Conserved extended haplotypes discriminate HLA-DR3-homozygous Basque patients with type 1 diabetes mellitus and celiac disease

Abstract

The major susceptibility locus for type 1 diabetes mellitus (T1D) maps to the human lymphocyte antigen (HLA) class II region in the major histocompatibility complex on chromosome 6p21. In southern European populations, like the Basques, the greatest risk to T1D is associated with DR3 homo-and heterozygosity and is comparable to that of DR3/DR4, the highest risk genotype in northern European populations. Celiac disease (CD) is another DR3-associated autoimmune disorder showing certain overlap with T1D that has been explained by the involvement of common genetic determinants, a situation more frequent in DR3-rich populations, like the Basques. As both T1D-and CD-associated HLA alleles are part of conserved extended haplotypes (CEH), we compared DR3-homozygous T1D and CD patients to determine whether CEHs were equally distributed between both disorders or there was a differential contribution of different haplotypes. We observed a very pronounced distribution bias (Po10 À5 ) of the two major DR3 CEHs, with DR3-B18 predominating in T1D and DR3-B8 in CD. Additionally, high-density single nucleotide polymorphism (SNP) analysis of the complete CEH [A*30-B*18-MICA*4-F1C30-DRB1*0301-DQB1*0201-DPB1*0202] revealed extraordinary conservation throughout the 4.9 Mbp analyzed supporting the existence of additional diabetogenic variants (other than HLA-DRB1*0301-DQB1*0201), conserved within the DR3-B18 CEH (but not in other DR3 haplotypes) that could explain its enhanced diabetogenicity.

HLA DR-DQ Haplotypes and Genotypes and Type 1 Diabetes Risk

“…Because the estimated "control" frequencies are low, the CIs are broad, and a statistically significant hierarchy of risk for all diplotypes cannot be established from these data, but clearly, the DR3/4, the DR4/4, and DR4/8 diplotypes (excluding DRB1*0404) have the highest risk. The estimated risk for the DR3/3 diplotype is somewhat lower than in other studies (31); this difference may reflect the well-known risk heterogeneity of the DR3 haplotype (32,33), which implicates loci other than DRB1, DQA1, and DQB1 in determining the extent of risk on DR3 haplotypes. Type 1 diabetes risk in closely related DR-DQ haplotypes.…”

Impact of highly conserved HLA haplotype on acute graft-versus-host disease

“…Recently, high-density SNP analysis in the HLA region made it possible to confirm the genetic fixity of HLA haplotype. [14][15][16] We determined the consensus sequence of these HLA haplotypes using multi-SNP data of unrelated persons with homozygous HLA haplotype, and the majority of persons who share the same HLA alleles in HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 as common HLA haplotypes possess at least a 3.3-Mb conserved region from HLA-A to -DPB1. Furthermore, we showed that those Japanese common HLA haplotypes extend far beyond the HLA-A.…”

The Past, Present, and Future of Genetic Associations in Type 1 Diabetes

“…It is increased in T1DM individuals (18% vs 9% of Caucasian controls) [21] presumably due to the DRB1*0301 and DQB1*0201 alleles and not as much to the HLA-B8 and HLA-A1 portion of the haplotype. The DR3-B8-A1 haplotype confers less risk than other DR3 haplotypes, with higher risk found in the less common DR3-B18-A30 (Basque) haplotype as well as other non-B8, DR3-positive individuals [22,23]. This would implicate susceptibility loci telomeric to class II alleles, although association studies alone have not been able to pinpoint a specific locus in such a complex region of the genome.…”