Investigating genetic variants in type 1 diabetes

I tested whether the major histocompatability complex (MHC) class I polypeptide-related sequence A and B (MICA and MICB), two highly polymorphic genes in the MHC region on chromosome 6p21, were associated with type 1 diabetes. I designed a sequencing-based assay that could capture the majority of the MICA and MICB alleles, and genotyped MICA and MICB in a sample set of 818 UK and USA families. I found no association between any alleles of these genes and type 1 diabetes. In the second study, I tested five known type 2 diabetes susceptibility genes for association with type 1 diabetes. I genotyped variants in TCF7L2, FTO, PPARG, KCNJ11 and ADIPOQ in samples from up to 7,647 cases with type 1 diabetes and 7.156 controls, and found no convincing association with any of these genes. Thirdly, I participated in one of the first genome-wide association scans, in which we genotyped over 10,000 nonsynonymous single nucleotide polymorphisms. This study led to the discovery of the association of the IF1H1 region with type 1 diabetes. In my fourth study, I investigated whether variation in gene copy number of two chemokine genes, CCL3L1 and CCL4L1, is associated with type 1 diabetes, CCL3L1 and CCL4L1 exhibit complex copy number variation and code for two of the ligands of the CCR5 chemokine receptor, a non-functional variant of which is associated with protection from type 1 diabetes. Although I found no disease association with copy number of these genes, my results have implications for assay development of copy number variants. Finally, I initiated functional studies of one of the newly discovered type 1 diabetes genes, CLEC16A on chromosome 16p13. The function of this gene is, as yet, unknown. RNA interference results suggested that reduced CLEC16A expression inhibits the growth of three cell lines as well as primary mononuclear cells.EThOS - Electronic Theses Online ServiceGBUnited Kingdo