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Research Article
Evaluation of HLA-G 14 bp Ins/Del and +3142G>C
Polymorphism with Susceptibility and Early Disease Activity in
Rheumatoid Arthritis
Mohammad Hashemi,1,2 Mahnaz Sandoughi,3Seyed Amirhossein Fazeli,3
Gholamreza Bahari,2Maryam Rezaei,2and Zahra Zakeri4
1Cellular and Molecular Research Center, Zahedan University of Medical Sciences, Zahedan 98167-43181, Iran
2Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan 98167-43181, Iran
3Department of Internal Medicine, School of Medicine, Zahedan University of Medical Sciences, Zahedan 98167-43181, Iran
4Department of Internal Medicine, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran 19857-17443, Iran
Correspondence should be addressed to Zahra Zakeri; zah zakeri@yahoo.com
Received April ; Revised June ; Accepted July
Academic Editor: Maja Krajinovic
Copyright © Mohammad Hashemi et al. is is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Purpose/Background. Mounting evidence designates that HLA-G plays a role in the regulation of inammatory processes and
autoimmune diseases. ere arecontroversial reports concerning the impact of HLA-G gene polymorphism on rheumatoid arthritis
(RA). is study was aimed at examining the impact of bp ins/del and +G>C polymorphism with susceptibility and early
disease activity in RA patients in a sample of the Iranian population. Methods. is case-control study was done on patients
with RA and healthy subjects. e HLA-G rs (+G>C) and rs ( bp ins/del) variants were genotype by
polymerase chain reaction-restriction fragment length polymorphism (PCR-RFP) and PCR method, respectively. Results.eHLA-
G+G>C polymorphism signicantly decreased the risk of RA in codominant (OR = ., % CI = .–., 𝑝 = 0.038,GC
versus GG; OR = ., % CI = .–., 𝑝 = 0.034, CC versus GG), dominant (OR = ., % CI = .–., 𝑝 = 0.011,GC+
CC versus GG), and allele (OR = ., % CI = .–., 𝑝 = 0.004, C versus G) inheritance models tested. Our nding did not
support an association between HLA-G bp ins/del variant and risk/protection of RA. In addition, no signicant association was
found between the polymorphism and early disease activity. Conclusion. In summary, our results showed that HLA-G +G>C
gene polymorphism signicantly decreased the risk of RA in a sample of the Iranian population.
1. Introduction
Rheumatoid arthritis (RA) is the most common autoimmune
disease of unknown etiology aecting approximately .–%
of the human population worldwide [, ]. e disease is -
times more common in females than in males. It has been
proposed that both genetic and environmental factors are
involved in the expression and complications of the disease
[–].Geneticfactorsareassumedtocontributetoupto%
oftheriskofdevelopingRA[].
Human leucocyte antigen-G (HLA-G), a nonclassical
major HLA class Ib molecule, may suppress functions of
natural killer (NK) cells, CD+, CD+ lymphocytes, and den-
dritic cell [–]. HLA-G protein potentially exists as seven
isoforms including four membrane-bound (HLA-G, -G,
-G, and -G) as well as three secreted soluble (HLA-G,
-G, and -G) proteins [].
HLA-G gene, which is located on chromosome
(p.), contains a bp insertion (ins)/deletion (del) and a
+G>C(rs)polymorphismin
-untranslated
region (UTR) of HLA-G. HLA-G expression rate and
plasmalevelareinuencedbypolymorphisminthepromoter
region as well as -untranslated region (UTR) variants [–
].
Abpins/delpolymorphisminexoninthe
UTR of
HLA-G was found to be associated with the stability and splic-
ing patterns of HLA-G mRNA isoforms. e homozygous
deletion of bp confers a more stable mRNA as compared
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Advances in Medicine
Volume 2016, Article ID 4985745, 7 pages
http://dx.doi.org/10.1155/2016/4985745
Advances in Medicine
to the homozygous insertion genotype [, , ]. Low levels
of membrane bound and sHLA-G levels are associated with
the ins allele [].
+G>CpolymorphisminuencestheanityofHLA-
G mRNA targeted by dierent microRNAs as demonstrated
by an in silico study []. +G allele has a binding site
with higher anity for miR-a, miR-b, and miR-
downregulating the expression of HLA-G [, ].
e common polymorphism of the HLA-G seems to
aectitslevelofexpressionandmayhaveanimpacton
disease susceptibility in autoimmune disorders. It has been
reported that plasma soluble HLA-G (sHLA-G) levels were
lower in RA patients than in controls [].
Several studies investigated the impact of common poly-
morphism of HLA-G (+G>Candbpins/del)onRA
risk in various population, but the ndings have been con-
troversial [–]. erefore, the present study was aimed at
examining whether rs (+G>C) and rs
( bp ins/del) polymorphism in the HLA-G gene were
associated with susceptibility to RA in a sample of Iranian
population.
2. Material and Methods
2.1. Patients. Atotalofsubjectsincludingpatients
with RA fullling the American College of Rheuma-
tology/European League Against Rheumatism for RA []
and unrelated healthy subjects were enrolled in the
study. e cases were selected from RA patients admitted
to the Rheumatology Clinic of university-aliated hospital
(Ali-Ebne-Abitaleb Hospital, Zahedan, Iran). e control
group consisted of whose age and sex matched healthy
individualswithnoclinicalsymptomsorfamilyhistoriesof
RA, and they were unrelated to RA patients, had no known
autoimmune diseases, and were from the same geographical
origin as the patients with RA (Zahedan, Iran). e project
was approved by local ethics committee of Zahedan Univer-
sity of Medical Sciences and informed consent was obtained
from all participants. Genomic DNA was extracted from
peripheral blood samples using salting out method as
described previously [].
Among all the participant patients, early RA subjects
who were symptomatic for ≤yearenrolledforsubsequent
follow-upstudy.Allthepatientswereonstandardtherapeutic
regimen. e disease activity was determined by disease
activity score (DAS-) at the beginning and the end of
the follow-up study (at least months) by the same specialist
rheumatologist. At the end of the study, the patients were
stratied into remitting (DAS- <.) and nonremitting
(DAS- ≥.) patients.
Genotyping of HLA-G rs (+G>C) variant
was performed by PCR-RFLP methods. e set of forward
and reverse primers were -CATGCTGAACTGCATTCC-
TTCC-and -CTGGTGGGACAAGGTTCTACTG-
[]. Amplication was done with an initial denaturation step
at ∘Cformin,followedbycyclesofsat
∘C, s
at ∘C, and s at ∘Cwithanalstepat
∘Cformin.
𝜇L of PCR products was digested with BaeGI restriction
enzyme (Fermentas). G allele digested and produced bp
M1 2 3 45
500 bp
400 bp
300 bp
200 bp
100 bp
F : Photograph of the PCR products of HLA-G +G>C
polymorphism by polymerase chain reaction-restriction fragment
length polymorphism method (PCR-RFLP). G allele digested by
BaeGI restriction enzyme and produced bp and bp while C
alleleundigestedbp.M:DNAMarker;Lanesand:GC;Lanes
and : GG; Lane : CC.
M1234567
500 bp
300 bp
200 bp
100 bp
F : Photograph of the PCR products of HLA-G bp ins/del
polymorphism by polymerase chain reaction (PCR). Product sizes
were bp for del and bp for ins allele. M: DNA Marker; Lanes
, , and : ins/ins; Lanes and : ins/del; Lanes and : del/del.
and bp (digested), while C allele undigested and produced
bp (Figure ).
Genotyping of HLA-G rs ( bp ins/del) variant
wasdonebypolymerasechainreaction[].eforwardand
reverse primers were -TCACCCCTCACTGTGACTGATA-
and -GCACAAAGAGGAGTCAGGGTT-,respec-
tively. In each . mL PCR reaction tube, 𝜇Lofgenomic
DNA (∼ ng/mL), 𝜇Lofeachprimer(𝜇M), 𝜇Lofx
Prime Taq Premix (Genet Bio, Korea), and 𝜇L ddH2Owere
added. e PCR cycling conditions were as follows: an initial
denaturation step of min at ∘C followed by cycles of
s at ∘C, annealing at ∘C for s, and extension at ∘C
for s, with nal extension at ∘Cformin.ePCR
products were separated by electrophoresis in % agarose
gels and observed under ultraviolet light. Product sizes were
bpfordelandbpforinsallele(Figure).
2.2. Statistical Analysis. Statistical analysis of the data was
done using statistical soware package SPSS soware.
Independent sample 𝑡-test for continuous data and 𝜒2test
for categorical data were used. e associations between
Advances in Medicine
T : Association of HLA-G polymorphisms and the risk of RA.
HLA-G polymorphisms Case
𝑛(%)
Control
𝑛(%) OR (% CI) 𝑝𝑝
c
14-bp ins/del (rs66554220)
Codominant
Ins/ins (.) (.) . —
Ins/del (.) (.) . (.–.) . .
Del/del (.) (.) . (.–.) . .
Dominant
Ins/ins (.) (.) .
Ins/del + del/del (.) (.) . (.–.) . .
Recessive
Ins/ins + ins/del (.) (.) .
Del/del (.) (.) . (.–.) . .
Allele
Ins (.) (.) . —
Del (.) (.) . (.–.) . .
+3142G>C(rs1063320)
Codominant
GG (.) (.) . —
GC (.) (.) . (.–.) . .
CC (.) (.) . (.–.) . .
Dominant
GG (.) (.) .
GC + CC (.) (.) . (.–.) . .
Recessive
GG + GC (.) (.) .
CC (.) (.) . (.–.) . .
Allele
G (.) (.) . —
C (.) (.) . (.–.) . .
𝑝c: Bonferroni-corrected 𝑝.
genotypes of HLA-G geneandRAwereassessedbycomput-
ing the odds ratio (OR) and % condence intervals (%
CI) from logistic regression analyses. Haplotype analysis
was performed using SNPStats soware (a web tool for the
analysis of association studies). 𝑝value less than . was
considered statistically signicant. e Bonferroni correction
was applied by multiplying 𝑝values by the number of SNPs
analyzed.
3. Results
In this study, we recruited RA patients ( female and
male; mean age 45.3 ± 14.1 years) and unrelated healthy
subjects ( female and male; mean age: 46.1 ± 12.3
years). ere was no signicant dierence between the groups
concerning sex and age (𝑝 = 0.815 and 𝑝 = 0.465,resp.).
e genotype and allele frequencies of HLA-G polymor-
phism in RA patients and in controls are shown in Table .
HLA-G rs (+G>C) variant decreased the risk of
RA in codominant (OR = ., % CI = .–., 𝑝 = 0.038,
GC versus GG; OR = ., % CI = .–., 𝑝 = 0.034,CC
versus GG) and dominant (OR = ., % CI = .–.,
𝑝 = 0.011, GC + CC versus GG) tested inheritance models.
HLA-G rs C allele signicantly decreased the risk of
RA (OR = ., % CI = .–., 𝑝 = 0.004)comparedto
Gallele.
Overall, both chi-square comparison and logistic regres-
sion analysis (which was calculated in each model of
inheritance) did not reveal an association between HLA-G
rs polymorphism and RA risk (Table ).
In the combined analysis of two HLA-G variants, subjects
carrying deldel/GG genotypes had signicantly higher risk of
RA than bp deldel/+GG (Table ).
Haplotype analysis is shown in Table . Haplotype
+G/ bp del signicantly increased the risk of RA (OR
= ., % CI = .–., 𝑝 = 0.012), while +C/ bp
del decreased the risk of RA (OR = ., % CI = .–.,
𝑝 = 0.019) compared to +G/ bp ins.
Advances in Medicine
T : Interaction of bp ins/del and +G>C polymorphism of HLA-G gene on rheumatoid arthritis (RA) risk.
bp ins/del +G>CRA cases
𝑛(%)
Controls
𝑛(%) OR (% CI) 𝑝𝑝
c
Ins/ins GG (.) (.) . — —
Ins/del GG (.) (.) . (.–.) . .
Del/del GG (.) (.) . (.–.) . .
Ins/del GC (.) (.) . (.–.) . .
Del/del GC (.) (.) . (.–.) . .
Ins/ins GC (.) (.) . (.–.) . .
Del/del CC (.) (.) . (.–.) . .
Ins/del CC (.) (.) . (.–.) . .
Ins/ins CC (.) (.) ———
𝑝c: Bonferroni-corrected 𝑝.
T : Haplotype association of HLA-G +G>C and bp ins/del variants with rheumatoid arthritis (RA) risk.
+G>C bp ins/del RA cases (frequency) Controls (frequency) OR (% CI) 𝑝
G Ins . . . —
G Del . . . (.–.) .
C Del . . . (.–.) .
C Ins . . . (.–.) .
Baseline demographic and clinical characteristics of total
follow-upcohortandtheremittingandnonremittingsub-
groups are shown in Table . We determined the association
of HLA-G polymorphism with early disease activity. Our
resultsrevealednosignicantassociationbetweenHLA-G
+G>C and HLA-G bp ins/del variant and early disease
activity (Table ).
e genotype frequency of the HLA-G polymorphism
was examined for Hardy-Weinberg equilibrium (HWE).
+G>CpolymorphismincasesandcontrolswasinHWE
(𝜒2= 0.50,𝑝 = 0.480 and 𝜒2= 0.96,𝑝 = 0.328, resp.), while
the bp I/D variant in cases and controls was not in HWE
(𝜒2= 13.94,𝑝 = 0.0002 and 𝜒2= 8.38,𝑝 = 0.004,resp.).
4. Discussion
HLA-G is a nonclassical HLA class I molecule that can bind
to immune cells and inhibit their function [, ]. It is
involved in several immunoregulatory processes and may
potentially be involved in the pathogenesis of RA. Genetic
variants in coding and noncoding regions of the HLA-G may
aect biological features of the molecule. Expression rate of
HLA-G gene and plasma level are aected by variants in the
promoter region as well as UTR [].
In the present study, we investigated the impact of HLA-
G bp ins/del and +G>C polymorphism on risk of
RA in a sample of Iranian population. e ndings of our
study showed an association between HLA-G +G>C
polymorphism and RA in our population. e GC as well as C
allele decreased the risk of RA in our population. Regarding
HLA-G bp ins/del variant, we did not nd any statistically
signicantdierenceineithergenotypeoralleledistribution
between patients and controls. e deldel/GG genotypes
signicantly increased the risk of RA compared to insins/GG.
In addition, we did not nd an association between HLA-G
variants and disease activity. In contrast to our ndings, Rizzo
et al. [] investigated early rheumatoid arthritis (ERA)
patients during a -month follow-up disease treatment
period. ey found that the frequency of bp del allele was
associated with disease remission. ey concluded that HLA-
G may be a candidate biomarker to evaluate early prognosis
and disease activity in ERA patients.
A meta-analysis performed by Lee et al. [] revealed
no signicant association between HLA-G bp I/D and
+G/C polymorphism and RA risk. Similar negative
ndings have been reported in Brazilian [] and Indian
population []. Although Veit et al. [] have observed no
dierences in allelic and genotypic frequencies of the HLA-G
bp ins/del polymorphism between RA patients and con-
trols, the bp ins/del polymorphism was associated with
juvenile idiopathic arthritis in Brazilian population. In
anotherstudy,Veitetal.[]reportedthat+GGgenotype
signicantly increased the risk of RA (odds ratio (OR) = .,
% condence interval (CI) = .–., 𝑝 = 0.030). Kim
et al. [] investigated the impact of rs (-T/C)
and rs (-C/T) promoter polymorphism of HLA-G
gene on RA in Korean population. ey found no signicant
dierences in distributions of genotypes and haplotypes
between RA patients and control subjects.
Verbruggen et al. [] found that the levels of sHLA-G
in patients with RA were signicantly lower than healthy
controls. ey suggested that patients with low sHLA-G levels
were unable to suppress self-reactive cells leading to devel-
opment of autoimmunity. e -untranslated region (UTR)
has a major role in HLA-G regulation [, ]. It has been
proposed that polymorphism exerts a signicant eect in the
Advances in Medicine
T : Baseline demographic and clinical characteristics of total follow-up cohort and the remitting and nonremitting subgroups.
Parameters Total patients
(𝑛=30)
Remitting patients
(𝑛=15)
Nonremitting
patients (𝑛=15)𝑝
Age (mean ±SD) . ±. . ±. . ±. NS∗
Gender (%)
Male (.) (.) (.) NS
Female (.) (.) (.)
BMI (Kg/m2)(mean ±SD) . ±. . ±. . ±. NS
Cigarette (pack/years; mean ±SD) . ±. . ±. . ±.
Hookah (%) (.) (.) () NS
Education NS
Illiterate (%) (.) (.) (.)
Less than diploma (%) (.) (.) (.)
Diploma (%) (.) (.) (.)
Higher education (%) (.) (.) (.)
Length of symptom prior to study (months; mean ±SD) . ±. . ±. . ±. NS
Positive rheumatoid factor (%) (.) () (.) NS
Comorbidity NS
No comorbidity (%) (.) (.) (.)
Type diabetes mellitus (%) (.) (.) (.)
Hypertension (%) (.) (.) (.)
Dyslipidemia (%) () (.) (.)
Other factors (%) (.) (.) (.)
∗Nonsignicant.
T : Association of HLA-G polymorphism in remitting and nonremitting RA patients.
Genotypes Remitting patients
𝑛(%)
Nonremitting patients
𝑛(%) OR (% CI) 𝑝
14-bp ins/del
Genotype
Ins/ins (.) (.) . —
Ins/del (.) (.) . (.–.) .
Del/del (.) (.) . (.–.) .
Allele
Ins (.) (.) . —
Del (.) (.) . (.–.) .
+3142G>C
Genotype
GG (.) (.) . —
CG (.) (.) . (.–.) .
CC (.) (.) ——
Allele
G (.) (.) . —
C (.) (.) . (.–.) .
HLA-G function and may have an impact on the expression
of sHLA-G [–]. e HLA-G expression is inuenced by
bp ins/del as well as +G/C polymorphism in the -
untranslated region (UTR) of HLA-G gene and may have
possible implications of clinical signicance [].
e discrepancy in ndings among studies may be due to
genetic and environmental dierences between the dierent
populations being investigated.
e limitation of our study is that we have no data
regarding anti-CCP antibodies, RF antibody, HLA-DRB
Advances in Medicine
shared epitope, and smoking history. Consequently, we could
not evaluate the association between HLA-G variants and
these factors. However, we believe that our ndings provide
an important input into the debate concerning the clinical
relevance of studied variants. ere is no clear explanation for
deviation from HWE in our population. e possible reason
is that the HLA-G gene is under balancing selection [].
In summary, we found a signicant association between
HLA-G +G>C variant and susceptibility to RA in a
sample of Iranian population. Further association studies
with large sample size and dierent ethnicities are required
to verify our ndings.
Competing Interests
No competing nancial interests exist.
Acknowledgments
is work was suppor ted by a dissertation grant (MD thesis of
SAF no. ) from Zahedan University of Medical Sciences.
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