Functional Immunogenetics of Two GWAS Genes in Autoimmunity

Abstract

Type I diabetes (T1D) is a chronic T cell-mediated autoimmune disease that results in the destruction of insulin producing pancreatic beta cells. More than 50 genomic regions have been implicated by genome-wide association studies (GWAS) in the modulation of T1D risk. One such region located within chromosome 16p13.13 (Ch16p13.13) includes the candidate genes DEXI & CLEC16A. While our lab previously reported that Clec16a deficiency protected against autoimmunity by the modification of immune reactivity using the T1D nonobese diabetic (NOD) mouse model, conclusive evidence for the causality of Ch16p13.13 in disease association is missing. Due to T1D-associated SNPs within CLEC16A also impacting DEXI expression others have argued that DEXI is the causal gene in Ch16p13.13. Since functional data for DEXI’s role in T1D was lacking, we generated a Dexi knockout (KO) NOD mouse to resolve DEXI’s involvement in disease. The frequency of diabetes was not affected in Dexi-deficient NOD mice when compared to wild type (WT) NOD. Moreover, intercrossing Dexi-deficient NOD and Clec16a knockdown (KD) NOD mice allowed testing for possible interactions between Clec16a and Dexi and their potential effects on disease. We found that Dexi KO did not modify the previously observed protection in Clec16a KD NOD mice. This led to the conclusion that Dexi alone does not play a role in the autoimmune diabetes modeled by NOD mice. The data presented in this thesis work clarifies the previous dichotomy in the field by providing strongly suggestive evidence that CLEC16A, as opposed to DEXI, is causal for the T1D association of disease variants within Ch16p13.13.