Immunogenetics of Type 1 diabetes and Celiac disease

AbstractThe primary purpose of understanding disease etiology is to explain how a specific phenotype is determined by genotype. In pursue of this aim, exploring the diversity in DNA sequence variants that affect biomedical traits, especially those related to the onset and progression of genetically determined human disease. The human leukocyte antigens (HLA) are highly polymorphic cell surface proteins encoded in the major histocompatibility complex (MHC) region on chromosome 6. The HLA molecules are integral regulators for susceptibility to several autoimmune and inflammatory diseases, including type 1 diabetes (T1D) and celiac disease (CD), which share high-risk HLA haplotypes. Through next-generation sequencing (NGS), an integrated genotyping system of HLA loci was developed to genotype alleles of the MHC region. The full depth of allele association was used to target the novel mechanisms of HLA-associated risk alleles in T1D and CD. The research presented in this thesis aimed to use high-resolution genotyping with NGS of HLA loci and study extended associations in patients with T1D and CD as well as in a group of patients affected by both diseases (T1D w/CD). The main findings of importance were: -• HLA-DRB3, DRB4, and DRB5 affect the risk of islet autoimmunity and progression to the clinical onset of T1D and should be considered when examining the role of HLA-DR genetic risk. • Two distinct CD risk DR3-DQA1*05:01-DQB*02:01 haplotypes distinguished by either HLA-DRB3*01:01:02 and DRB3*02:02:01 alleles in the DRB3*01:01:02- DQA1*05:01-DQB1*02:01 extended haplotype distinguished the risk of CD, indicating that different DRB1*03:01-DQB1*02:01 haplotypes confer different risks for CD among patients of Scandinavian background. • HLA-DRB4*01:03:01, DRB3*01:01:02, and DRB3*02:02:01 are associated with T1D and CD of which DRB4*01:03:01 confers the strongest risk allele for T1D w/CD.• HLA-A*68:01:02 was identified as an additional allele positively associated between T1D w/CD and T1D. In conclusion, by utilizing high-resolution sequencing technologies for extended genotyping of HLA class I and II genetic determinants, the full spectrum of alleles and haplotypes variation associated with T1D and CD were explored. This basic knowledge should prove helpful contribution in building comprehensive inventories of genotype-phenotype relationships and resolving some of the HLA roles in the heritability risk for either T1D or CD, as well as in genetic models for the risk of developing both diseases