Open AccessFine mapping of a major histocompatibility complex in ankylosing spondylitis: Association of the HLA–DPA1 and HLA–DPB1 regions
Author(s) -
DíazPeña Roberto,
Aransay Ana M.,
BrugesArmas Jacome,
LópezVázquez Antonio,
RodríguezEzpeleta Naiara,
Mendibil Iñaki,
Sánchez Alejandra,
TorreAlonso Juan Carlos,
Bettencourt Bruno F.,
Mulero Juan,
Collantes Eduardo,
LópezLarrea Carlos
Publication year - 2011
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.30555
Subject(s) - linkage disequilibrium , single nucleotide polymorphism , human leukocyte antigen , haplotype , ankylosing spondylitis , immunology , genotyping , major histocompatibility complex , medicine , biology , genetics , allele , genotype , gene , antigen
Objective To investigate the potential association of major histocompatibility complex (MHC) markers other than HLA–B27 with ankylosing spondylitis (AS). Methods A total of 603 patients with AS and 542 healthy control subjects, all of whom were HLA–B27 positive, were selected for this study based on clinical criteria. First, high‐density genotyping across the MHC region (2,360 single‐nucleotide polymorphisms [SNPs]) was performed in a cohort of 191 patients and 241 control subjects. After a fine‐mapping study, 5 SNPs from the HLA–DPA1/DPB1 region were validated in a second cohort of 412 patients with AS and 301 healthy control subjects. Results Seventeen SNPs located within or near the HLA–DPA1 and HLA–DPB1 loci showed association with AS ( P = 1.38 × 10 −5 to 0.05). In addition, multimarker tests, both linkage disequilibrium and sliding windows, showed association of some groups of adjacent SNPs within the HLA–DPA1/DPB1 region with AS ( P = 1.0 × 10 −4 to 3.96 × 10 −7 ). We validated the association by genotyping 5 SNPs from the DPA1/DPB1 region in an additional cohort and obtained P values from 6.42 × 10 −5 to 0.01 in the analysis of the combined cohorts. Subtyping analysis of HLA–DPA1 and HLA–DPB1 showed that HLA–DPA1*01:03, A1*02:01, and B1*13:01 were the subtypes most susceptible to AS. Conclusion HLA markers and linkage disequilibrium blocks near HLA–DPA1 and HLA–DPB1 are statistically associated with AS. We identified a region located around the HLA–DPA1 and HLA–DPB1 loci associated with AS, another region within the MHC that is different from HLA–B27.