Refining immunogenetic risk assessment for Type 1 Diabetes in the Belgian population

Abstract

Introduction
Type 1 diabetes is a multifactorial disease that arises as a result of the complex interaction between genetic and environmental factors. Over 50 risk loci have been identified. Regardless of the magnitude of the odds ratio, these chromosomal regions need first to be confirmed in independent populations, because each confirmed gene provides a key piece of the aetiology of
the disease. In addition, it is also important to study them in different populations using large representative groups because they may have potential applications in: 1) disease classification; 2) risk assessment in the presence or absence of islet autoantibodies; 3) understanding the genetic basis of disease heterogeneity; 3) generating mechanistic hypotheses that can be tested in functional studies; 5) and in the long run diabetes prevention, cure and personalised medicine.
Scope and aims
In line with the above considerations and the goals of the Belgian Diabetes Registry, the aims of this doctoral thesis were: 1) to confirm or refute the type 1 diabetes association of a number of candidate genes (IL2RA/CD25, IFIH1,TNFA) suggested by GWAS or other studies in a large representative group of well-characterised patients under age 40 years, healthy controls and families; 2) to study their interaction with the major or previously confirmed genetic markers, diabetes phenotypes and immune and functional markers. These studies were carried out in order to search for the genetic basis of disease heterogeneity, to generate mechanistic hypotheses that can be tested in functional studies and to try to improve on the determination of genetic risk assessment for type 1 diabetes in the Belgian population.
Summary of results
* TNFA was associated with type 1 diabetes independently of HLA-DQ linked risk. The HLADQA1*
0501-DQB1*0201-TNFa1 extended haplotype was identified as a diabetogenic
14 haplotype and confers significantly higher cumulative risks for developing type 1 diabetes under age 40 compared to the risk of HLA-DQA1*0501-DQB1*0201 haplotype alone. This extended haplotype is part of the conserved A30-B18-DR3 extended haplotype.
* IFIH1 was not associated with type 1 diabetes both before and after stratification according to HLA-DQ-linked risk. IFIH1 showed no correlation with disease phenotype and immune markers for type 1 diabetes.
* IL2RA/CD25 was associated with type 1 diabetes independently of sex and this association was present in both early-onset and late-onset disease. The association was more pronounced in early onset disease but was not dependent on a specific disease phenotype, immune marker, or HLA-DQ, INS and PTPN22 genotypes.
* The design of these studies underscores the importance of national diabetes registries in disclosing the interaction between genetic, clinical and biological characteristics and the importance of statistical power analyses in studies planned in independent populations.
Discussion and perspectives
The contribution of these markers (IL2RA/CD25, IFIH1 and TNFA) to the determination of genetic risk assessment for type 1 diabetes in the Belgian population was relatively small. In addition, the genotype-phenotype correlations and the gene-gene interactions studies were not informative with respect to understanding the genetic basis of disease heterogeneity and generating mechanistic hypotheses that can be tested in functional studies. That notwithstanding, future studies of genetic susceptibility loci could still have important implications in life sciences and medicine. HLA class I polymorphisms are currently being tested in the Belgian population. The HLA-DQ, INS VNTR, CTLA4, PTPN22 and IL2RA/CD25 are being tested in the Cameroonian population - sub-Saharan Africa.

Date of Award	7 Sept 2010
Original language	English
Awarding Institution	Vrije Universiteit Brussel
Supervisor	Bart Van der Auwera (Promotor), Frans Gorus (Co-promotor), Christiaan Van Schravendijk (Co-promotor), Karin Vanderkerken (Jury), Pieter in 't Veld (Jury), Bart Keymeulen (Jury), Karen Sermon (Jury), Paolo Pozzilli (Jury), V Geenen (Jury) & Christophe De Block (Jury)