HLA Class I and Genetic Susceptibility to Type 1 Diabetes

Abstract

OBJECTIVEWe report here genotyping data and type 1 diabetes association analyses for HLA class I loci (A, B, and C) on 1,753 multiplex pedigrees from the Type 1 Diabetes Genetics Consortium (T1DGC), a large international collaborative study.RESEARCH DESIGN AND METHODSComplete eight-locus HLA genotyping data were generated. Expected patient class I (HLA-A, -B, and -C) allele frequencies were calculated, based on linkage disequilibrium (LD) patterns with observed HLA class II DRB1-DQA1-DQB1 haplotype frequencies. Expected frequencies were compared to observed allele frequencies in patients.RESULTSSignificant type 1 diabetes associations were observed at all class I HLA loci. After accounting for LD with HLA class II, the most significantly type 1 diabetes–associated alleles were B*5701 (odds ratio 0.19; P = 4 × 10−11) and B*3906 (10.31; P = 4 × 10−10). Other significantly type 1 diabetes–associated alleles included A*2402, A*0201, B*1801, and C*0501 (predisposing) and A*1101, A*3201, A*6601, B*0702, B*4403, B*3502, C*1601, and C*0401 (protective). Some alleles, notably B*3906, appear to modulate the risk of all DRB1-DQA1-DQB1 haplotypes on which they reside, suggesting a class I effect that is independent of class II. Other class I type 1 diabetes associations appear to be specific to individual class II haplotypes. Some apparent associations (e.g., C*1601) could be attributed to strong LD to another class I susceptibility locus (B*4403).CONCLUSIONSThese data indicate that HLA class I alleles, in addition to and independently from HLA class II alleles, are associated with type 1 diabetes.

Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations

“…Previous studies have shown several independent signals within the MHC region in multiple autoimmune diseases, including RA and systemic lupus erythematosus (54)(55)(56)(57), and specifically with HLA-A in type 1 diabetes (54). The data are less clear for MHC class III because of the strong LD there ( Figure 4C).…”

MECHANISMS IN ENDOCRINOLOGY: Insulin and type 1 diabetes: immune connections

“…This historical bias was due to the long-known association between diabetes and HLA class II predisposing and protective alleles. The recent recognition that HLA class I alleles can also modulate T1D risk (61,64,65) has further emphasized the role of CD8CT cells. More recently, a direct association between these T cells and b-cell destruction has been suggested in humans.…”

Immunologic and Genetic Factors in Type 1 Diabetes Mellitus

“…More than 20 putative diabetes predisposing genes have been identified, but most of them have only a weak association, and in many cases the association has been difficult to confirm. The one exception is the HLA genes, which are thought to contribute as much as 50% of the genetic risk for Type 1 (DM) (Noble, Valdes et al 2010). Although HLA genes may be necessary, by themselves they seem not to be sufficient to produce the disease.…”