DOI: 10.1111/j.1471-0528.2011.02963.

x
www.bjog.org

Fertility and assisted reproduction

Association of the interferon-c gene (CA)n repeat

polymorphism with endometriosis
JJ Kim,a,b YM Choi,a,c SS Hwang,d SH Yoon,e GH Lee,f SJ Chae,g KR Hwang,h SY Moona,c
a
Department of Obstetrics and Gynaecology, Seoul National University College of Medicine, Seoul b Healthcare System Gangnam Centre,
Seoul National University Hospital, Seoul c The Institute of Reproductive Medicine and Population, Medical Research Centre, Seoul National
University College of Medicine, Seoul d Department of Social and Preventive Medicine, College of Medicine, Inha University, Incheon
e
Department of Obstetrics and Gynaecology, Dongguk University Ilsan Hospital, Goyang f Department of Obstetrics and Gynaecology, Seoul
Medical Centre, Seoul g Department of Obstetrics and Gynaecology, Maria Fertility Hospital, Seoul h Department of Obstetrics and
Gynaecology, Seoul Municipal Boramae Hospital, Seoul, South Korea
Correspondence: Dr YM Choi, Department of Obstetrics and Gynaecology, The Institute of Reproductive Medicine and Population,
Medical Research Centre, Seoul National University College of Medicine, 28 Yungun-dong, Chongno-ku, Seoul 110-744, South Korea.
Email ymchoi@snu.ac.kr

Accepted 21 February 2011. Published Online 8 April 2011.

Objective To investigate whether the interferon-c (IFN-c) gene

(CA)n repeat polymorphism is associated with susceptibility to
endometriosis.
Design Casecontrol study.
Setting University Department of Obstetrics and Gynaecology.
Population Women with (n = 622) and without (n = 442)
endometriosis.
Methods Genotyping was performed by fluorescent polymerase

chain reaction (PCR) and gene-scan analysis.

Main outcome measures Genotype distribution and allele

frequency of the dinucleotide (CA)n repeat polymorphism in the

IFN-c gene.

Results Seven alleles (1218 repeats) of the IFN-c gene (CA)n

repeat polymorphism were found. In both patients with

endometriosis and controls the most common allele was
composed of 13 repeats, followed by an allele of 15 repeats,
and then by an allele of 12 repeats. Patients with endometriosis
had a significantly higher incidence of genotypes with alleles
composed of fewer repeats (1213 repeats), compared with the
controls (92.0 versus 84.4%, respectively, P < 001).
Conclusions Our results suggest that the (CA)n repeat

polymorphism in the IFN-c gene may be associated with a risk of

endometriosis in the South Korean population.
Keywords (CA)n repeat polymorphism, Endometriosis,

interferon-c.

Please cite this paper as: Kim J, Choi Y, Hwang S, Yoon S, Lee G, Chae S, Hwang K, Moon S. Association of the interferon-c gene (CA)n repeat
polymorphism with endometriosis. BJOG 2011;118:10611066.

Introduction
Endometriosis is defined as the presence of endometrial
tissue outside the uterus, and its prevalence has been
reported to range from 2 to 18% among women who seek
tubal ligation.1 Although the exact etiology of endometriosis
remains unclear, it has been hypothesized that seeding or
implantation of endometrial cells by transtubal regurgitation
is the main cause of this disease. The pathogenesis of endometriosis, however, is also found to be associated with a
derangement of the immune system, and especially with a
decreased clearance of peritoneal fluid endometrial cells as a
result of decreased cytotoxic T and natural killer (NK) cell
activity.26 A variety of inflammatory cytokines, such as

interleukin-1, tumour necrosis factor-a, and interferon-c

(IFN-c), have been reported to play important roles in
endometriosis.69 Among them, IFN-c is a multifunctional
cytokine mainly secreted by T helper type-1 (Th1) cells and
NK cells. It plays an important role in modulating immune
systems, including Th1 cell differentiation, macrophage activation, and anti-proliferative activities.10,11 In particular, it
polarizes T helper cells towards Th1 cells, and inhibits the
development of Th2 cells, thus playing a pivotal role in
T cell activation.12,13 Its role in endometriosis is unclear.
However, although IFN-c is known to inhibit the proliferation of human endometrial epithelium,14 the resistance of
endometriotic cells to IFN-c-induced cell growth inhibition
and apoptosis has been found to be a possible mechanism

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1061

Kim et al.

involved in the pathogenesis of endometriosis.15 In addition,

many studies have shown that the concentration of IFN-c is
decreased in the peritoneal fluid of patients with endometriosis,6,15,16 although results suggesting that the concentration
does not differ between patients with endometriosis and
controls have also been reported.17,18
The human IFN-c gene is located on chromosome
12p24.1, and in its first intron it has a dinucleotide (CA)n
repeat polymorphism that acts as a tissue non-specific
enhancer element.19,20 The influence of this polymorphism
on the function of IFN-c remains to be elucidated, but the
relationship between this cytokine production and the
(CA)n repeat polymorphism has been reported in previous
studies.21,22 In addition, recent studies have demonstrated a
possible association of the (CA)n repeat polymorphism
with several autoimmune diseases, such as insulin-dependent diabetes mellitus,10 Graves disease,23 lupus nephritis,22 and multiple sclerosis,24 suggesting the importance of
this polymorphism.
To date, only one study has explored the association
between the IFN-c gene polymorphism and the risk of
endometriosis.25 The present study aimed to determine
whether there is an association between the (CA)n repeat
polymorphism in the IFN-c gene and endometriosis.
We investigated the genotype distributions and allele
frequencies of the (CA)n repeat polymorphism in both
patients with endometriosis and in controls from a South
Korean population.

Genotyping of the (CA)n repeats polymorphism

Genomic DNA was isolated and extracted from peripheral
blood leukocytes with the Wizard DNA extraction kit (Promega, Madison, WI, USA). The CA dinucleotide repeat
polymorphism was assessed by using fluorescent polymerase chain reaction (PCR) and gene scan analysis, as
described previously.25 Genomic DNA (25 ng) was added
to a PCR mixture containing 1.5 m mmol/l MgCl2,
200 lmmol/l deoxyribonucleotide triphosphate (dNTP),
0.16 lmmol/l of each primer and 1.25 U of Taq polymerase (Takara, Shiga, Japan). The PCR primers for the CA
repeat polymorphism were 5-TGATTTTATTCTTACAACACA-3 (forward) and 5-CTTCCTGTAGGGTATTATTAT3 (reverse). The 5 end of the forward primer was labelled
with the fluorescent dye 5-carboxyfluorescein. The PCR
cycling conditions were as follows: an initial denaturation
step at 94C for 5 minutes, amplification for 35 rounds of
PCR at 94C for 1 minute, 60C for 45 seconds, and 72C
for 1 minute, followed by a final extension time of 10 minutes at 72C. PCR product was detected by electropherogram using the ABI Prism 310 DNA sequencer with
fluorescent DNA ladder. Data were analysed by genescan
analysis v2.1 (Perkin Elmer Applied Biosystems, Carlsbad,
CA, USA). To ascertain the lengths of the (CA)n, three
external reference samples with different numbers of
repeats were verified by direct sequencing, and were
included in each experiment.

Statistical analyses

Methods
Subjects
Blood samples were taken from 1064 women who underwent laparoscopic surgery, exploratory laparotomy, or
transabdominal hysterectomy in the gynaecologic clinic at
Seoul National University Hospital. The diagnosis of endometriosis was based on surgical and histological criteria.
A total of 622 endometriosis patients were recruited, and
442 patients without evidence of endometriosis served as
controls. None of the subjects had received hormone
therapy during the previous 12 months. The stage of
disease was determined by the revised guidelines of the
American Society for Reproductive Medicine:26 a total of
125 and 497 patients were diagnosed with stage-I/II
and stage-III/IV endometriosis, respectively. Patients with
leiomyoma, adenomyosis, and invasive carcinoma of the
uterine cervix or ovary were excluded from the control
group. The mean age of patients with endometriosis was
significantly lower than that of the controls (32.5 7.0
versus 44.1 8.1; P < 0.001). The review board for human
research of the Seoul National University Hospital
approved this project, and written informed consent was
obtained from each woman.

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The differences in the global allele frequency or genotype

distribution between the endometriosis patients and controls
were evaluated by chi-square test. Genotype distribution was
also examined for significant departures from Hardy
Weinberg equilibrium by a goodness-of-fit chi-square test.
A CochranMantelHaenszel statistic was used to specifically examine the trend over groups. All data analyses were
performed using spss v17.0 (SPSS Inc., Chicago, IL, USA)
or sas v9.2 (SAS Institute, Cary, NC, USA), and significance
was accepted for two-sided P values of <0.05. For the purpose of correcting for multiple testing, the statistical significance was specified by means of the Bonferroni correction.

Results
Seven alleles (1218 repeats) of the IFN-c (CA)n repeat
polymorphism were found in all subjects analysed in our
study. The allele frequencies are presented in Figure 1 and
Table 1. In both patients with endometriosis and the controls, the most common allele was that with 13 repeats
(49.5 and 46.3% in patients and controls, respectively),
followed by that with 15 repeats (29.8 and 34.0% in
patients and controls, respectively), and then that with
12 repeats (15.3 and 13.1% in patients and controls,

2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2011 RCOG

Interferon-c gene in endometriosis

14 repeats the aspect of allele frequencies changed, with

higher frequencies found in the controls. Thus, the low
point at the interface of both distributions (14 repeats) was
used as a cut-off to divide alleles into two groups: short
(S; 1213 repeats) and long (L; 1418 repeats) groups.
When the IFN-c (CA)n polymorphism was stratified
according to the presence of S or L alleles, the genotype
distribution was in HardyWeinberg equilibrium in controls (P = 0.7 by the goodness-of-fit chi-square test). There
was also a significant difference in genotype distribution
between the endometriosis and control groups (Table 2).
Moreover, subjects were divided into the SS + SL and LL
genotypes according to the presence of the short allele: the
SS + SL genotype rates were 92.0% for the patients with
endometriosis and 84.4% for the controls (P < 0.001).
For further analysis, the endometriosis group was
divided into stage-I/II and stage-III/IV subgroups,
according to the staging classification of the American
Society for Reproductive Medicine. We found that differences in genotype distribution remained significant between
each of the endometriosis subgroups and controls
(Table 2). However, the doseresponse relationship
between the severity of endometriosis and genotype was
only observed across SS + SL and LL genotypes.

respectively). The global allele frequency in endometriosis

patients was significantly different from that in the controls
(P = 0.029).
There was a bimodal distribution of (CA)n repeat frequencies in our subjects (Figure 1). In particular, after
P = 0.139

50

Endometriosis

45

Control

Allele frequency (%)

40
P = 0.039

35
30
25
20
15

P = 0.163

10
5
0

P = 0.137

12

13

P = 0.066
P = 0.335
P = 0.239

14
15
16
(CA)n repeats number

17

18

Figure 1. Interferon-c gene (CA)n microsatellite polymorphism allele

frequencies in both patients with endometriosis and controls. In both
patients with endometriosis and in controls, the most common allele
was the 13-repeat allele (49.5 and 46.3% in patients and controls,
respectively), followed by the 15-repeat allele (29.8 and 34.0%), and
the 12-repeats allele (15.3 and 13.1%). There was a bimodal
distribution of (CA)n repeat frequencies in our subjects, and the low
point at the interface of both distributions was used as a cut-off
to divide alleles into two groups: short (S; 1213 repeats) and long
(L; 1418 repeats). The P value above each column was evaluated by
a chi-square test between the endometriosis patients and the controls,
and was considered significant at values <0.007 after Bonferronis
correction.

Discussion and conclusion

In this study there were significant differences in global
allele frequency and genotype distribution of the IFN-c
gene (CA)n repeat polymorphism between a large number
of endometriosis patients and controls. Patients with endometriosis had a significantly higher incidence of genotypes
with alleles composed of shorter repeats (1213 repeats)

Table 1. Interferon-c gene (CA)n microsatellite polymorphism allele frequencies in patients with endometriosis and controls
Allele

12
13
14
15
16
17
18

repeats
repeats
repeats
repeats
repeats
repeats
repeats

Total ES
(n = 1244) (%)

190
616
10
371
25
7
25

(15.3)
(49.5)
(0.8)
(29.8)
(2.0)
(0.6)
(2.0)

P value
for global
allele frequency*
0.029

Control
(n = 884) (%)

116
409
14
301
29
2
13

Stage-I/II ES
(n = 250)** (%)

(13.1)
(46.3)
(1.6)
(34.0)
(3.3)
(0.2)
(1.5)

37
131
1
73
5
1
2

(14.8)
(52.4)
(0.4)
(29.2)
(2.0)
(0.4)
(2.0)

Stage-III/IV ES
(n = 994)** (%)

153
485
9
298
20
6
23

(15.4)
(48.8)
(0.9)
(30.0)
(2.0)
(0.6)
(2.3)

P***

0.163
0.287
0.172
0.061
0.083
0.208
0.161

In both patients with endometriosis and controls, the most common allele was the 13-repeat allele (49.5 and 46.3% in patients and controls,
respectively), followed by the 15-repeat allele (29.8 and 34.0%, respectively), and then the 12-repeats allele (15.3 and 13.1%, respectively).
*The global allele frequency between the controls and the total number of endometriosis patients was evaluated by chi-square test with a
2 7 table.
**P values for global allele frequencies were 0.290 for stage-I/II endometriosis patients, and 0.048 for stage-III/IV patients, respectively (evaluated
by the chi-square test in comparison with the control group).
***The P value for the trend was calculated with the CochranMantelHaenszel statistic using the SAS v9.2 proc freq cmh option.

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Kim et al.

Table 2. Genotype distributions according to the presence of shorter (CA)n repeats (12/13 repeats) in patients with endometriosis and in controls
Group

Genotype distributions using the additive model

n
Control
Stage-I/II ES
Stage-III/IV ES
Total ES

442
125
497
622

SS (%)
151
51
183
234

(34.2)
(40.8)
(35.4)
(36.6)

SL (%)
222
66
272
338

(50.2)
(52.8)
(56.3)
(55.5)

LL (%)
69
8
42
50

(15.6)
(6.4)
(8.3)
(7.9)

P*

Genotype distributions using the dominant

model
P**
0.494

0.024
0.003
0.001

SS + SL (%)
373
117
455
572

(84.4)
(93.6)
(91.5)
(92.0)

LL (%)
69
8
42
50

(15.6)
(6.4)
(8.5)
(8.0)

P*

P**
0.0002

0.008
0.001
<0.001

There was a bimodal distribution of (CA)n repeat frequencies in our subjects, and the low point at the interface of both distributions was used as
a cut-off to divide alleles into two groups: short (S; 1213 repeats) and long (L; 1418 repeats) groups. Subjects were divided into the SS + SL
and LL genotypes according to the presence of the short allele, and the LL genotype rates were 8.0% for the patients with endometriosis and
15.6% for controls, respectively (P < 0.001).
*Evaluated by the chi-square test in comparison with the control group.
**The P value for the trend was calculated with the CochranMantelHaenszel statistic using the SAS 9.2 proc freq cmh option.

compared with the controls (92.0 versus 84.4%, respectively, P < 0.001), and these results suggest that the (CA)n
repeat polymorphism in the IFN-c gene may be associated
with a risk of endometriosis in the South Korean population.
To the best of our knowledge, this is the second report
to investigate an association between the IFN-c gene (CA)n
repeat polymorphism and endometriosis. The first study
also reported that the IFN-c gene (CA)n repeat polymorphism was associated with susceptibility to endometriosis
in the Japanese population.25 In that study, the global allele
frequency in patients with endometriosis was also significantly different from that in controls, but the difference
resulted from an increase in the frequency of the 13-repeats
allele in patients with endometriosis (the frequency of the
13-repeats allele was 53.8% in patients with endometriosis
and 44.0% in controls; P = 0.0352); this was a finding that
was not observed in our study (the frequency of the
13-repeats allele was 49.5% in the endometriosis patients
and 46.3% in the controls; P = 0.349). Considering that
the 13/13-repeats genotype may lower the expression of
IFN-c,22 and considering its association with other diseases,22,27 the 13-repeats allele could have functional significance. Based on the findings of our study, it remains to be
determined as to why positive associations were linked with
the combinations of short sizes of repeats (alleles with 12
and 13 repeats), and were not seen with the 13-repeat
alleles, in contrast with the reported relationship between
IFN-c cytokine production and (CA)n repeat polymorphism. When in vitro IFN-c production was compared
among genotypes, Pravica et al.21 reported that individuals
homozygous for the 12-repeat alleles showed significantly
more in vitro production of IFN-c than individuals with
other allele combinations. However, Saha et al.28 reported
the 12/12 genotype may act as one of the factors that could

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lead to the low production of IFN-c. As mentioned above,

Miyake et al.22 found lower IFN-c expression levels with
the 13/13 genotype. Considering the above results, the
functional significance or the net effect of combinations of
12 and 13 repeats, or of alleles other than the 12- and 13repeat alleles (the long allele in our study), remains to be
determined.
In both our study and a previous Japanese study, the
composition of the patients with endometriosis was similar,
with most of them having advanced-stage endometriosis
(stage-III/IV rates were 71.9% for the previous study, and
79.9% for ours). The South Korean population may be
genetically distinct from the Japanese population. However,
unlike populations from England,29 and India,28,30,31 the
13-repeats allele was the most frequent allele in South
Koreans,32 and among Japanese women,22,25 suggesting
similar presentations in both ethnicities. Salanti et al.33
have emphasised the importance of sample sizes being large
enough to achieve satisfactory power in genetic association
studies. In our study, the number of patients with endometriosis was nearly triple that of the previous study (546 versus 185), and the number of control patients was also
much larger than that of the previous study (442 versus
176). In addition, the mean age of the patients with endometriosis was significantly lower than that of the controls
(32.5 7.0 versus 44.1 8.1 years; P < 0.001). Recruiting
controls from an older group has the merit of maximising
the probability that these subjects are unaffected by endometriosis,34 and thus may have influenced our results
favourably.
In our study, there was a significant difference in the
genotype distribution of the IFN-c gene (CA)n repeat polymorphism between patients with endometriosis and controls. However, the doseresponse relationship between the
severity of endometriosis and genotype was only observed

2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2011 RCOG

Interferon-c gene in endometriosis

across SS + SL and LL genotypes. An uncertainty in the

doseresponse relationship would weaken the causality
between the genetic aberrations in IFN-c and endometriosis, and our study has a limitation on this point. We also
did not examine the differences in IFN-c cytokine levels
according to genotype. The best way to prove a causality
between the IFN-c gene (CA)n repeat polymorphism and
endometriosis might be to find the doseresponse relationship between repeat polymorphisms, IFN-c cytokine production, and stage of disease. Therefore, additional studies
including all three steps outlined above may provide an
important clue for elucidating the pathogenesis of endometriosis.
Traditionally, the management of endometriosis has
focused on ovarian suppression, but mounting evidence
suggests that endometriosis is a disease involving altered
immune function. Although we did not examine the
changes in IFN-c levels according to its genotype, a better
understanding of the role of IFN-c or its polymorphism
will allow for the modulation of inflammation as an alternative approach for the management of endometriosis.
Although the role of IFN-c in endometriosis is still
largely unknown, and immunological changes per se will
not explain the whole pathophysiology of endometriosis,
the main findings of our study suggest that the genotype
distribution of the IFN-c gene (CA)n repeat polymorphism
in the endometriosis group was significantly different from
that of the controls. Although our results should be interpreted with caution until replicated, considering the results
of the previous study as well as our own, both of which
reported an association between the IFN-c gene (CA)n
repeat polymorphism and endometriosis, the IFN-c gene
polymorphism may be associated with immunological aberrancies involved in endometriosis. Future research, containing the changes in IFN-c levels according to both its
genotype and the stage of endometriosis, may provide an
important clue for elucidating the pathogenesis of this
disease.

Disclosure of interests
None of the authors have any conflict of interest to report.

Contribution to authorship
JJK: drafting the article and revising it critically for important intellectual content. YMC: substantial contribution to
conception and design of study, final approval of the
version to be published. SSH: statistical analysis of data.
SHY: substantial contribution to the acquisition of data.
GHL: substantial contribution to analysis and interpretation of data. SJC: substantial contribution to the acquisition of data. KRH: substantial contribution to the
acquisition of data. SYM: final approval of the version to
be published.

Details of ethics approval

The review board for human research of the Seoul National
University Hospital approved this project (27 March 2002;
ref. no. H-0202-088-003).

Funding
This study was supported by a grant from the Korea Health
21 R&D Project, Ministry of Health and Welfare, Republic
of Korea (01-PJ10-PG6-01GN13-0002).

Acknowledgements
None. j

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2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2011 RCOG