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

  • Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS)
  • Comprehensive Health Research Center

Abstract and Figures

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.
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Clinical and epidemiological research
Ann Rheum Dis 2012;71:714–717. doi:10.1136/annrheumdis-2011-200661714
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.
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
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).
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 (
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;
Received 24 August 2011
Accepted 11 December 2011
Published Online First
31 January 2012
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
16_annrheumdis-2011-200661.indd 71416_annrheumdis-2011-200661.indd 714 3/30/2012 3:18:00 PM3/30/2012 3:18:00 PM on November 13, 2012 - Published by ard.bmj.comDownloaded from
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
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 (;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.
SNP genotyping
Seventeen SNPs with putative associations with AS were identi-
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,
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|
CDC42EP5, LAIR2 rs12985351|rs8111398|rs7251986|rs10418813|rs8111811|rs8100732|
CDC42EP5, LAIR2 rs12985351|rs8111398|rs7251986|rs10418813|rs8111811|rs8100732|
16_annrheumdis-2011-200661.indd 71516_annrheumdis-2011-200661.indd 715 3/30/2012 3:18:01 PM3/30/2012 3:18:01 PM on November 13, 2012 - Published by ard.bmj.comDownloaded from
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).
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
symbol Location A1
controls p Value
controls p Value
controls p Value
controls p Value
rs1055234 59349813 CNOT3 Intron C 0.412 0.531 1.42×10−4 0.465 0.520 0.039 0.450 0.523 0.054 0.447 0.525 9.72×10−6
rs8111398 59694904 LAIR2 Flanking_5UTR G 0.392 0.493 9.45×10−4 0.442 0.458 0.531 0.500 0.451 0.204 0.437 0.469 0.06
rs2287828 59705936 LAIR2 5UTR A 0.019 0.013 0.503 0.015 0.039 0.002 0.007 0.012 0.504 0.014 0.023 0.07
rs4591276 59721179 LAIR2 Flanking_3UTR C 0.029 0.010 0.022 0.016 0.038 0.007 0.057 0.023 0.017 0.027 0.024 0.547
A1, minor allele nucleotide; AS, ankylosing spondylitis; MAF, minor allele frequency; SNP, single nucleotide polymorphism.
Table 3 Allelic and genotypic frequencies of the single nucleotide polymorphism rs17771961 and HLA-Bw4I80 in patients with AS and healthy
controls (all HLA-B27-positive) in cohort 1
Bw4I80 present Bw4I80 absent
Allele frequency GG vs CG+CC Allele frequency GG vs CG+CC
Controls 129 (82) 29 (18) 52 (66) 27 (34) 314 (80) 76 (20) 128 (66) 67 (34)
AS patients 92 (90) 10 (10) 42 (82) 9 (18) 270 (83) 54 (17) 113 (70) 49 (30)
p Value 0.07 0.04 0.04 0.04 NS NS NS NS
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.
16_annrheumdis-2011-200661.indd 71616_annrheumdis-2011-200661.indd 716 3/30/2012 3:18:01 PM3/30/2012 3:18:01 PM on November 13, 2012 - Published by ard.bmj.comDownloaded from
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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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... Several other diverse diseases have been associated with mutations in the CNOT3 gene. A link has been established between CNOT3 and susceptibility to ankylosing spondylitis [403]. CNOT3 was identified as an oncogenic driver gene mutated in 7 out of 89 adult T-ALLs; its knockdown causes tumors in a sensitized Drosophila melanogaster model [404]. ...
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... A microarray analysis suggests that the expression of cytoplasm organization-, autophagy-, cell death-and cell proliferation-related genes are up-regulated in CNOT3-depleted mouse embryonic fibroblasts (MEFs) [11]. Dysregulation of CNOT3 expression is found to be relevant to human diseases such as ankylosing spondylitis [12], retinitis pigmentosa [13] and even cancers [6]. CNOT3 is identified as a tumor suppressor and its mutation is found in T cell acute lymphoblastic leukemia [14]. ...
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Chemotherapeutic resistance always results in poor clinical outcomes of cancer patients and its intricate mechanisms are large obstacles in overcoming drug resistance. CCR4-NOT transcription complex subunit 3 (CNOT3), a post-translational regulator, is suggested to be involved in cancer development and progression. However, its role in chemotherapeutic resistance is not well understood. In this study, after screening the CNOT3 mRNA in a cancer microarray database called Oncomine and examining the expression levels of CNOT3 mRNA in normal tissues and lung cancer tissues, we found that CNOT3 was up-regulated in lung cancer tissues. Besides, its high-expression was associated with poor prognosis of lung cancer patients. We also found higher expression level of CNOT3 and lower expression level of receptor-interacting protein kinase 3 (RIPK3) in cisplatin-resistant A549 (A549/DDP) cells, and knocking down CNOT3 expression could sensitize A549/DDP cells to cisplatin-induced apoptosis. We demonstrated that CNOT3 depletion up-regulated the expression level of RIPK3 and the enhanced apoptosis was mediated by the elevated RIPK3 to further trigger Caspase 8 activation. Taken together, our results reveal a role of CNOT3 in cisplatin resistance of lung cancer and provide a potential target for lung cancer therapy.
... We examined the distribution of HLA-B alleles in patients with AS and control subjects in a Spanish population previously described by our group 5,6 . A total of 1300 individuals were studied as 3 distinct cohorts. ...
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To the Editor: Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease that primarily involves the axial skeleton and the sacroiliac joints. The susceptibility to AS is almost entirely attributable to genetic factors; their heritability is estimated at around 90%1. The MHC class I is the most significant genetic region for the disease, and most of its genetic association is driven by HLA-B272. There is evidence suggesting that the presence of other HLA-B alleles, including B*14, B*38, B*39, B*40, and B*52, may also confer greater susceptibility to AS3. A recent study examined HLA loci associations of AS genotyping of 7264 MHC single-nucleotide polymorphisms (SNP), in 9069 affected individuals and 13,578 controls4. Genotyping data were followed by imputation of SNP, classical HLA alleles, and residues at polymorphic amino acid positions of HLA proteins. In addition to HLA-B*27, the association was identified with B*13:02, B*40:01, B*40:02, B*47:01, and HLA-B*51:01 (risk alleles); and B*07:02 and B*57:01 … Address correspondence to C. Lopez-Larrea, Department of Immunology, Hospital Universitario Central de Asturias, C/Celestino Villamil s/n, 33006-Oviedo, Spain. E-mail: inmuno{at}
... From eight LAIR2 SNPs that were investigated, only rs2287828 is associated with PF in individual SNP analyses (Table 1). It is located in the 5′UTR region of LAIR2 and it is also associated with susceptibility to ankylosing spondylitis (Díaz-Peña et al. 2012). Our analyses revealed statistical evidence of SNP-SNP interactions in LAIR2: we found rs2287828 to interact with rs2042287 and rs114834145, while rs114834145 also interacts with rs2277974 (Table 2). ...
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The leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) is a collagen-binding inhibitory receptor important for the regulation of immune responses, expressed on the majority of peripheral blood mononuclear cells (PBMC). LAIR-2 is a soluble homolog that antagonizes LAIR-1 inhibitory function by binding the same ligands. We sought to investigate whether LAIR1 and LAIR2 single nucleotide polymorphisms (SNP) are associated with differential mRNA expression levels. We analyzed 14 SNPs of LAIR1 (6) and LAIR2 (8) by mass spectrometry-based genotyping and extracted mRNA from PBMC of 177 healthy subjects, followed by quantitative assays. Four SNPs of LAIR1 and two SNPs of LAIR2 mark differential mRNA levels in healthy individuals. To verify the biological relevance of these findings, we analyzed additional 515 individuals (282 patients and 233 controls) to check if LAIR1 and LAIR2 differential mRNA expression could be related to susceptibility to pemphigus foliaceus (PF), an autoimmune blistering skin disease endemic in Brazil. Two LAIR1 variants (rs56802430 G, OR = 1.52, p = 0.0329; rs11084332 C, OR = 0.57, p = 0.0022) and one LAIR2 (rs2287828 T+, OR = 1.9, p = 0.0097) contribute to differential susceptibility to PF. Furthermore, we demonstrate interactions among four LAIR2 SNPs (rs2042287, rs2287828, rs2277974 and rs114834145). A haplotype harboring these SNPs is strongly associated with higher LAIR2 mRNA levels (4.5-fold, p = 0.0069) and with higher susceptibility to PF (OR = 4.02, p = 0.0008). We suggest that LAIR1 and LAIR2 genetic variants are associated with regulation of gene expression and variable PF susceptibility, and show indirect association of LAIR2 differential mRNA expression with PF pathogenesis. Our data demonstrate how this relatively unknown disease can add invaluable knowledge regarding the role of LAIR1 and LAIR2 in immune responses.
... Finally, several reports suggest that dysregulation of CNOT3 expression is relevant to a wide-range of human diseases. SNP analysis revealed that there is a significant association between CNOT3 polymorphism and cardiac repolarization duration (Neely et al., 2010) or susceptibility to ankylosing spondylitis (Díaz-Peña et al., 2012). In addition, CNOT3 was identified as a modifier of mutations in the causative gene of retinitis pigmentosa, PRPF31, which prevents the manifestation of this disease (Venturini et al., 2012). ...
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The carbon catabolite repression 4 (CCR4)-negative on TATA-less (NOT) complex serves as one of the major deadenylases of eukaryotes. Although it was originally identified and characterized in yeast, recent studies have revealed that the CCR4-NOT complex also exerts important functions in mammals, -including humans. However, there are some differences in the composition and functions of the CCR4-NOT complex between mammals and yeast. It is noteworthy that each subunit of the CCR4-NOT complex has unique, multifunctional roles and is responsible for various physiological phenomena. This heterogeneity and versatility of the CCR4-NOT complex makes an overall understanding of this complex difficult. Here, we describe the functions of each subunit of the mammalian CCR4-NOT complex and discuss the molecular mechanisms by which it regulates homeostasis in mammals. Furthermore, a possible link between the disruption of the CCR4-NOT complex and various diseases will be discussed. Finally, we propose that the analysis of mice with each CCR4-NOT subunit knocked out is an effective strategy for clarifying its complicated functions and networks in mammals.
... Importantly, a role for LAIR-2 in systemic autoimmunity is suggested by the observation of increased LAIR-2 levels in synovial fluid of patients with rheumatoid arthritis [6], [11] and ankylosing spondylitis [12]. However, data concerning the possible role of LAIR-2 and LAIR molecules/collagen interactions in organ-specific autoimmunity are lacking. ...
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Leukocyte-associated Ig-like receptor (LAIR) is a small family-receptor able to inhibit immune cell function via collagen binding. It exists as both membrane-bound and soluble forms. LAIR-1 functions as an inhibitory receptor on natural killer cells, T lymphocytes and monocytes. In addition to LAIR-1, the human genome encodes LAIR-2, a soluble homolog. Several studies have focused on LAIR-1, whereas few investigations concentrate on the expression and function of LAIR-2. We demonstrate the presence of high LAIR-2 levels in 74/80 sera from patients with autoimmune thyroid diseases (both Graves' disease and autoimmune thyroiditis). LAIR-2 levels seemed not to be related to specific clinical manifestations, such as thyroid functions (hypo- or hyperthyroidism), or specific clinical features (such as ophtalmopathy). In addition, serum LAIR-2 is able, in vitro, to bind its natural ligand, collagen. Since LAIR-2 has been found to have higher affinity for collagens than LAIR-1 did, we hypothesize a potential regulating capability of serum LAIR-2 in finally regulating the inhibitory capability of LAIR-1.
... In this regard, several findings indicate that, against the genetic background of HLA-B27, variation at the killer immunoglobulin-like receptors and their corresponding specific HLA-B and HLA-C ligands may generate compound genotypes that yield different levels of inhibition or activation in NK cells and T cells, and thereby recognize or lyse targets in immune responses, contributing to the pathogenesis of AS (58,59). Recently, we have reported results supporting the hypothesis that KIR3DL1 synergizes with HLA-B27 by influencing this balance between activating and inhibitory signals (60). Further functional studies of the role of NK cells are essential to define their role in AS. ...
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Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease that primarily involves the axial skeleton and the sacroiliac joint, but may also affect peripheral joints and entheses. AS susceptibility is clearly attributable to genetic factors and the link between human leukocyte antigen (HLA)-B27 and AS is the strongest association between an HLA class I molecule and a disease. However, there is evidence for the involvement of other, non-B27 factors within the major histocompatibility complex (MHC) in AS susceptibility. MHC class I is clearly the most significant genetic region for the disease, although most of the genetic association of this region is driven by HLA-B27. Moreover, several studies have investigated the MHC class II region and its association with AS. This review summarizes the current findings concerning the MHC genetics of the disease, focusing in particular on the associations of HLA with AS found in different ethnic populations throughout the world, and the possible mechanisms underlying them.
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The genetic and epigenetic architecture of clinical and subclinical hypothyroidism remains unclear. We investigated the impact of long noncoding RNA (LncRNA)-PAX8-AS1 and LAIR-2 genetic variants on the susceptibility to clinical and subclinical hypothyroidism, their influence on LncRNA-PAX8-AS1 and LAIR-2 expression and their potential as hypothyroid biomarkers. Hundred clinical hypothyroid patients, 110 subclinical hypothyroid patients, and 95 healthy controls were enrolled. Gene expression analysis and genotyping were performed by qPCR. LAIR-2 protein, a proinflammatory mediator, was tested by ELISA. Serum LncRNA-PAX8-AS1 was downregulated, whereas LAIR-2 mRNA and protein levels were upregulated in clinical and subclinical hypothyroid patients compared to healthy controls. LncRNA-PAX8-AS1 rs4848320 and rs1110839 were associated with increased risk of clinical hypothyroidism. Interestingly, both SNPs were associated with differential expression of serum LncRNA-PAX8-AS1 among clinical hypothyroid patients. LAIR-2 rs2287828 was associated with elevated risk of both clinical and subclinical hypothyroidism. Harboring the rs2287828 T allele augmented the LAIR-2 mRNA expression among clinical hypothyroid patients, while elevated both LAIR-2 mRNA and protein levels in subclinical hypothyroid patients. The rs4848320-rs1110839-rs2287828 TTT, CTT, and CGT haplotypes were associated with increased hypothyroid risk. Surprisingly, serum LncRNA-PAX8-AS1 and LAIR-2 mRNA expression demonstrated superior diagnostic accuracy for clinical hypothyroidism and turned out as independent predictors in the multivariate analysis. Conclusively, LncRNA-PAX8-AS1 and LAIR-2 genetic variants are novel genetic biomarkers of hypothyroidism that could alter the LncRNA-PAX8-AS1 and LAIR-2 expression. LncRNA-PAX8-AS1 and LAIR-2 expression profiles have the potential as effective diagnostic and prognostic indicators of hypothyroidism.
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The Ccr4-Not complex is a conserved multi-subunit complex in eukaryotes that carries 2 enzymatic activities: ubiquitination mediated by the Not4 RING E3 ligase and deadenylation mediated by the Ccr4 and Caf1 orthologs. This complex has been implicated in all aspects of the mRNA life cycle, from synthesis of mRNAs in the nucleus to their degradation in the cytoplasm. More recently the complex has also been implicated in many aspects of the life cycle of proteins, from quality control during synthesis of peptides, to assembly of protein complexes and protein degradation. Consistently, the Ccr4-Not complex is found both in the nucleus, where it is connected to transcribing ORFs, and in the cytoplasm, where it was revealed both associated with translating ribosomes and in RNA processing bodies. This functional and physical presence of the Ccr4-Not complex at all stages of gene expression raises the question of its fundamental role. This review will summarize recent evidence designing the Not3/5 module of the Ccr4-Not complex as a functional module involved in coordination of the regulation of gene expression between the nucleus and the cytoplasm.
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Killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) loci are both highly polymorphic. The aim of this study was to perform a KIR genotype analysis and examine, in concert with HLA-B27 genotypes, their influence on ankylosing spondylitis (AS) susceptibility in two Asian populations (one from China, 42 patients and 30 controls, and another from Thailand, 30 patients and 16 controls). In the Chinese population, we observed an increase of KIR3DS1, KIR2DS5, and KIR2DL5 gene frequencies in AS patients (p(c) < 0.005, p(c) < 0.001, and p(c) < 0.01, respectively). A similar increase was reported in the Thai population: KIR3DS1, KIR2DS5, and KIR2DL5 gene frequencies were higher in AS (p(c) < 0.05, p < 0.05, and p(c) < 0.05, respectively). Upon analyzing the KIR3DL1/3DS1 genotypes, we determined significant differences in both populations. The frequency of 3DL1/3DL1 was decreased in AS (p(c) < 0.005 and p(c) < 0.05 in the Chinese and Thai populations, respectively), whereas 3DL1/3DS1 demonstrated an increased frequency in AS (p(c) < 0.005 in the Chinese population and p(c) < 0.05 in the Thai population).
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To identify susceptibility loci for ankylosing spondylitis, we undertook a genome-wide association study in 2,053 unrelated ankylosing spondylitis cases among people of European descent and 5,140 ethnically matched controls, with replication in an independent cohort of 898 ankylosing spondylitis cases and 1,518 controls. Cases were genotyped with Illumina HumHap370 genotyping chips. In addition to strong association with the major histocompatibility complex (MHC; P < 10(-800)), we found association with SNPs in two gene deserts at 2p15 (rs10865331; combined P = 1.9 x 10(-19)) and 21q22 (rs2242944; P = 8.3 x 10(-20)), as well as in the genes ANTXR2 (rs4333130; P = 9.3 x 10(-8)) and IL1R2 (rs2310173; P = 4.8 x 10(-7)). We also replicated previously reported associations at IL23R (rs11209026; P = 9.1 x 10(-14)) and ERAP1 (rs27434; P = 5.3 x 10(-12)). This study reports four genetic loci associated with ankylosing spondylitis risk and identifies a major role for the interleukin (IL)-23 and IL-1 cytokine pathways in disease susceptibility.
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To replicate and refine the reported association of ankylosing spondylitis (AS) with two non-synonymous single nucleotide polymorphisms (nsSNPs) on chromosome 16q22.1. Firstly, 730 independent UK patients with AS were genotyped for rs9939768 and rs6979 and allele frequencies were compared with 2879 previously typed historic disease controls. Secondly, the two data sets were combined in meta-analyses. Finally, 5 tagging SNPs, located between rs9939768 and rs6979, were analysed in 1604 cases and 1020 controls. The association of rs6979 with AS was replicated, p=0.03, OR=1.14 (95% CI 1.01 to 1.28), and a trend for association with rs9939768 detected, p=0.06, OR=1.25 (95% CI 0.99 to 1.57). Meta-analyses revealed association of both SNPs with AS, p=0.0008, OR=1.31 (95% CI 1.12 to 1.54) and p=0.0009, OR=1.15 (95% CI 1.06 to 1.23) for rs9939768 and rs6979, respectively. New associations with rs9033 and rs868213 (p=0.00002, OR=1.23 (95% CI 1.12 to 1.36) and p=0.00002 OR=1.45 (95% CI 1.22 to 1.72), respectively, were identified. The region on chromosome 16 that has been replicated in the present work is interesting as the highly plausible candidate gene, tumour necrosis factor receptor type 1 (TNFR1)-associated death domain (TRADD), is located between rs9033 and rs868213. It will require additional work to identify the primary genetic association(s) with AS.
Inherited genetic variation has a critical but as yet largely uncharacterized role in human disease. Here we report a public database of common variation in the human genome: more than one million single nucleotide polymorphisms (SNPs) for which accurate and complete genotypes have been obtained in 269 DNA samples from four populations, including ten 500-kilobase regions in which essentially all information about common DNA variation has been extracted. These data document the generality of recombination hotspots, a block-like structure of linkage disequilibrium and low haplotype diversity, leading to substantial correlations of SNPs with many of their neighbours. We show how the HapMap resource can guide the design and analysis of genetic association studies, shed light on structural variation and recombination, and identify loci that may have been subject to natural selection during human evolution.
The killer cell immunoglobulin-like receptors (KIRs) form a group of regulatory molecules that specifically recognize HLA class I molecules. The aim of this study was to analyze the possible contribution of the KIR3DL1 and KIR3DS1 alleles, in addition to HLA-B27, in the susceptibility to ankylosing spondylitis (AS) in a population of individuals from Spain. We genotyped the KIR3DS1 and KIR3DL1 alleles in 2 cohorts of patients with AS and healthy control subjects. In total, 270 patients with AS and 435 healthy, HLA-B27-positive matched control subjects from Spain were enrolled. The KIR3DS1 and KIR3DL1 alleles were genotyped by sequence-specific oligonucleotide probe-polymerase chain reaction, and their association with AS was analyzed. All individuals were typed for HLA-B. The KIR3DS1*013 allele was solely responsible for the increased frequency of the activator receptor KIR3DS1 in patients with AS compared with healthy HLA-B27-positive control subjects (35.7% versus 22.6% [P = 10(-6)], odds ratio 1.90, 95% confidence interval 1.50-2.40). The increased frequency of the KIR3DS1*013 allele in patients with AS was independent of the presence or absence of the HLA-Bw4I80 epitope. Moreover, the null allele KIR3DL1*004 was a unique inhibitory KIR3DL1 allele that showed a negative association with AS in the presence of HLA-Bw4I80. The increased frequency of the KIR3DS1*013 allele in patients with AS is clearly independent of the presence of the HLA-Bw4I80 epitope, whereas the presence of inhibitory allotypes such as KIR3DL1*004 demonstrated a negative association in patients with AS in the presence of HLA-Bw4I80. As a consequence, the influence of KIR genotypes on AS susceptibility would be mediated by a general imbalance between protective/inhibitory and risk/activating allotypes.
Cellular activity of natural killer cells (NK cells) is defined by the balance between activating and inhibitory signals coming from their receptors. With respect to this response, killer immunoglobulin-like receptors (KIR) are unique because of their diversity and capacity to recognize specific human leukocyte antigen (HLA) class I allotypes. Up to the present few studies have experimentally been developed concerning the role of KIR genes in spondyloarthropathies (SpA) and its clear relationship with HLA-B27. However, the role of the HLA-B27 heavy chain homodimers and their possible recognition by KIR receptors in the pathogenesis of spondylarthritides has been studied. Moreover, it has been suggested that NK cells and their receptors could play a role in ankylosing spondylitis (AS) development. Several association studies based on a model in which KIRs synergize with HLAs have also been published. This interaction may generate compound genotypes which provide different levels of activation or inhibition. Furthermore, some of these have been associated with certain SpA, such as ankylosing spondylitis (AS) and psoriatic arthritis (PsA).
Using a standard microcytotoxicity technique of tissue typing, the HL-A 27 antigen was identified in 72 out of 75 patients with classical ankylosing spondylitis and in 3 out of 75 controls. The same antigen was found in 31 out of 60 first-degree relatives.
The New York and the Rome diagnostic criteria for ankylosing spondylitis (AS) and the clinical history screening test for AS were evaluated in relatives of AS patients and in population control subjects. The New York criterion of pain in the (dorso) lumbar spine lacks specificity, and the chest expansion criterion is too insensitive. The Rome criterion of low back pain for more than 3 months is very useful. Our study showed the clinical history screening test for AS to be moderately sensitive, but it might be better in clinical practice. As a modification of the New York criteria, substitution of the Rome pain criterion for the New York pain criterion is proposed.
TATA-binding protein (TBP) forms complexes with various nuclear proteins and plays roles in all eukaryotic transcription. We previously identified TBP-interacting protein 120 (TIP120) from rat liver. TIP120 stimulates in vitro transcription generally. Homologs of TIP120 exist in various higher eukaryotes including D. melanogaster, C. elegans, and A. thaliana. Here, we isolated cDNA of a novel rat TIP120-like protein, named TIP120B. Rat TIP120B was composed of 1,235 amino acids and was 60% identical to the original TIP120 (re-named TIP120A). However, TIP120B gene was expressed specifically in the muscle tissues, which was contrary to the ubiquitous expression of TIP120A. Moreover, TIP120B protein was observed exclusively in the muscle tissues. TIP120B is therefore suggested to be a muscle-specific protein. Northern blot analysis of the mouse embryo revealed that the expression of TIP120B was temporarily increased during the embryogenesis, whereas TIP120A maintained a constant expression level. Pull-down assay using GST-fused TBP demonstrated that TBP specifically associated with TIP120B in the nuclear extract. These results indicate that TIP120B is a muscle-specific TIP120 family protein and can also interact with TBP. TIP120B is supposed to have a specific role in muscle tissues, which may be diffrerent from that of TIP120A.