A high density SNP genotyping approach within the 19q13 chromosome region identifies an association of a CNOT3 polymorphism with ankylosing spondylitis

Abstract

To identify genomic variants in the 19q13 chromosome region associated with ankylosing spondylitis (AS) in human leucocyte antigen (HLA)-B27-positive populations.
High-throughput genotyping of 1536 haplotype-tag single nucleotide polymorphisms (SNPs) was performed in 249 patients with AS and 302 healthy controls. Some of the identified associations were validated by genotyping four SNPs in two additional cohorts consisting of 412 cases/301 controls and 144 cases/203 controls. All individuals selected (both cases and controls) were HLA-B27-positive.
Two markers in two different genes (CNOT3 and LAIR2) showed significant association (p<10(-3)) with AS. In addition, sliding windows analysis showed association of groups of adjacent SNPs in regions located around CNOT3 (Chr19: 59347459-59356564, p=2.43 × 10(-4) to 6.54 × 10(-4)). The associations were validated by genotyping four SNPs from regions located near LAIR2 and CNOT3 genes (rs1055234, rs8111398, rs2287828 and rs4591276) in two additional cohorts. The CNOT3 polymorphism (rs1055234) remained associated with AS (combined p=9.73 × 10(-6)). One SNP, located downstream of KIR3DL1, was detected which, tested in combination with HLA-Bw4I80, was associated with AS.
A novel significant association was detected between SNP rs1055234 and AS susceptibility.

Full text

Clinical and epidemiological research
Ann Rheum Dis 2012;71:714–717. doi:10.1136/annrheumdis-2011-200661714
ABSTRACT
Objective To identify genomic variants in the 19q13
chromosome region associated with ankylosing
spondylitis (AS) in human leucocyte antigen (HLA)-B27-
positive populations.
Methods High-throughput genotyping of 1536
haplotype-tag single nucleotide polymorphisms (SNPs)
was performed in 249 patients with AS and 302 healthy
controls. Some of the identifi ed associations were
validated by genotyping four SNPs in two additional
cohorts consisting of 412 cases/301 controls and 144
cases/203 controls. All individuals selected (both cases
and controls) were HLA-B27-positive.
Results Two markers in two different genes (CNOT3
and LAIR2) showed signifi cant association (p<10−3)
with AS. In addition, sliding windows analysis showed
association of groups of adjacent SNPs in regions
located around CNOT3 (Chr19: 59347459-59356564,
p=2.43×10−4 to 6.54×10−4). The associations were
validated by genotyping four SNPs from regions located
near LAIR2 and CNOT3 genes (rs1055234, rs8111398,
rs2287828 and rs4591276) in two additional cohorts. The
CNOT3 polymorphism (rs1055234) remained associated
with AS (combined p=9.73×10−6). One SNP, located
downstream of KIR3DL1, was detected which, tested in
combination with HLA-Bw4I80, was associated with AS.
Conclusion A novel signifi cant association was
detected between SNP rs1055234 and AS susceptibility.
INTRODUCTION
Ankylosing spondylitis (AS) is a common infl amma-
tory arthritis affecting the axial skeleton. The asso-
ciation of human leucocyte antigen (HLA)-B27 with
ankylosing spondylitis (AS) is among the strongest
between an HLA molecule and a disease.1 However,
non-B27 genes also seem to be involved in the aeti-
ology of AS,2–5 with the 16q chromosome region
being the strongest non-major histocompatibility
complex (MHC) region associated with AS.2 6
Linkage results have shown that some genes on
chromosome 19q can contribute to the development
of AS.2 Leucocyte receptor complex (LRC), which is
located at chromosome 19q13.4, encodes a multigene
family that differs in both gene content and allelic
polymorphisms. LRC encodes cell surface molecules
with distinctive immunoglobulin-like extracellular
domains including killer immunoglobulin (Ig)-like
receptors (KIR), leucocyte Ig-like receptors (LILR)
and leucocyte-associated Ig-like receptors (LAIR) (see
fi gure S1 in online supplement). KIRs have attracted
attention with regard to their potential role in AS
because the proteins they encode can bind HLA class
I molecules with different affi nity and modulate the
activation and inhibition of natural killer (NK) cells
and CD8+ T cells. Several studies have examined
the role of KIRs in spondyloarthropathies (SpA),
and an association with the KIR3DL1/3DS1 locus
in AS has been reported.7–9 Specifi cally, KIR3DL1
binds the HLA-B containing the serological-defi ned
epitope (determined by amino acid position 79–83
of the molecule), and all HLA-B27 subtypes carry the
Bw4 epitope except B*27:08 and other related sub-
types which carry Bw6. In addition, HLA-B27 heavy
chain homodimers, implicated in the pathogenesis
of SpA,10 bind to several of these leucocyte receptors
including LILRA1, LILRB2, KIR3DL1 and KIR3DL2.
The aim of the present study is to search for
associations between genetic variants of genes
located in the 19q13 region and AS in HLA-B27-
positive populations. We also analysed other can-
didate genes based on their role in the immune
response and possible implication in autoimmune
diseases: TNFRSF11B (OPG), TNFSF11 (RANKL),
TNFRSF11A (RANK), IL-1 family gene cluster,
cytokine cluster (5q), cytokine cluster (21q), IL17A,
IL17RA, IL10RA, NOD2 and CYP2D6 (see table S1
in online supplement).
METHODS
Study participants
A total of 805 patients with AS and 806 healthy
controls, both cases and controls being HLA-B27-
positive, were studied as three distinct cohorts.
Cohort 1 comprised 249 patients with AS and
302 healthy control subjects (225 cases/271 con-
trols from Spain and 24 cases/31 controls from the
Azores); cohort 2 included 412 AS cases/301 con-
trols from Spain; and cohort 3 consisted of 144 AS
cases/203 controls from Portugal. The patients with
AS were diagnosed following New York criteria.11
▶ Additional fi gures and tables
are published online only. To view
these fi les please visit the journal
online (http://ard.bmj.com/
content/71/5.toc).
For numbered affi liations see
end of article
Correspondence to
Carlos López Larrea,
Department of Immunology,
Hospital Universitario Central de
Asturias, C/ Celestino Villamil
s/n, 33006-Oviedo, Spain;
inmuno@hca.es
Received 24 August 2011
Accepted 11 December 2011
Published Online First
31 January 2012
CONCISE REPORT
A high density SNP genotyping approach within
the 19q13 chromosome region identifi es an
association of a CNOT3 polymorphism with
ankylosing spondylitis
Roberto Díaz-Peña,1 Ana M Aransay,2 Beatriz Suárez-Álvarez,1 Jacome Bruges-Armas,3
Naiara Rodríguez-Ezpeleta,2 María Regueiro,2,4 Fernando M Pimentel-Santos,5,6
Juan Mulero,7 Alejandra Sánchez,7 Eduardo Collantes,8 Rubén Queiro,9 Javier Ballina,9
Helena Alves,10 Carlos López-Larrea1
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Clinical and epidemiological research
Ann Rheum Dis 2012;71:714–717. doi:10.1136/annrheumdis-2011-200661 715
Single nucleotide polymorphism selection and genotyping
The customised panel containing 1536 haplotype-tag SNPs
(ht-SNPs) located within the candidate genes shown in table
S1 in the online supplement was designed based on the
HapMap European population.12 ht-SNPs were selected using
the following criteria: minor allele frequency ≥0.01 and r2>0.8.
High-throughput genotyping in cohort 1 was performed with
Golden-Gate technology using Sentrix Array Matrixes (Illumina
Inc, San Diego, California, USA).13 Genotyping of the replica-
tion stage (cohorts 2 and 3) was performed by iPLEX technol-
ogy (MassARRAY, Sequenom, San Diego, California, USA) (see
fi gure S2 in online supplement).
KIR3DL1 genotyping data for 244 patients with AS and 172
healthy controls were obtained in a previous study.8
Statistical analysis
A total of 1137 SNPs were considered for the present association
study after strict quality criteria fi ltering: SNPs with minor allele
frequency in the studied population <0.01, missingness >0.1
and/or Hardy–Weinberg equilibrium p<0.001 were removed.
Statistical analysis of high density SNP genotyping data was
performed as follows: (1) allele frequencies were compared
between AS patient and control populations by χ2 test, and ORs
with 95% CI were calculated with PLINK software;14 (2) haplo-
type analysis was performed using Haploview version 4.1 soft-
ware (http://www.broadinstitute.org/haploview/haploview);15
and (3) sliding windows of 2–10 SNPs each were tested for asso-
ciation analyses by χ2 test with PLINK software.14 SPSS V.13
statistical software was used to assess the role of SNPs located
around the KIR gene family and the infl uence of Bw4 ligand on
AS susceptibility. The signifi cance of these associations was
determined using the χ2 test with Yates’ correction or the Fisher
exact test.
RESULTS
SNP genotyping
Seventeen SNPs with putative associations with AS were identi-
fi ed (see table S2 in online supplement). Only two markers in
two different genes showed signifi cant associations (p<10−3):
rs1055234 (located in an intron of CNOT3, p=1.42×10−4) and
rs8111398 (located upstream of LAIR2, p=9.45×10−4). Sixteen
additional markers in 14 genes showed suggestive associations
(0.01>p>0.001). The associations of the remaining genes
included in the study were not signifi cant.
The sliding window omnibus test revealed several SNP blocks
associated with AS (table 1). The p values obtained for the slid-
ing window test of a region comprising CDC42EP5 and LAIR2
genes (Chr19: 59.690.540 to 59.705.936) ranged from 5.29×10−4
to 9.02×10−4. We also found an association in a region located
between CNOT3 and TMC4 genes (Chr19: 59.349.813 to
59.356.564, p=2.43×10−4 to 6.54×10−4).
In addition to the sliding window test, we also per-
formed case-control studies based on linkage disequilibrium
(LD) haplotype block reconstruction. A region located near
CDC42EP5 and LAIR2 genes was identifi ed with haplotypes
showing an association with AS (see fi gure S3 in online sup-
plement). This region was divided into haplotype blocks and
some alleles of rs8111398/rs7251986/rs10418813 haplotype
(Chr19: 59.694.904 to 59.697.915) appeared to be statistically
associated with AS (AAG, p=9.0×10−4 and GGG, p=0.001,
respectively).
To validate the results, we replicated the analysis in two
additional cohorts. The incidence of four SNPs was studied
in AS cases and controls in cohorts 2 and 3: two SNPs with
p<10−3—rs1055234 (located in an intron of CNOT3) and
rs8111398 (located upstream of LAIR2)—and two SNPs in strong
LD with rs8111398 located along the LAIR2 gene—rs2287828
(located in the 5′-UTR of LAIR2) and rs4591276 (located down-
stream of LAIR2). The results were combined with cohort 1
(table 2). The joint association analysis confi rmed a signifi cant
association between SNP rs1055234 and AS susceptibility (com-
bined p=9.73×10−6).
KIR/LILR region
No signifi cant association was obtained for SNPs located around
LILR and KIR gene families. However, when we analysed whether
the presence of Bw4 ligand affects the association between these
markers and AS susceptibility in cohort 1, we found interest-
ing results (table 3). For the rs17771961 (located downstream
of KIR3DL1), individuals with CC or CG genotype and Bw4I80
epitope showed a lower prevalence of AS than B27-positive,
Bw4I80-positive controls (18% vs 34%, p<0.05). We also analy-
sed the impact of specifi c polymorphisms of KIR3DL1 alleles.
Although no signifi cant differences were found, rs17771961-C
Table 1 Gene region, marker composition and association values (only p values <10−3 are shown) obtained
with the χ2 test for sliding widows of 2–10 single nucleotide polymorphisms (PLINK)19 with the genotyping
data of cohort 1
Gene (S) Markers p Value
CNOT3 rs2241790|rs1055234 4.74×10−4
CNOT3 rs1055234|rs11606 6.54×10−4
CNOT3, TMC4 rs1055234|rs11606|rs36657 2.43×10−4
CDC42EP5, LAIR2 rs12985351|rs8111398|rs7251986 8.43×10−4
LAIR2 rs8111398|rs7251986|rs10418813 8.57×10−4
CNOT3, TMC4 rs1055234|rs11606|rs36657|rs36656 4.04×10−4
CDC42EP5, LAIR2 rs12985351|rs8111398|rs7251986|rs10418813 7.11×10−4
CDC42EP5, LAIR2 rs12985351|rs8111398|rs7251986|rs10418813|rs8111811 8.28×10−4
CDC42EP5, LAIR2 rs12985351|rs8111398|rs7251986|rs10418813|rs8111811|rs8100732 8.01×10−4
CDC42EP5, LAIR2 rs12985351|rs8111398|rs7251986|rs10418813|rs8111811|rs8100732|
rs4806517|rs4806766
5.29×10−4
CDC42EP5, LAIR2 rs12985351|rs8111398|rs7251986|rs10418813|rs8111811|rs8100732|
rs4806517|rs4806766|rs2042290
7.09×10−4
CDC42EP5, LAIR2 rs12985351|rs8111398|rs7251986|rs10418813|rs8111811|rs8100732|
rs4806517|rs4806766|rs2042290|rs2287828
9.02×10−4
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Clinical and epidemiological research
Ann Rheum Dis 2012;71:714–717. doi:10.1136/annrheumdis-2011-200661716
showed a strong correlation with KIR3DL1*004 (see table S3 in
online supplement).
DISCUSSION
Previous studies have shown strong evidence for a link between
AS and the genes localised on chromosome 19q.2 We have car-
ried out a high-throughput genotyping of SNPs in order to test
for associations between AS and genes from the 19q13 region
and some other additional candidate genes in HLA-B27-positive
populations. Our research supports the involvement of non-
MHC regions within 19q13 in the development of AS. A sig-
nifi cant association was detected between SNP rs1055234 and
AS susceptibility. Furthermore, the sliding window omnibus
test revealed several haplotype associations with AS in regions
located around CNOT3.
The protein encoded by the gene CNOT3, a subunit of
CCR4-NOT transcription complex, is suggested to be involved
in global gene regulation by interacting with TATA-binding
proteins (TBP). TBP-interacting protein 120 B (TIP120B) affects
tissue-specifi c transcriptional regulation via interaction with
CNOT3.16 Interestingly, TIP120B is considered to be a muscle-
specifi c protein and might play a unique role in muscle tissues.17
In this way, genetic variation in CNOT3 may affect its interac-
tion with TIP120B, modulate gene regulation and increase AS
susceptibility. We also identifi ed one SNP (rs8111398, located
upstream of LAIR2) and several haplotypes from regions located
around LAIR2 associated with AS. LAIR2 is an inhibitory receptor
expressed on the majority of peripheral blood mononuclear cells
(PBMCs) and thymocytes;18 its function is unclear. Interestingly,
LAIR2 levels were increased in the joints of patients with rheu-
matoid arthritis compared with patients with osteoarthritis and
might be a good candidate gene in AS susceptibility.19 However,
we did not confi rm the incidence of the three SNPs located along
the LAIR2 gene with AS in the two additional cohorts.
KIRs have attracted attention with regard to their potential role
in SpA.7 They can bind HLA class I molecules with different affi n-
ity and modulate the activation and inhibition of NK cells and
CD8+ T cells and, especially, the inhibitory receptor KIR3DL1
binds HLA-Bw4 of alleles including HLA-B27. No association
was detected for SNPs located around the KIR gene family but
one SNP, rs17771961, located downstream of KIR3DL1, tested in
combination with its natural ligand HLA-Bw4I80, was associated
with AS. We also found a correlation between rs17771961-C and
KIR3DL1*004, compatible with the protective effect in AS sus-
ceptibility of this allele in the presence of HLA-Bw4I80.8 These
observations support the hypothesis that KIR3DL1 synergises
with HLA-Bw4I80 by infl uencing the balance between activating
and inhibition for NK and/or CD8+ T cells.
In summary, our results indicate that regions within chromo-
some 19q are associated with AS. These regions are near the
CNOT3 gene, which could be involved in the pathogenesis of
AS. Further research on different ethnic backgrounds and large
population cohorts are needed to confi rm these fi ndings.
Competing interests None.
Funding This work was supported by FIS 08/0566, FICYT PC10-70 and
ETORTEK/2005–2010 grants.
Ethics approval Hospital Universitario Central de Asturias.
Provenance and peer review Not commissioned; externally peer reviewed.
Author affi liations 1Department of Immunology, Hospital Universitario Central de
Asturias, Oviedo, Spain
2Genome Analysis Platform, Functional Genomics Unit, CIC bioGUNE, Bizkaia
Technology Park, Derio, Spain
3Institute for Molecular and Cell Biology, University of Porto, Porto, Portugal
4Department of Molecular and Human Genetics, College of Medicine, Florida
International University, Miami, Florida, USA
5CEDOC, Faculdade de Ciências Médicas da Universidade Nova de Lisboa, Lisboa, Portugal
6CHLO, Department of Rheumatology, Hospital de Egas Moniz, Lisboa, Portugal
7Department of Rheumatology, H U Puerta de Hierro, Madrid, Spain
8Hospital Universitario “Reina Sofía”, IMIBIC, Universidad de Córdoba, Córdoba, Spain
9Rheumatology Department, Hospital Universitario Central de Asturias, Oviedo, Spain
10Centro de Histocompatibilidade do Norte, Porto, Portugal
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Table 2 Association analysis of replicated SNPs as single markers in cohorts 1, 2, 3 and joint analysis (PLINK)19
SNP information Cohort 1 Cohort 2 Cohort 3 Joint analysis
SNP Position
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symbol Location A1
MAF AS
patients
MAF
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MAF AS
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MAF
controls p Value
MAF AS
patients
MAF
controls p Value
MAF AS
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rs17771961
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OR (95% CI) 2.07 (0.96 to 4.45) 0.48 (0.22 to 1.04) 2.42 (1.03 to 5.71) 0.41 (0.17 to 0.97) – – – –
Numbers of individuals and corresponding percentages (in parentheses) that presented with the corresponding allele or genotype are described. The allele frequency in the absence of
Bw4I80 was determined in 195 controls and 162 patients, and the allele frequency in the presence of Bw4I80 was determined in 79 controls and 51 patients.
p Values were determined by two-tailed Fisher exact test.
AS, ankylosing spondylitis; NS, not signifi cant.
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doi: 10.1136/annrheumdis-2011-200661
31, 2012 2012 71: 714-717 originally published online JanuaryAnn Rheum Dis
Roberto Díaz-Peña, Ana M Aransay, Beatriz Suárez-Álvarez, et al.
polymorphism with ankylosing spondylitis
identifies an association of a CNOT3
within the 19q13 chromosome region
A high density SNP genotyping approach
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