetics of T1D is far from complete, as approximately 30% of the familial clustering of T1D remains unexplained. Indeed, it is likely that more disease-related pathways remain to be discovered.
This study plans to complete an ongoing, comprehensive, and genome-wide study of the genetics of T1D in Finland, home of the highest incidence of T1D in the world.
The location of other possible susceptibility genes ha been difficult. If we could identify the key genes and their pathways involved in the chronic inflammation of the pancreatic islets, then we could categorize at-risk subjects or patients according to genotype, and therefore, according to the underlying mechanism of the disease. The starting point for the launch of such a pharmacogenetic approach is the identification of the disease associated genes and their functions I humans.
The vast majority of the studies of the etiology of T1D have deal with pre-adolecent cases only. Our proposed study will be unique as it covers the age at onset of newly diagnosed cases up to 40 years (much more widely but accurately at the same time) than any study before.
The aim of this study is to find the genes conferring susceptibility to type 1 diabetes in the Finnish population, and eventually to replicate the results in noon Finnish setting.
The specific aims are:
1. Create a world-class resource of accessible DNA samples and data for the study of Type 1 Diabetes (T1D) genetics in Finland
2. Carry out a GWAS in two stages to locate novel T1D susceptibility loci, in two stages:
a. Stage 1: genotipying at ca. 906 000 SNPs (single nucleoitide polymorphism) of 1 200 DNA samples from early onset cases and 800 late onset, and 6 000 controls previously supplemented
b. Stage 2: the ca. 5 000 SNPs mostly associated with disease or age-at-diagnosis from Stage 1 will be genotype in newly collected 1 000 early-onset and 1 000 late onset T1D cases and 2 000 controls. This will include ca. 2 000 SNP from MHC region, to provide a comprehensive fine map of the region when combined with HLA typing data from target c.
c. Perform HLA gene typing at three class I and class II loci in 2 000 T1D cases and 2 000 T1D controls, to find novel association
d. Genotyping ~50 SNPs within confirmed and strongly-suspected loci for T1D and T2D in all 4,000 T1D cases and 3,000 controls.
e. Test susceptibility genes for association with age-at-diagnosis, autoantibody profiles, and C-peptide levels.
In addition, to the DNA data bank, we will establish cell line repository, to facilitate the research into genetics of T1D and its complications in this special population also in the future. The collection and storing of lymphocyte cells for over 100 subjects have already been done in a previous phase of the study.
The unique genetic history of the Finnish population makes it a powerful place to search for novel T1D loci. To take advantage of this fact, we have assembled an international collaboration of experienced researchers with expertise in all areas of modern genetics, and designed the most powerful study to date to characterize the genetics of T1D in the Finnish population.