HLA-DPB1*0402 Protects Against Type 1A Diabetes Autoimmunity in the Highest Risk DR3-DQB1*0201/DR4-DQB1*0302 DAISY Population

Abstract

OBJECTIVE-A major goal in genetic studies of type 1A diabetes is prediction of anti-islet autoimmunity and subsequent diabetes in the general population, as Ͼ85% of patients do not have a first-degree relative with type 1A diabetes. Given prior association studies, we hypothesized that the strongest candidates for enhancing diabetes risk among DR3-DQB1*0201/DR4-DQB1*0302 individuals would be alleles of DP and DRB1*04 subtypes and, in particular, the absence of reportedly protective alleles DPB1*0402 and/or DRB1*0403. RESEARCH DESIGN AND METHODS-We genotyped 457DR3-DQB1*0201/DR4-DQB1*0302 Diabetes Autoimmunity Study of the Young (DAISY) children (358 general population and 99 siblings/offspring of type 1 diabetic patients) at the DPB1, DQB1, and DRB1 loci using linear arrays of immobilized sequencespecific oligonucleotides, with direct sequencing to differentiate DRB1*04 subtypes.RESULTS-By survival curve analysis of DAISY children, the risk of persistently expressing anti-islet autoantibodies is ϳ55% for relatives (children with a parent or sibling with type 1 diabetes) in the absence of these two protective alleles vs. 0% (P ϭ 0.02) with either protective allele, and the risk is 20 vs. 2% (P ϭ 0.004) for general population children. Even when the population analyzed is limited to DR3-DQB1*0201/DR4-DQB1*0302 children with DRB1*0401 (the most common DRB1*04 subtype), DPB1*0402 influences development of anti-islet autoantibodies.CONCLUSIONS-The ability to identify a major group of general population newborns with a 20% risk of anti-islet autoimmunity should enhance both studies of the environmental determinants of type 1A diabetes and the design of trials for the primary prevention of anti-islet autoimmunity.

Conditional analyses on the T1DGC MHC dataset: novel associations with type 1 diabetes around HLA-G and confirmation of HLA-B

“…Of note, rs2229634 in the ITPR3 gene, 445 kb centromeric of rs439121 (and thus outside region 4), was recently reported associated with T1D in a Swedish study, 36 but did not show significant independent association in our analyses (data not shown), which is in agreement with other replication attempts. 6,10,37 HLA-DPB1 has been implicated in T1D previously, predominantly involving the DPB1*0202, 0301 and 0402 alleles, 4,28,29,[38][39][40][41][42][43] but conflicting evidence has led some authors to question the status of this locus as an independent risk factor. 44,45 Some of this controversy could be explained by our findings, as HLA-DPB1 alone was not enough to explain all of the association in this region, and the redundancy with rs9368757 points to the possibility that another locus could account for the apparent effect of HLA-DPB1.…”

Genetics of Type 1 Diabetes

“…Most of the DP variation is provided by the DPB1 gene. Although not as strong as the effect of the established predisposing and protective DR-DQ haplotypes, variation at DPB1 also contributes to T1D risk (Noble et al 2000;Cucca et al 2001;Valdes et al 2001;Cruz et al 2004;Stuchlikova et al 2006;Baschal et al 2007;Varney et al 2010). Demonstrating that an observed association in the HLA region is a true disease susceptibility effect, and not due simply to linkage disequilibrium (LD) with risk DR-DQ haplotyes, is a necessary step in establishing other genes in the HLA region as potential T1D risk loci.…”

Analysis of Single Nucleotide Polymorphisms Identifies Major Type 1A Diabetes Locus Telomeric of the Major Histocompatibility Complex

“…In contrast, for common forms of type 1A diabetes, single genes with major influence outside of the major histocompatibility complex (MHC) region have apparently been ruled out, because whole genome association of large and independent populations have not identified single non-MHC genes with high odds ratios for diabetes risk (5). The MHC is the principal determinant for type 1A diabetes risk, with the largest contribution attributed to the HLA-DR/DQ alleles, including contributions from HLA-DRB1*04 subtypes and HLA-DP alleles (6,7).…”