Survivin promoter polymorphisms and autoantibodies in endometriosis

Journal of Reproductive Immunology 96 (2012) 95–100

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Survivin promoter polymorphisms and autoantibodies in endometriosis Merit Lamp a , Merli Saare a,b,c , Ülle Kadastik d , Helle Karro a,d , Andres Salumets a,b,c , Raivo Uibo b,c,e , Maire Peters a,b,∗ a b c d e

Department of Obstetrics and Gynecology, University of Tartu, L. Puusepa 8, 51014 Tartu, Estonia Competence Centre on Reproductive Medicine and Biology, Tiigi 61b, 50410 Tartu, Estonia Institute of General and Molecular Pathology, University of Tartu, Ravila 19, 50411 Tartu, Estonia Tartu University Hospital’s Women’s Clinic, L. Puusepa 8, 51014 Tartu, Estonia Centre of Excellence for Translational Medicine, University of Tartu, Ravila 19, 50411 Tartu, Estonia

a r t i c l e

i n f o

Article history: Received 11 September 2012 Accepted 10 October 2012

Keywords: Autoantibody Endometriosis Single nucleotide polymorphism Smoking Survivin

a b s t r a c t Expression of survivin, an inhibitor of apoptosis, is increased in endometriotic lesions and probably favors the survival of endometrial fragments in the peritoneal cavity. The aim of this study was to evaluate associations between survivin promoter polymorphisms and the risk of endometriosis, as well as to compare the immunoreactivity to survivin in sera of patients with and without endometriosis. We studied 149 women with endometriosis, 196 fertile women from the general population (control group A) and 47 women who had undergone diagnostic laparoscopy and had no evidence of endometriosis (control group B). There were no significant differences in the genotypic distribution of the survivin gene promoter region −241C/T, −235G/A and −31G/C single nucleotide polymorphisms (SNP) between endometriosis patients and the two control groups. In addition, also median antisurvivin autoantibody levels were similar among patients and controls (group B). However, anti-survivin antibody concentrations seemed to be influenced by cigarette smoking, being significantly lower in sera of actively smoking women compared to non-smokers (median OD: 0.019 vs. 0.155, respectively, P < 0.001), and by the −235G/A SNP, as A allele carriers were significantly more frequent among women with a high antibody level (OD ≥ 2.0) compared to those with lower concentrations (OD < 2.0) (23.1% vs. 4.1%, respectively, P = 0.008). Based on these results, we conclude that survivin promoter polymorphisms are not associated with susceptibility to endometriosis in the Estonian population, and though the expression of survivin is increased in endometriotic lesions, autoimmune reactivity against it is similar in women with and without the disease. © 2012 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Survivin is an inhibitor of apoptosis protein regulated in a cell cycle dependent manner. Initial studies

∗ Corresponding author at: Department of Obstetrics and Gynecology, University of Tartu, L. Puusepa 8, 51014 Tartu, Estonia. Tel.: +372 7330402; fax: +372 7330409. E-mail address: [email protected] (M. Peters). 0165-0378/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jri.2012.10.001

found survivin expression in fetal tissues and placenta but only in a few terminally differentiated adult tissues (Ambrosini et al., 1997). Instead, elevated survivin levels were observed in different tumor types (rev. in Altieri, 2003) and were related to reduced levels of apoptosis. However, even though at remarkably lower levels than in cancer cells, many normal adult tissues and cell types have recently been found to express survivin (rev. in Fukuda and Pelus, 2006). The presence of survivin mRNA and protein has also been demonstrated in normal cycling

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endometrium (Konno et al., 2000) with highest levels in the proliferative phase of the menstrual cycle (Lehner et al., 2002; Nabilsi et al., 2010). Survivin gene expression in human endometrium is regulated by sex hormones, showing higher expression after treatment with estrogen and decreased levels after treatment with progestins (Nabilsi et al., 2010). Similarly to endometrial cancer, overexpression of survivin is characteristic to several non-malignant endometrial pathologies like endometrial hyperplasia (Erkanli et al., 2007) and endometriosis (Ueda et al., 2002). In endometriosis, survivin gene expression is significantly higher in ectopic lesions than in eutopic endometrial tissue (Ueda et al., 2002; Fujino et al., 2006; Zhang et al., 2009) and the reduced number of apoptotic cells in endometriotic lesions can be associated with elevated survivin expression level (Ueda et al., 2002). Early stage peritoneal lesions with high proliferative activity show higher levels of survivin in comparison to more advanced lesions suggesting that in the first stages of lesion development survivin may be linked to the escape of endometrial tissue fragments from apoptosis (Fujino et al., 2006). In endometriotic ovarian cysts, survivin expression has also been detected, with highest level in outer fibrous capsule microvessels (Goteri et al., 2005). In the survivin promoter area, three polymorphic nucleotide substitutions have been found: C to T at position −241, G to A at −235 and G to C at −31 (Xu et al., 2004). The highly frequent −31G/C single nucleotide polymorphism (SNP) is located at a CDE/CHR (cell cycle-dependent element/cell cycle homology region) repressor element (Xu et al., 2004) and the presence of the C allele has been shown to positively alter survivin transcription level (Jang et al., 2008; Wagner et al., 2008; Kawata et al., 2010). The data about low-frequency −235G/A and −241C/T transitions effect are more controversial revealing either no impact or slightly positive influence of minor alleles on promoter activity (Xu et al., 2004; Wagner et al., 2008; Boidot et al., 2010). Based on the functional effects of the survivin promoter area SNPs and elevated expression of survivin in ectopic endometrial tissue we hypothesized that the presence of alternative promoter variants might influence the development of endometriosis, and increased survivin expression could stimulate autoimmune reactivity and autoantibody production against survivin in women with endometriosis. In this study, we investigated both the associations between three survivin promoter SNPs and the risk of endometriosis in Estonian women, as well as the immunoreactivity to survivin in sera of patients with and without endometriosis.

have been published previously (Saare et al., 2010; Lamp et al., 2011). Endometriosis stages were divided according to the American Society for Reproductive Medicine revised classification system (ASRM, 1997) as follows: stage I–II: 92 patients; stage III–IV: 57 patients. In addition, 47 women (mean age 30.0 ± 6.1 years) who had undergone diagnostic laparoscopy for infertility (n = 35) or pelvic pain (n = 12), and had no evidence of endometriosis, were enrolled in this study as a second control group (control group B). Serum and peripheral blood samples of endometriosis patients and group B women were obtained before surgery. The DNA samples of group A were obtained from the Estonian Genome Center. The study was approved by the Ethics Review Committee on Human Research of the University of Tartu (Tartu, Estonia), and an informed consent was obtained from each participant. 2.2. Genotyping Survivin gene promoter region polymorphisms −241C/T (rs17878467), −235G/A (rs17887126), and −31G/C (rs9904341) were detected by Sanger sequencing. The PCR primers survF (5 -ATCACGGTAGTGGCCCAGTC-3 ) and survR (5 -CTTGAATGTAGAGATGCGGTG-3 ) were used for PCR, and for sequencing an additional primer survseq (5 -GAACTCCAGGACTCAAGTGA-3 ) was used. Sequencing was performed on an ABI 3130xl Genetic Analyzer (PE Applied Biosystems, Foster City, CA). 2.3. ELISA Serum anti-survivin antibodies were detected with a specific ELISA kit (Uscn Life Science Inc, Wuhan, China) according to the manufacturer’s protocol. Each sample was tested in duplicate and the mean OD values were used for further analysis. 2.4. Statistical analysis

2. Materials and methods

Statistical tests were carried out using PASW 18.0 software (SPSS, Chicago, IL). Genotype frequencies of all SNPs were analyzed for deviation from Hardy–Weinberg equilibrium using the 2 test. Logistic regression analysis was used to evaluate the effect of genotypes on risk for endometriosis. Possible confounding factors, like height and smoking status (revealed by our previous studies) (Lamp et al., 2011), were included in the model. Mann–Whitney U test or Kruskal–Wallis test were used to compare serum survivin autoantibody median OD values between study groups. A P value of <0.05 was considered to be statistically significant. Post hoc power calculations for genetic associations were performed using G*Power 3 software version 3.1.3 (Faul et al., 2009).

2.1. Patients

3. Results

The demographic and clinical data of 149 women (mean age ± SD, 32.1 ± 6.1 years) with surgically and histologically confirmed endometriosis and 196 healthy women (mean age 38.0 ± 6.7 years) having at least two children and no medical history of endometriosis (control group A)

The distribution pattern of survivin gene promoter region −241C/T, −235G/A and −31G/C SNP genotypes in endometriosis patients (n = 149) and control groups A (n = 196) and B (n = 47) is shown in Table 1. Genotype frequencies of all investigated SNPs were consistent

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Table 1 Genotype frequencies of survivin promoter region polymorphisms among endometriosis patients and control groups A and B. Genotype

−241C/T CC CT TT −235G/Ab GG GA −31G/C GG GC CC a b

Patients (n = 149)

Control group A (n = 196)

Control group B (n = 47) a

OR (95% CI)a

P-Value

44 (93.6) 3 (6.4) 0 (0.0)

Reference 2.06 (0.56–7.54) –

0.275 –

0.951

46 (97.9) 1 (2.1)

Reference 2.52 (0.31–20.62)

0.389

0.904 0.788

14 (29.8) 24 (51.1) 9 (19.1)

Reference 0.58 (0.27–1.22) 0.49 (0.18–1.36)

0.152 0.172

n (%)

n (%)

OR (95% CI)

P-Value

132 (88.6) 17 (11.4) 0 (0.0)

168 (85.7) 25 (12.8) 3 (1.5)

Reference 1.07 (0.53–2.14) –

0.854 –

140 (94.0) 9 (6.0)

185 (94.4) 11 (5.6)

Reference 1.03 (0.40–2.63)

67 (45.0) 64 (42.9) 18 (12.1)

83 (42.3) 86 (43.9) 27 (13.8)

Reference 0.97 (0.61–1.56) 0.91 (0.45–1.83)

n (%)

Logistic regression analysis adjusted by height and smoking status. There were no individuals carrying the minor homozygous genotype.

with Hardy–Weinberg equilibrium for cases and controls (all P > 0.08). No statistically significant differences in the distribution of genotypes were observed between endometriosis patients and the control groups. The differences in genotype frequencies between patients and control groups A and B remained insignificant also after subdividing endometriosis patients by the severity of the disease (stage I–II or stage III–IV) (data not shown). To determine if women with endometriosis show increased autoimmunity against survivin, and whether this could help to detect endometriosis in a non-invasive manner, sera from 98 endometriosis patients (55 women with stage I–II and 43 with stage III–IV endometriosis, mean age 30.9 ± 6.5 years) and 47 women from control group B were tested for anti-survivin antibodies. Women from group B were selected for antibody analysis because they were of the same age as endometriosis patients (30.0 ± 6.1 years vs. 30.9 ± 6.5 years, respectively, P > 0.05), presented with similar gynecological symptoms and were proved to be endometriosis-free by laparoscopic surgery. The median levels of autoantibodies to survivin did not differ significantly between study groups; median ODs were 0.119 and 0.078 for controls and endometriosis patients, respectively (P > 0.05). Interestingly, anti-survivin autoantibody levels seemed to be associated with smoking status in all women studied, as median OD values were significantly lower in sera of actively smoking women (n = 32) compared to non-smokers (n = 113) (0.019 vs. 0.155, respectively; P < 0.001). This difference was also statistically significant when patients and controls were analyzed separately. Since smoking seemed to influence antibody levels, comparison of median OD values in endometriosis patients and controls was repeated including only non-smoking women (79 patients and 34 controls), which confirmed that anti-survivin antibodies were not associated with endometriosis (median ODs 0.146 vs. 0.187, respectively; P > 0.05). In addition, autoantibody levels were similar also in women with stage I–II and stage III–IV disease (median ODs 0.074 and 0.104, respectively; P > 0.05). The correlations between survivin autoantibodies and survivin promoter genotypes were assessed among non-smoking study participants, revealing no significant associations with median antibody levels. However,

when the frequency of elevated antibody concentrations (OD ≥ 1.0 or OD ≥ 2.0) was analyzed, an association was found between the −235G/A SNP A allele and the highest anti-survivin antibody level (OD ≥ 2) (Table 2). 4. Discussion In the current study, we tested associations between survivin promoter region polymorphisms and endometriosis development and analyzed the autoimmune reactivity against survivin in endometriosis patients. We found that −241C/T, −235G/A and −31G/C SNP genotype distributions were similar in endometriosis patients and controls. In addition, no difference in serum anti-survivin antibody concentration was seen between women with and without endometriosis. An interesting finding, however, was the correlation of serum autoantibody level with cigarette smoking and with the survivin −235G/A SNP. Beliard et al. (2004) have shown that endometriotic cells have a lower sensitivity to apoptosis than eutopic endometrial cells. Therefore, decreased susceptibility of endometrial tissue to apoptosis could be related to the success of implantation of these cells to ectopic sites (Beliard et al., 2004). Considering the importance of the physiological role of survivin in normal endometrial functioning (Nabilsi et al., 2010), its overexpression in endometriotic tissue (Ueda et al., 2002), and the reduced apoptotic properties of endometriotic cells, survivin seems an attractive candidate gene for endometriosis susceptibility study. According to our best knowledge, this is the first study to test the possible associations between survivin polymorphisms and endometriosis risk. The survivin gene locates at chromosome 17q25 and consists of 4 exons and 3 introns (Ambrosini et al., 1997). The genetic studies of survivin promoter area have revealed the presence of several SNPs, including −241C/T, −235G/A and −31G/C close to the survivin translation start site (Xu et al., 2004). Immunohistochemical and mRNA expression studies have shown that the alternative promoter variants may considerably elevate survivin level (Gazouli et al., 2009; Boidot et al., 2010; Kawata et al., 2010). During the last years, the association of survivin promoter region functional polymorphisms with different tumors has been extensively examined and a recent meta-analysis suggests

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Table 2 Associations between anti-survivin antibody levels and different survivin promoter genotypes among all studied non-smoking women.a Genotype −241C/Tc CC CT −235G/Ac GG GA −31G/C GG GC CC a b c

n

OD < 1.0 n (%)

OD ≥ 1.0 n (%)

P-Valueb

OD < 2.0 n (%)

OD ≥ 2.0 n (%)

P-Valueb

101 11

77 (90.6) 8 (9.4)

24 (88.9) 3 (11.1)

0.796

89 (89.9) 10 (10.1)

12 (92.3) 1 (7.7)

0.784

105 7

81 (95.3) 4 (4.7)

24 (88.9) 3 (11.1)

0.231

95 (95.9) 4 (4.1)

10 (76.9) 3 (23.1)

0.008

46 52 14

32 (37.6) 42 (49.4) 11 (13.0)

14 (51.9) 10 (37.0) 3 (11.1)

0.419

37 (37.4) 49 (49.5) 13 (13.1)

9 (69.2) 3 (23.1) 1 (7.7)

0.089

Antibody levels are expressed as OD values. 2 test. There were no individuals carrying the minor homozygous genotype.

an important relationship between −31G/C minor allele and cancer development, especially in Asian population (Srivastava et al., 2012). In the present study, we compared the genotype frequencies of the −241C/T, −235G/A and −31G/C polymorphisms in endometriosis patients to those in the control group. We used two control groups in our study, one consisting of women with proved fertility and no medical history of endometriosis from the Estonian general population (group A), and the second consisting of women who had undergone diagnostic laparoscopy for different gynecologic conditions and had no evidence of endometriosis (group B). All three SNPs were distributed similarly among endometriosis patients and in population controls. In the control group B, genotype frequencies were slightly different than in women with endometriosis, however, it did not reach statistical significance for any of the SNPs, suggesting that these polymorphisms are not associated with disease susceptibility. The selection of controls for studies on endometriosis is complicated since surgery is needed for the definite exclusion of endometriosis. When women are enrolled from the general population based on their self-reported medical history, some undiagnosed endometriosis cases might be included in the control group, making it more difficult to find weak associations. Then again, patients who have undergone gynecological surgery and are endometriosis-free, in general suffer from some other gynecological disorder and might thus form a slightly biased sample. For this reason we decided to use both types of controls in the present study. However, since the number of women in group B was limited, a larger group of patients laparoscopically proved to be endometriosis-free should be analyzed, to confirm our results. Post hoc power calculations based on our sample size using control group A revealed that with 80% power and false positive rate of 5% the minimal detectable odds ratios for the −31G/C, −241C/T and −235G/A SNPs were 1.73, 2.26 and 3.37, respectively. Therefore we cannot exclude that some weak associations exist, however, strong associations between these survivin promoter region polymorphisms and endometriosis risk are unlikely. Several studies have shown that the levels of antisurvivin antibodies are elevated in sera of cancer patients (Rohayem et al., 2000; Eto et al., 2007; Soling et al., 2007). Endometriotic cells express more survivin than normal endometrial cells (Ueda et al., 2002; Fujino et al., 2006;

Watanabe et al., 2009) and we hypothesized that high protein level may stimulate humoral immunoreactivity to survivin in endometriosis patients. In addition, we wanted to test if antibodies against survivin could be used as a diagnostic marker to distinguish endometriosis patients from those with similar complaints but without the disease. Therefore, we compared anti-survivin antibody levels in sera of endometriosis patients to those of control group B women. In the present study, the anti-survivin antibody levels were comparable between the two groups showing no detectable raise in sera of endometriosis patients. Thereby, according to our data, anti-survivin antibodies cannot be used as a biomarker for endometriosis. Some studies on cancer patients have shown that anti-survivin antibody concentrations are not directly correlated with survivin expression levels in tumor tissues (Soling et al., 2007; Karanikas et al., 2009). This might explain, to some extent, why we observed no significant difference in anti-survivin antibody levels between women with and without endometriosis. On the other hand, as survivin is also expressed in normal endometrium, it is possible that the increase in its expression in endometriotic lesions is not sufficient to induce a stronger autoimmune response than in healthy women. An interesting finding in the current study was the strong association between anti-survivin antibody level and smoking status of study participants. The median antibody values detected in sera of non-smoking women were significantly higher than in those of active smokers. Since our study group consisted only of premenopausal women, one of the possible reasons for lower antibody levels in active smokers might be the anti-estrogenic effect of cigarette smoking. It has been shown that women who smoke have lower estrogen levels than non-smoking women (Shiverick and Salafia, 1999; Soldin et al., 2011). As estrogens have been found to stimulate survivin expression in the endometrium and in estrogen-sensitive cancer cells (Frasor et al., 2003; Nabilsi et al., 2010), the antiestrogenic effect of smoking could lead to a reduction in survivin expression and thus to a lower autoimmune reactivity against it. However, additional research in different populations and larger study groups is required to fully reveal the impact of smoking on anti-survivin antibody level.

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As the smoking status was found to be the major contributor to survivin autoantibody levels, the associations between survivin promoter region SNPs and anti-survivin antibody levels were analyzed only among non-smoking women. The analyses revealed no correlation between median autoantibody levels and genotypes. Nevertheless, an association was found between high autoantibody level (OD values ≥2.0) and the −235G/A SNP, with three out of seven A allele carriers showing very high autoantibody levels. However, this result should be considered with caution, as the A allele frequency in our study group was very low and there were no AA homozygous individuals. It is difficult to speculate on the biological background of this finding, as the data about the impact of the −235G/A polymorphism on survivin expression is scarce and inconsistent (Xu et al., 2004; Wagner et al., 2008; Boidot et al., 2010). In in vitro gene reporter assays the −235G/A SNP has been shown to have no effect on survivin promoter activity (Xu et al., 2004; Wagner et al., 2008). However, in a recent study on breast carcinomas, a strong association between the A allele and increased survivin mRNA level was detected (Boidot et al., 2010). The −235G/A SNP seems to create a second binding-site for the transcription factor GATA-1 in the survivin promoter, which could explain increased gene expression in the presence of the A allele (Boidot et al., 2010). In conclusion, this case–control study suggests that variation in the survivin promoter area does not influence susceptibility to endometriosis in Estonian population. Still, a replication study using a higher number of gynecological patients with surgically excluded endometriosis might be useful to confirm this result. In addition, autoimmune reactivity against survivin appears to be similar in women with and without endometriosis; therefore anti-survivin antibody detection cannot be applied as a non-invasive diagnostic test for endometriosis. Survivin autoantibody level seems to be influenced by the survivin −235G/A SNP and by cigarette smoking, but these associations need further confirmation. Nevertheless, future studies on survivin autoantibodies in female subjects should consider smoking status as a possible confounding factor. Acknowledgements This research was funded by the European Union Regional Development Fund and by Enterprise Estonia, Grant no. EU30200, by the Estonian Science Foundation (grants 6573 and 6585) and by the Estonian Ministry of Education and Research (core grants SF0180044s09 and SF0180035s08). The authors thank the personnel of the Department of Immunology and the Department of Human Biology and Genetics from the Institute of General and Molecular Pathology, University of Tartu, for their technical support and guidance. References Altieri, D.C., 2003. Survivin, versatile modulation of cell division and apoptosis in cancer. Oncogene 22, 8581–8589.

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