ARTHRITIS & RHEUMATISM
Vol. 63, No. 11, November 2011, pp 3305–3312
DOI 10.1002/art.30555
© 2011, American College of Rheumatology
Fine Mapping of a Major Histocompatibility Complex in
Ankylosing Spondylitis
Association of the HLA–DPA1 and HLA–DPB1 Regions
Roberto Dı ´az-Pen ˜a,
1
Ana M. Aransay,
2
Jacome Bruges-Armas,
3
Antonio Lo ´pez-Va ´zquez,
1
Naiara Rodrı ´guez-Ezpeleta,
2
In ˜aki Mendibil,
2
Alejandra Sa ´nchez,
4
Juan Carlos Torre-Alonso,
5
Bruno F. Bettencourt,
3
Juan Mulero,
4
Eduardo Collantes,
6
and Carlos Lo ´pez-Larrea
7
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 associa-
tion 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 disequili-
brium 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.
Ankylosing spondylitis (AS) is a chronic inflam-
matory rheumatic disease that primarily involves the
axial skeleton and the sacroiliac joint but also may af-
fect peripheral joints and entheses. Susceptibility to the
disease is clearly attributable to genetic factors, because
the sibling recurrence risk rate is 82 (1), and twin-based
studies estimate that disease heritability exceeds 90%
(2). The high frequency of HLA–B27 in patients with
spondylarthropathies such as AS (95% of patients with
AS carry B27) has emerged as one of the best examples
of a disease association with an HLA marker. Indeed,
evidence for the role of HLA–B27 in AS comes from
linkage and association studies both in humans and in
transgenic animal models (3,4).
The HLA–B27 family contains a large number of
allelic variants, or subtypes, that differ in terms of ethnic
distribution and the heterogeneity of which has been
Supported by the Fondo de Investigacio ´n Sanitaria, Instituto
de Salud Carlos III, Madrid (grant PI080566) and the Fundacio ´n para
el Fomento en Asturias de la Investigacio ´n Cientı ´fica (FICYT grants
PC10-70 and ETORTEK/2005-2010).
1
Roberto Dı ´az-Pen ˜a, PhD, Antonio Lo ´pez-Va ´zquez, MD:
Hospital Universitario Central de Asturias, Oviedo, Spain;
2
Ana M.
Aransay, PhD, Naiara Rodrı ´guez-Ezpeleta, PhD, In ˜aki Mendibil:
CIC bioGUNE, Derio, Spain;
3
Jacome Bruges-Armas, MD, Bruno F.
Bettencourt, BSc: University of Porto, Porto, Portugal;
4
Alejandra
Sa ´nchez, MD, Juan Mulero, PhD: Hospital Universitario Puerta de
Hierro, Madrid, Spain;
5
Juan Carlos Torre-Alonso, MD: Hospital
Monte Naranco, Oviedo, Spain;
6
Eduardo Collantes, MD: Hospital
Reina Sofı ´a and University of Cordova, Cordova, Spain;
7
Carlos
Lo ´pez-Larrea, PhD: Hospital Universitario Central de Asturias,
Oviedo, Spain, and Fundacion Renal In ˜igo Alvarez de Toledo, Ma-
drid, Spain.
Address correspondence to Carlos Lo ´pez-Larrea, PhD, De-
partment of Immunology, Hospital Universitario Central de Asturias,
C/Celestino Villamil s/n, 33006 Oviedo, Spain. E-mail: inmuno@
hca.es.
Submitted for publication September 16, 2010; accepted in
revised form July 12, 2011.
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