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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
2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2011 RCOG
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Kim et al.
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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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
50
Endometriosis
45
Control
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
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.
2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2011 RCOG
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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
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*
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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2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2011 RCOG
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.
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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