title: 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 (P<10(-5)) 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.
authors.affiliation: Endocrinology and Diabetes Research Group, Hospital de Cruces, Barakaldo, Bizkaia, Spain.
authors.forename: J R
authors.initials: JR
authors.lastname: Bilbao
authors.forename: B
authors.initials: B
authors.lastname: Calvo
authors.forename: A M
authors.initials: AM
authors.lastname: Aransay
authors.forename: A
authors.initials: A
authors.lastname: Martin-Pagola
authors.forename: G
authors.initials: G
authors.lastname: Perez de Nanclares
authors.forename: T A
authors.initials: TA
authors.lastname: Aly
authors.forename: I
authors.initials: I
authors.lastname: Rica
authors.forename: J C
authors.initials: JC
authors.lastname: Vitoria
authors.forename: S
authors.initials: S
authors.lastname: Gaztambide
authors.forename: J
authors.initials: J
authors.lastname: Noble
authors.forename: P R
authors.initials: PR
authors.lastname: Fain
authors.forename: Z L
authors.initials: ZL
authors.lastname: Awdeh
authors.forename: C A
authors.initials: CA
authors.lastname: Alper
authors.forename: L
authors.initials: L
authors.lastname: Castaño
mesh_terms: D002446:Celiac Disease / Q000235:genetics* / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D015803:HLA-DR3 Antigen / Q000235:genetics*; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D013030:Spain
chemical_list: D015803:HLA-DR3 Antigen