title: HLA and celiac disease susceptibility: new genetic factors bring open questions about the HLA influence and gene-dosage effects.
abstract: Celiac disease (CD) is a chronic inflammatory disorder triggered after gluten ingestion in genetically susceptible individuals. The major genetic determinants are HLA-DQA1*05 and HLA-DQB1*02, which encode the DQ2 heterodimer. These alleles are commonly inherited in cis with DRB1*03∶01, which is associated with numerous immune-related disorders, in some cases contributing with a different amount of risk depending on the haplotype context. We aimed at investigating those possible differences involving DRB1*03∶01-carrying haplotypes in CD susceptibility. A family (274 trios) and a case-control sample (369 CD cases/461 controls) were analyzed. DRB1*03∶01-carrying individuals were classified according to the haplotype present (ancestral haplotype (AH) 8.1, AH 18.2 or non-conserved haplotype) after genotyping of HLA-DRB1, -DQA1, -DQB1, -B8, TNF -308, TNF -376 and the TNFa and TNFb microsatellites. We observe that the AH 8.1 confers higher risk than the remaining DRB1*03∶01-carrying haplotypes, and this effect only involves individuals possessing a single copy of DQB1*02. CD risk for these individuals is similar to the one conferred by inherit DQA1*05 and DQB1*02 in trans. It seems that an additional CD susceptibility factor is present in the AH 8.1 but not in other DRB1*03∶01-carrying haplotypes. This factor could be shared with individuals possessing DQ2.5 trans, according to the similar risk observed in those two groups of individuals.
authors.affiliation: UGC de Inmunología, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
authors.forename: Luz María
authors.initials: LM
authors.lastname: Medrano
authors.forename: Bárbara
authors.initials: B
authors.lastname: Dema
authors.forename: Arturo
authors.initials: A
authors.lastname: López-Larios
authors.forename: Carlos
authors.initials: C
authors.lastname: Maluenda
authors.forename: Andrés
authors.initials: A
authors.lastname: Bodas
authors.forename: Natalia
authors.initials: N
authors.lastname: López-Palacios
authors.forename: M Ángeles
authors.initials: MÁ
authors.lastname: Figueredo
authors.forename: Miguel
authors.initials: M
authors.lastname: Fernández-Arquero
authors.forename: Concepción
authors.initials: C
authors.lastname: Núñez
mesh_terms: D002446:Celiac Disease / Q000235:genetics*; D002648:Child; D005260:Female; D018628:Gene Dosage / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male
chemical_list: D059811:HLA-DRB1 Chains