Investigation of Candidate Genes and HLA-Related Risk Factors in a Genetic Study of Autoimmune Disease

Collectively autoimmune diseases constitute a major burden to society. Though the etiology of autoimmune diseases remain largely unknown, evidence supports a substantial genetic component. For many autoimmune diseases, twin studies demonstrate a dramatically higher disease concordance rate in monozygotic twins than in dizygotic twins. Genes in the major histocompatibility complex (MHC) region on the short arm of chromosome 6, particularly the human leukocyte antigen (HLA) class II genes, are strongly associated with risk of developing rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS) and type 1 diabetes (T1D). The MHC class II transactivator gene (CIITA, also called MHC2TA), located on the short arm of chromosome 16, encodes an important transcription factor (CIITA) regulating the genes required for HLA class II MHC-restricted antigen presentation. Thus CIITA is a strong biological candidate for studies of autoimmune disease. Directly adjacent to CIITA lies the C-type lectin domain family 16, member A gene (CLEC16A, previously called KIAA0350). CLEC16A is a sugar binding receptor containing a putative immunoreceptor and was recently identified as a novel T1D and MS susceptibility locus through genomewide association (GWA) studies.HLA may also influence susceptibility to autoimmune disease through other inherited and noninherited mechanisms, in addition to genetic transmission of risk alleles. Evidence for increased maternal-offspring HLA compatibility and differences in both maternal vs. paternal transmission rates (parent-of-origin effects) and nontransmission rates (noninherited maternal antigen (NIMA) effects) in autoimmune diseases have been reported.The investigation described in this dissertation tested hypotheses that (1) the CIITA -168A/G promoter polymorphism (rs3087456) influences susceptibility to RA (Chapter 2); (2) common genetic variation in CIITA influences susceptibility to RA in a case-control study (Chapter 3); (3) common genetic variation in CIITA influences susceptibility to SLE or specific secondary SLE phenotypes (Chapter 4); (4) common genetic variation in CIITA influences susceptibility to MS (Chapter 5); (5) common genetic variation in CLEC16A influences susceptibility to RA (Chapter 6); (6) the HLA class II DRB1 locus influences susceptibility to SLE through maternal-offspring HLA compatibility, parent-of-origin and NIMA effects (Chapter 7); and (7) the HLA classical loci influence susceptibility to T1D through maternal-offspring HLA compatibility, parent-of-origin and NIMA effects (Chapter 8). This dissertation includes the first study to fully characterize common genetic variation in CIITA and CLEC16A, including assesment of haplotypes, sex-specific effects, secondary clinical phenotypes and HLA risk alleles. Results do not provide evidence for association between CIITA and RA or SLE or for association between CLEC16A and RA. Interestingly, this study revealed evidence for an association between the CIITA missense mutation rs4774 and increased risk for MS in the presence of the HLA-DRB1*1501 risk allele. There was no linkage disequilibrium between CIITA and CLEC16A, and the observed association between CIITA and MS in the presence of HLA-DRB1*1501 was independent of the association between CLEC16A and MS.The first studies to examine maternal-offspring HLA compatibility in T1D and HLA-DRB1 parent-of-origin and NIMA effects in SLE, and the largest study to examine maternal-offspring HLA compatibility in SLE and HLA parent-of-origin and NIMA effects in T1D were also performed. No evidence that the HLA-DRB1 locus influences risk for SLE or that the classical HLA loci influence risk for T1D through these novel biological phenomena was revealed.