Immunological Investigations, 2014; 43(6): 595–605 ! Informa Healthcare USA, Inc. ISSN: 0882-0139 print / 1532-4311 online DOI: 10.3109/08820139.2013.833623
A Meta-analysis of the Association between p53 Codon 72 Polymorphism and Susceptibility to Endometriosis Gwan Gyu Song and Young Ho Lee Division of Rheumatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea Objective: The aim of this study was to determine whether the p53 codon 72 polymorphism is associated with susceptibility to endometriosis. Methods: A meta-analysis was conducted on the associations between the p53 codon 72 polymorphism and endometriosis using 1) allele contrast, 2) a recessive model, 3) a dominant model, and 4) homozygote contrast. Results: Nine studies involving 1,803 patients and 2,006 controls were considered in the meta-analysis. Meta-analysis of the p53 polymorphism showed no association between endometriosis and the p53 C allele (odds ratio (OR) ¼ 1.087, 95% confidence interval (CI) ¼ 0.921–1.282, p ¼ 0.323). Stratification by ethnicity indicated no association between the p53 C allele and endometriosis in Europeans and Latin Americans. However, a significant association was found between the p53 C allele and endometriosis in East Asians (OR ¼ 1.405, 95% CI ¼ 1.065–1.854, p ¼ 0.016). Furthermore, association was found between the p53 polymorphism and endometriosis in East Asians using the dominant model (OR ¼ 2.046, 95% CI ¼ 1.123–3.730, p ¼ 0.019). Conclusions: This meta-analysis demonstrates that the p53 codon 72 polymorphism may be associated with susceptibility to endometriosis in East Asians, but not in Europeans and Latin Americans. Keywords Endometriosis, meta-analysis, p53, polymorphism
INTRODUCTION Endometriosis is a chronic disease that is characterized by the growth of endometrial tissue outside the uterine cavity and frequently leads to dyspareunia, dysmenorrhea, pelvic pain, and infertility (Halis & Arici, 2004). Although the etiology of endometriosis is not fully understood, it is clear that genetics play a role (Kennedy, 1998). Endometriosis is a benign disease, but appears similar to malignancies, in that it can exist as a local invasion or spread to distant organs (Giudice & Kao, 2004; Varma et al., 2004). Tumor suppressor genes may play a role in the pathogenesis of endometriosis. The tumor suppressor gene p53 plays central roles in apoptosis and cell proliferation and death (Levine, 1997). Two common polymorphic variants of wild-type p53 (rs1042522) have been identified (Matlashewski et al., 1987). These arise from a single-base-pair substitution at codon 72, which results in either CCC (Pro) or CGC (Arg). These p53 variants have been shown to Correspondence: Young Ho Lee, Division of Rheumatology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, 1261, Anam-dong 5-ga, Seongbuk-gu, Seoul 136-705, Korea. E-mail: [email protected]
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influence the function of p53 proteins in apoptosis, cell cycle control, and DNA repair (Pim & Banks, 2004) In addition, it has been shown that the 2 variants differ biochemically and biologically (Dumont et al., 2003; Thomas et al., 1999). The p53 Pro variant (C allele) is a stronger transcription factor activator, but a poorer apoptotic inducer than the p53 Arg variant (G allele), which is more susceptible to degradation. Therefore, the p53 C allele codon 72 polymorphism is associated with several types of cancer (Koushik et al., 2004). The p53 codon 72 polymorphism has also been associated with endometriosis in some reports, but not all (Ammendola et al., 2008; Bianco et al., 2011; Chang et al., 2002; Govatati et al., 2012; Lattuada et al., 2004; Omori et al., 2004; Paskulin et al., 2012; Vietri et al., 2007; Ying et al., 2011). The reasons for this disparity may be small sample sizes, low statistical power, and/or clinical heterogeneity. Therefore, to overcome the limitations of individual studies, resolve inconsistencies, and reduce the likelihood of random errors producing false-positive or false-negative associations (Choi et al., 2006; Lee et al., 2005; Nath et al., 2005), we used meta-analysis. The aim of the present study was to determine using meta-analysis whether the p53 codon 72 polymorphism is associated with susceptibility to endometriosis.
METHODS Identification of Eligible Studies and Data Extraction We performed a search for studies that examined associations between the p53 codon 72 polymorphism and endometriosis. The literature was searched using the MEDLINE and EMBASE citation databases to identify available articles in which the p53 codon 72 polymorphism was analyzed in endometriosis. Combinations of keywords such as p53, polymorphism, and endometriosis were entered as the Medical Subject Heading (MeSH) components and as text words. The references in the identified studies were also investigated to identify additional studies not indexed by MEDLINE and EMBASE. Studies were included in the analysis if they satisfied the following criteria: (1) they were case-control studies, (2) contained p53 codon 72 genotype data, (3) included sufficient data to calculate odds ratios (ORs), and (4) the study included patients diagnosed with endometriosis. No language restriction was applied. We excluded the following: (1) studies including overlapping data; (2) studies in which the number of null and wild genotypes could not be ascertained; (3) studies in which family members were studied because their analysis was based on linkage considerations; and (4) studies in which the genotype distribution in the controls was not consistent with the Hardy– Weinberg equilibrium (HWE), as deviation from the HWE among controls suggests the possibility of bias during control selection or genotyping errors. The following information was extracted from each study: author, year of publication, ethnicity of the study population, demographics, and number of cases and controls for each p53 codon 72 genotype. The frequencies of the alleles were calculated from corresponding genotype distributions. Data were extracted from the original studies by two independent reviewers. Discrepancies between the reviewers were resolved by reaching a consensus or by a third reviewer.
p53Codon 72 Polymorphism and Endometriosis
Evaluations of Statistical Associations A chi-squared test was used to determine whether the observed genotype frequencies conformed to H-W expectations. Meta-analyses were performed using 1) allelic contrast, 2) homozygote contrast, 3) recessive, and 4) dominant models. Point estimates of risks, odds ratios (ORs), and 95% confidence intervals (CIs) were estimated for each study, and within-study and betweenstudy variations and heterogeneities were assessed using Cochran’s Qstatistic. This heterogeneity test assesses the null hypothesis that all studies evaluated the same effect. The effect of heterogeneity was quantified using I2, which ranges between 0% and 100% and represents the proportion of betweenstudy variability that can be attributed to heterogeneity rather than chance (Higgins & Thompson, 2002). I2 values of 25%, 50%, and 75% were nominally assigned as low, moderate, and high estimates. The fixed effects model assumes that a genetic factor has a similar effect on endometriosis susceptibility across all studies investigated, and that observed variations among studies are caused by chance alone (Egger et al., 1997). The random effects model assumes that different studies show substantial diversity and assesses both within-study sampling errors and between-study variances (DerSimonian & Laird, 1986). When study groups are homogeneous, the 2 models are similar, but if this is not the case, the random effects model usually provides wider CIs than the fixed effects model; the random effects model is best used in the presence of significant betweenstudy heterogeneity (DerSimonian & Laird, 1986). Statistical manipulations were undertaken using a comprehensive meta-analysis computer program (Biostat, Englewood, NJ, USA). The power of each study was computed as the probability of detecting an association between the p53 polymorphism and diseases at a level of significance of 0.05, assuming an OR of 1.5 (small effect size). The power analysis was performed using the G*Power statistical program (http://www.psycho.uni-duesseldorf.de/aap/projects/gpower). Evaluation of Publication Bias Funnel plots are often used to detect publication bias. However, due to the limitations of funnel plotting, which requires a range of studies of varying sizes involving subjective judgments, we evaluated the publication bias using Egger’s linear regression test (Egger et al., 1997), which measures funnel plot asymmetry using a natural logarithm scale of ORs.
RESULTS Studies Included in the Meta-analysis Fifty-one studies were identified by electronic and manual searching and 12 were selected for a full-text review based on the title and abstract details (Ammendola et al., 2008; Bianco et al., 2011; Chang et al., 2002; GallegosArreola et al., 2012; Gloria-Bottini et al., 2013; Govatati et al., 2012; Hsieh & Lin, 2006; Lattuada et al., 2004; Omori et al., 2004; Paskulin et al., 2012; Vietri et al., 2007; Ying et al., 2011). Three studies were excluded because one contained no data (Gloria-Bottini et al., 2013), one had duplicate data(28), and one had a genotype distribution in controls that was not in HWE (GallegosArreola et al., 2012). Therefore, 9 studies met our inclusion criteria
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Figure 1. Study flow chart.
(Ammendola et al., 2008; Bianco et al., 2011; Chang et al., 2002; Govatati et al., 2012; Lattuada et al., 2004; Omori et al., 2004; Paskulin et al., 2012; Vietri et al., 2007; Ying et al., 2011), and in total these contained 1,803 patients and 2,006 controls (Figure 1, Table 1). These studies consisted of 3 European, 3 East Asian, 2 Latin American, and 1 South Asian study. Thus, ethnicityspecific meta-analysis was conducted on the European, East Asian, and Latin American populations. Selected details of the individual studies are summarized in Table 1. The statistical powers of these 9 studies ranged from 28.3% to 93.7%. One of the studies had a statistical power greater than 80% (Table 1). Frequencies of the C Allele of the p53 Codon 72 Polymorphism in Different Ethnic Groups The mean frequency of the C allele of the p53 codon 72 polymorphism was 37.5% among all the normal controls, and Europeans had lower C allele prevalence than the other ethnic groups. Again, among the normal controls, the frequencies of the C allele in the European, Latin American, East Asian, and South Asian populations were 28.2, 30.0, 41.8, and 46.2%, respectively (Table 2). Meta-analysis of the Relationship Between the p53 Codon 72 Polymorphism and Endometriosis Susceptibility A summary of meta-analysis findings concerning associations between the p53 polymorphism and endometriosis is shown in Table 3. Meta-analysis of the p53
Brazil India Taiwan Brazil Italy Italy Italy Japan Taiwan
Paskulin et al. (2012) Govatati et al. (2012) Ying et al. (2011) Bianco et al. (2011) Ammendola et al. (2008) Vietri et al. (2007) Lattuada et al. (2004) Omori et al. (2004) Chang et al. (2002)
Latin American South Asian East Asian Latin American European European European East Asian East Asian
Ethnicity 98 720 180 198 129 104 151 105 118
Case 300 500 330 169 147 88 152 180 140
Control 50 206 34 103 59 64 84 37 12
GG
Ref.:reference a Assuming an odds ratio of 1.5 (small effect size) at a 0.05 level of significance.
Country
Author (Ref)
Numbers
Table 1. Characteristics of the individual studies included in the meta-analysis.
35 373 99 73 57 36 60 51 79
GC
Case
13 141 47 22 13 4 7 17 27
CC 158 141 107 81 68 48 91 71 43
GG 114 256 169 65 59 36 47 75 70
GC
Control
28 103 54 23 20 4 14 34 27
CC
0.455 0.728 0.000 0.336 0.708 0.372 0.962 0.859 0.006
Association P value
51.4 93.7 61.7 48.2 38.2 28.3 41.3 39.3 36.1
Power (%)a
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C allele (%)
No. of studies
Case
Control
Case
Control
3 3 2 1 9
768 806 592 1,440 3,606
774 1,300 938 1,000 4,012
26.2 51.0 30.1 45.5 40.1
28.2 41.8 30.0 46.2 37.5
polymorphism showed no association between endometriosis and the p53 C allele in all study subjects (OR ¼ 1.087, 95% CI ¼ 0.921–1.282, p ¼ 0.323; Figure 2, Table 3). Stratification by ethnicity indicated no association between the p53 C allele and endometriosis in Europeans and Latin Americans (OR ¼ 0.929, 95% CI ¼ 0.737–1.158, p ¼ 0.490; OR ¼ 0.974, 95% CI ¼ 0.771– 1.231, p ¼ 0.826; Figure 3, Table 3). However, association was found between the p53 C allele and endometriosis in East Asians (OR ¼ 1.405, 95% CI ¼ 1.065–1.854, p ¼ 0.016) (Figure 3, Table 3). Furthermore, association was found between the p53 polymorphism and endometriosis in East Asians using the dominant model (OR ¼ 2.046, 95% CI ¼ 1.123–3.730, p ¼ 0.019; Table 3). Analysis using the recessive model and the homozygote contrast showed the trend of the same p53 C allele pattern in East Asians (OR ¼ 1.359, 95% CI ¼ 0.995–1.854, p ¼ 0.054; OR ¼ 2.097, 95% CI ¼ 0.985–4.466, p ¼ 0.055; Table 3). Heterogeneity and Publication Bias There was no between-study heterogeneity in the meta-analyses of the p53 polymorphism in Europeans and Latin Americans, but some heterogeneity was found during meta-analyses of the p53 polymorphism in the East Asian groups and total populations. However, no evidence of heterogeneity was identified in the meta-analyses using the recessive model of the p53 polymorphism (Table 3). Publication bias causes a disproportionate number of positive studies and poses a problem for meta-analyses, but Egger’s regression test showed no evidence of publication bias in the studies analyzed (Egger’s regression test p values were 40.1) (Figure 4, Table 3).
DISCUSSION Although the multifactorial nature of endometriosis is well recognized, genetic factors are considered strong determinants of these diseases, and therefore, researchers have been encouraged to search for the genes responsible. In this meta-analysis, we combined the results from previous studies to analyze the association between p53 codon 72 polymorphism and susceptibility to endometriosis. Our meta-analysis showed a significant association between the p53 codon 72 polymorphism and endometriosis in East Asians, but no association in Europeans and Latin Americans. The association observed between the p53 codon 72 polymorphism and the risks of endometriosis in this meta-analysis suggest that this polymorphism is a risk factor for
Overall European East Asian Latin American
Overall European East Asian Latin American
Overall European East Asian Latin American
CC vs. GC + CC (Recessive)
CC + GC vs. CC (Dominant)
CC vs. GG
9 3 3 2
9 3 3 2
9 3 3 2
9 3 3 2
No. of studies
OR, odds ratio; CI, confidence interval; F, fixed model; R, random model.
Overall European East Asian Latin American
Population
P53 C vs. G
Polymorphism
1.171 0.671 2.097 1.012
1.208 1.005 2.046 0.941
1.035 0.640 1.359 1.047
1.087 0.929 1.405 0.974
OR
0.784–1.748 0.384–1.171 0.985–4.466 0.622–1.647
0.929–1.571 0.755–1.337 1.123–3.730 0.693–1.277
0.864–1.239 0.373–1.096 0.995–1.854 0.657–1.669
0.921–1.282 0.737–1.158 1.065–1.854 0.771–1.231
95% CI
Test of association
Table 3. Meta-analysis of the associations between the p53 codon 72 polymorphism and endometriosis.
0.441 0.160 0.055 0.962
0.159 0.972 0.019 0.696
0.711 0.104 0.054 0.847
0.323 0.490 0.016 0.826
p Value
R F R F
R F R F
F F F F
R F R F
Model
0.002 0.864 0.027 0.181
0.002 0.467 0.026 0.463
0.122 0.746 0.138 0.190
0.009 0.793 0.099 0.231
p Value
Test of heterogeneity
67.2 0 72.2 43.9
67.7 0 73.5 0
37.1 0 48.5 41.6
60.5 0 56.6 30.2
I2
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Figure 2. Odds ratios and 95% confidence intervals of individual studies and pooled data for the association between the C allele of the p53 codon 72 polymorphism and endometriosis in all study subjects.
Figure 3. Odds ratios and 95% confidence intervals of individual studies and pooled data for the association between the C allele of the p53 codon 72 polymorphism and endometriosis in each ethnic group.
endometriosis in East Asians, but not in Europeans and Latin Americans. It is unclear why the association of this polymorphism differs among diverse ethnic groups. However, it may be explained by ethnic difference, because the frequency of the C allele of the p53 codon 72 polymorphism varies across different ethnicities. The p53 Pro allele had a frequency of 28.2% in the European, 30.0% in the Latin American, 41.8% in the East Asian, and 46.2% in the South Asian populations. Endometriosis could be associated with an imbalance between apoptosis and proliferation. It is known the Pro variant of the p53 codon 72 polymorphism is a less efficient inducer of apoptosis than the Arg variant (Dumont et al., 2003; Thomas et al., 1999), and the dysregulation of apoptosis could contribute to the pathogenesis of endometriosis (Taniguchi et al., 2011). In the present study, we observed an over-representation of the Pro allele in endometriosis as compared
p53Codon 72 Polymorphism and Endometriosis
Figure 4. Funnel plot of studies showing the association between the C allele of the p53 codon 72 polymorphism and endometriosis in all study subjects (Egger’s regression p value ¼ 0.898).
with controls. We suggest that the association between the Pro allele of the p53 codon 72 and endometriosis susceptibility might be due to less efficient apoptosis-induction by the Pro allele. However, our results should be interpreted with caution because of the limited number of studies included in this meta-analysis, which restricted further subgroup analyses. This meta-analysis differs from a previous meta-analysis analyzing the relationship between the p53 codon 72 polymorphism and endometriosis risk performed by Jia et al. (2012). Specifically, in the present report, 4 more studies (Bianco et al., 2011; Govatati et al., 2012; Paskulin et al., 2012; Ying et al., 2011), 1,196 more patients, and 1,299 more controls were included; and one study was excluded due to duplicate data (Hsieh & Lin, 2006). However, the result of this meta-analysis regarding the association of the p53 Pro allele with the development of endometriosis is in agreement with the previous study. Interactions between genes are common and may have an important role in determining the susceptibility to multifactorial disease (Ammendola et al., 2008). The possibility of interaction between p53 codon 72 and PTPN22 polymorphisms has been observed. The protective role of Arg/Arg against endometriosis observed in the Chinese population was present in the Italian population but only in subjects carrying the T allele of PTPN22 polymorphism (Ammendola et al., 2008; Gloria-Bottini et al., 2013). The interaction with PTPN22 suggests a possible explanation for the differences observed among populations (Ammendola et al., 2008). These systems may have different frequencies in Oriental as compared to European populations resulting in different strength of the association between p53 and endometriosis. The present study has some limitations that require consideration. First, heterogeneity and confounding factors might have distorted the meta-analysis. In addition, publication bias would have affected the results because studies that produced negative results may not have been published or may have been missed. Despite, our use of Egger’s regression test, we cannot eliminate the
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possibility of bias. Second, this meta-analysis included data from European, East Asian, and Latin American patients, and therefore, our results are only applicable to these ethnic groups. Third, the p53 codon 72 polymorphism may also be associated with the severity of endometriosis. However, the small amount of data available did not allow us to perform meta-analysis on the association between the p53 codon 72 polymorphisms and disease severity. Fourth, the number of studies was too small to conclude the association between the p53 polymorphism and endometriosis, especially in the different ethnic groups. Indeed, only 3 p53 polymorphism studies were conducted on East Asian and European patients and only 2 on Latin American patients. The meta-analysis suggests that the p53 codon 72 polymorphism is associated with susceptibility to endometriosis in Asians, but not in Europeans and Latin Americans. In addition, the mean frequency of the C allele of the p53 codon 72 polymorphism varied across ethnicity. These findings suggest that further investigations are needed to determine the associations between p53 polymorphisms and endometriosis susceptibility in different ethnic groups. Specifically, larger scale studies in different ethnic populations are required to explore the roles of polymorphisms of the p53 gene in the pathogeneses of endometriosis.
DECLARATION OF INTEREST The authors have no financial and non-financial conflicts of interest to declare. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. The authors alone are responsible for the content and writing of the paper.
REFERENCES Ammendola M, Gloria-Bottini F, Sesti F, et al. (2008). Association of p53 codon 72 polymorphism with endometriosis. Fertil Steril, 90, 406–8. Bianco B, Christofolini DM, Brandes A, et al. (2011). [Analysis of codon 72 polymorphism of the TP53 gene in infertile women with and without endometriosis]. Rev Bras Ginecol Obstet, 33, 37–42. Chang CC, Hsieh YY, Tsai FJ, et al. (2002). The proline form of p53 codon 72 polymorphism is associated with endometriosis. Fertil Steril, 77, 43–5. Choi SJ, Rho YH, Ji JD, et al. (2006). Genome scan meta-analysis of rheumatoid arthritis. Rheumatology (Oxford), 45, 166–70. DerSimonian R, Laird N. (1986). Meta-analysis in clinical trials. Control Clin Trials, 7, 177–88. Dumont P, Leu JI, Della Pietra 3rd AC, et al. (2003). The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nat Genet, 33, 357–65. Egger M, Smith GD, Phillips AN. (1997). Meta-analysis: Principles and procedures. BMJ, 315, 1533–7. Egger M, Davey Smith G, Schneider M, Minder C. (1997). Bias in meta-analysis detected by a simple, graphical test. BMJ, 315, 629–34. Gallegos-Arreola MP, Figuera-Villanueva LE, Puebla-Perez AM, et al. (2012). Association of TP53 gene codon 72 polymorphism with endometriosis in Mexican women. Genet Mol Res, 11, 1401–8. Giudice LC, Kao LC. (2004). Endometriosis. Lancet, 364, 1789–99. Govatati S, Chakravarty B, Deenadayal M, et al. (2012). p53 and risk of endometriosis in Indian women. Genet Test Mol Biomarkers, 16, 865–73.
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Gloria-Bottini F, Ammendola M, Saccucci P, et al. (2013). The association of PTPN22 polymorphism with endometriosis: Effect of genetic and clinical factors. Eur J Obstet Gynecol Reprod Biol, 169, 60–63. Halis G, Arici A. (2004). Endometriosis and inflammation in infertility. Ann N Y Acad Sci, 1034, 300–15. Higgins JP, Thompson SG. (2002). Quantifying heterogeneity in a meta-analysis. Stat Med, 21, 1539–58. Hsieh YY, Lin CS. (2006). P53 codon 11, 72, and 248 gene polymorphisms in endometriosis. Int J Biol Sci, 2, 188–93. Jia S, Xu L, Chan Y, et al. (2012). p53 codon 72 polymorphism and endometriosis: A meta-analysis. Arch Gynecol Obstet, 285, 1657–61. Kennedy S. (1998). The genetics of endometriosis. J Reprod Med, 43, 263–8. Koushik A, Platt RW, Franco EL. (2004). p53 codon 72 polymorphism and cervical neoplasia: A meta-analysis review. Cancer Epidemiol Biomarkers Prev, 13, 11–22. Lattuada D, Vigano P, Somigliana E, et al. (2004). Analysis of the codon 72 polymorphism of the TP53 gene in patients with endometriosis. Mol Hum Reprod, 10, 651–4. Lee YH, Witte T, Momot T, et al. (2005). The mannose-binding lectin gene polymorphisms and systemic lupus erythematosus: Two case-control studies and a metaanalysis. Arthritis Rheum, 52, 3966–74. Levine AJ. p53, the cellular gatekeeper for growth and division. Cell, (1997).88, 323–31. Matlashewski GJ, Tuck S, Pim D, et al. (1987). Primary structure polymorphism at amino acid residue 72 of human p53. Mol Cell Biol, 7, 961–3. Nath SK, Harley JB, Lee YH. (2005). Polymorphisms of complement receptor 1 and interleukin-10 genes and systemic lupus erythematosus: A meta-analysis. Hum Genet, 118, 225–34. Omori S, Yoshida S, Kennedy SH, et al. (2004). Polymorphism at codon 72 of the p53 gene is not associated with endometriosis in a Japanese population. J Soc Gynecol Investig, 11, 232–6. Paskulin DD, Cunha-Filho JS, Souza CA, et al. (2012). TP53 PIN3 and PEX4 polymorphisms and infertility associated with endometriosis or with post-in vitro fertilization implantation failure. Cell Death Dis, 3, e392.1–6. Pim D, Banks L. (2004). p53 polymorphic variants at codon 72 exert different effects on cell cycle progression. Int J Cancer, 108, 196–9. Taniguchi F, Kaponis A, Izawa M, et al. (2011). Apoptosis and endometriosis. Front Biosci (Elite Ed), 3, 648–62. Thomas M, Kalita A, Labrecque S, et al. (1999). Two polymorphic variants of wild-type p53 differ biochemically and biologically. Mol Cell Biol, 19, 1092–100. Varma R, Rollason T, Gupta JK, Maher ER. (2004). Endometriosis and the neoplastic process. Reproduction, 127, 293–304. Vietri MT, Molinari AM, Iannella I, et al. (2007). Arg72Pro p53 polymorphism in Italian women: No association with endometriosis. Fertil Steril, 88, 1468–9. Ying TH, Tseng CJ, Tsai SJ, et al. (2011). Association of p53 and CDKN1A genotypes with endometriosis. Anticancer Res, 31, 4301–6.
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A Meta-analysis of the Association between p53 Codon 72 Polymorphism and Susceptibility to Endometriosis Gwan Gyu Song and Young Ho Lee Division of Rheumatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea Objective: The aim of this study was to determine whether the p53 codon 72 polymorphism is associated with susceptibility to endometriosis. Methods: A meta-analysis was conducted on the associations between the p53 codon 72 polymorphism and endometriosis using 1) allele contrast, 2) a recessive model, 3) a dominant model, and 4) homozygote contrast. Results: Nine studies involving 1,803 patients and 2,006 controls were considered in the meta-analysis. Meta-analysis of the p53 polymorphism showed no association between endometriosis and the p53 C allele (odds ratio (OR) ¼ 1.087, 95% confidence interval (CI) ¼ 0.921–1.282, p ¼ 0.323). Stratification by ethnicity indicated no association between the p53 C allele and endometriosis in Europeans and Latin Americans. However, a significant association was found between the p53 C allele and endometriosis in East Asians (OR ¼ 1.405, 95% CI ¼ 1.065–1.854, p ¼ 0.016). Furthermore, association was found between the p53 polymorphism and endometriosis in East Asians using the dominant model (OR ¼ 2.046, 95% CI ¼ 1.123–3.730, p ¼ 0.019). Conclusions: This meta-analysis demonstrates that the p53 codon 72 polymorphism may be associated with susceptibility to endometriosis in East Asians, but not in Europeans and Latin Americans. Keywords Endometriosis, meta-analysis, p53, polymorphism
INTRODUCTION Endometriosis is a chronic disease that is characterized by the growth of endometrial tissue outside the uterine cavity and frequently leads to dyspareunia, dysmenorrhea, pelvic pain, and infertility (Halis & Arici, 2004). Although the etiology of endometriosis is not fully understood, it is clear that genetics play a role (Kennedy, 1998). Endometriosis is a benign disease, but appears similar to malignancies, in that it can exist as a local invasion or spread to distant organs (Giudice & Kao, 2004; Varma et al., 2004). Tumor suppressor genes may play a role in the pathogenesis of endometriosis. The tumor suppressor gene p53 plays central roles in apoptosis and cell proliferation and death (Levine, 1997). Two common polymorphic variants of wild-type p53 (rs1042522) have been identified (Matlashewski et al., 1987). These arise from a single-base-pair substitution at codon 72, which results in either CCC (Pro) or CGC (Arg). These p53 variants have been shown to Correspondence: Young Ho Lee, Division of Rheumatology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, 1261, Anam-dong 5-ga, Seongbuk-gu, Seoul 136-705, Korea. E-mail: [email protected]
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influence the function of p53 proteins in apoptosis, cell cycle control, and DNA repair (Pim & Banks, 2004) In addition, it has been shown that the 2 variants differ biochemically and biologically (Dumont et al., 2003; Thomas et al., 1999). The p53 Pro variant (C allele) is a stronger transcription factor activator, but a poorer apoptotic inducer than the p53 Arg variant (G allele), which is more susceptible to degradation. Therefore, the p53 C allele codon 72 polymorphism is associated with several types of cancer (Koushik et al., 2004). The p53 codon 72 polymorphism has also been associated with endometriosis in some reports, but not all (Ammendola et al., 2008; Bianco et al., 2011; Chang et al., 2002; Govatati et al., 2012; Lattuada et al., 2004; Omori et al., 2004; Paskulin et al., 2012; Vietri et al., 2007; Ying et al., 2011). The reasons for this disparity may be small sample sizes, low statistical power, and/or clinical heterogeneity. Therefore, to overcome the limitations of individual studies, resolve inconsistencies, and reduce the likelihood of random errors producing false-positive or false-negative associations (Choi et al., 2006; Lee et al., 2005; Nath et al., 2005), we used meta-analysis. The aim of the present study was to determine using meta-analysis whether the p53 codon 72 polymorphism is associated with susceptibility to endometriosis.
METHODS Identification of Eligible Studies and Data Extraction We performed a search for studies that examined associations between the p53 codon 72 polymorphism and endometriosis. The literature was searched using the MEDLINE and EMBASE citation databases to identify available articles in which the p53 codon 72 polymorphism was analyzed in endometriosis. Combinations of keywords such as p53, polymorphism, and endometriosis were entered as the Medical Subject Heading (MeSH) components and as text words. The references in the identified studies were also investigated to identify additional studies not indexed by MEDLINE and EMBASE. Studies were included in the analysis if they satisfied the following criteria: (1) they were case-control studies, (2) contained p53 codon 72 genotype data, (3) included sufficient data to calculate odds ratios (ORs), and (4) the study included patients diagnosed with endometriosis. No language restriction was applied. We excluded the following: (1) studies including overlapping data; (2) studies in which the number of null and wild genotypes could not be ascertained; (3) studies in which family members were studied because their analysis was based on linkage considerations; and (4) studies in which the genotype distribution in the controls was not consistent with the Hardy– Weinberg equilibrium (HWE), as deviation from the HWE among controls suggests the possibility of bias during control selection or genotyping errors. The following information was extracted from each study: author, year of publication, ethnicity of the study population, demographics, and number of cases and controls for each p53 codon 72 genotype. The frequencies of the alleles were calculated from corresponding genotype distributions. Data were extracted from the original studies by two independent reviewers. Discrepancies between the reviewers were resolved by reaching a consensus or by a third reviewer.
p53Codon 72 Polymorphism and Endometriosis
Evaluations of Statistical Associations A chi-squared test was used to determine whether the observed genotype frequencies conformed to H-W expectations. Meta-analyses were performed using 1) allelic contrast, 2) homozygote contrast, 3) recessive, and 4) dominant models. Point estimates of risks, odds ratios (ORs), and 95% confidence intervals (CIs) were estimated for each study, and within-study and betweenstudy variations and heterogeneities were assessed using Cochran’s Qstatistic. This heterogeneity test assesses the null hypothesis that all studies evaluated the same effect. The effect of heterogeneity was quantified using I2, which ranges between 0% and 100% and represents the proportion of betweenstudy variability that can be attributed to heterogeneity rather than chance (Higgins & Thompson, 2002). I2 values of 25%, 50%, and 75% were nominally assigned as low, moderate, and high estimates. The fixed effects model assumes that a genetic factor has a similar effect on endometriosis susceptibility across all studies investigated, and that observed variations among studies are caused by chance alone (Egger et al., 1997). The random effects model assumes that different studies show substantial diversity and assesses both within-study sampling errors and between-study variances (DerSimonian & Laird, 1986). When study groups are homogeneous, the 2 models are similar, but if this is not the case, the random effects model usually provides wider CIs than the fixed effects model; the random effects model is best used in the presence of significant betweenstudy heterogeneity (DerSimonian & Laird, 1986). Statistical manipulations were undertaken using a comprehensive meta-analysis computer program (Biostat, Englewood, NJ, USA). The power of each study was computed as the probability of detecting an association between the p53 polymorphism and diseases at a level of significance of 0.05, assuming an OR of 1.5 (small effect size). The power analysis was performed using the G*Power statistical program (http://www.psycho.uni-duesseldorf.de/aap/projects/gpower). Evaluation of Publication Bias Funnel plots are often used to detect publication bias. However, due to the limitations of funnel plotting, which requires a range of studies of varying sizes involving subjective judgments, we evaluated the publication bias using Egger’s linear regression test (Egger et al., 1997), which measures funnel plot asymmetry using a natural logarithm scale of ORs.
RESULTS Studies Included in the Meta-analysis Fifty-one studies were identified by electronic and manual searching and 12 were selected for a full-text review based on the title and abstract details (Ammendola et al., 2008; Bianco et al., 2011; Chang et al., 2002; GallegosArreola et al., 2012; Gloria-Bottini et al., 2013; Govatati et al., 2012; Hsieh & Lin, 2006; Lattuada et al., 2004; Omori et al., 2004; Paskulin et al., 2012; Vietri et al., 2007; Ying et al., 2011). Three studies were excluded because one contained no data (Gloria-Bottini et al., 2013), one had duplicate data(28), and one had a genotype distribution in controls that was not in HWE (GallegosArreola et al., 2012). Therefore, 9 studies met our inclusion criteria
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Figure 1. Study flow chart.
(Ammendola et al., 2008; Bianco et al., 2011; Chang et al., 2002; Govatati et al., 2012; Lattuada et al., 2004; Omori et al., 2004; Paskulin et al., 2012; Vietri et al., 2007; Ying et al., 2011), and in total these contained 1,803 patients and 2,006 controls (Figure 1, Table 1). These studies consisted of 3 European, 3 East Asian, 2 Latin American, and 1 South Asian study. Thus, ethnicityspecific meta-analysis was conducted on the European, East Asian, and Latin American populations. Selected details of the individual studies are summarized in Table 1. The statistical powers of these 9 studies ranged from 28.3% to 93.7%. One of the studies had a statistical power greater than 80% (Table 1). Frequencies of the C Allele of the p53 Codon 72 Polymorphism in Different Ethnic Groups The mean frequency of the C allele of the p53 codon 72 polymorphism was 37.5% among all the normal controls, and Europeans had lower C allele prevalence than the other ethnic groups. Again, among the normal controls, the frequencies of the C allele in the European, Latin American, East Asian, and South Asian populations were 28.2, 30.0, 41.8, and 46.2%, respectively (Table 2). Meta-analysis of the Relationship Between the p53 Codon 72 Polymorphism and Endometriosis Susceptibility A summary of meta-analysis findings concerning associations between the p53 polymorphism and endometriosis is shown in Table 3. Meta-analysis of the p53
Brazil India Taiwan Brazil Italy Italy Italy Japan Taiwan
Paskulin et al. (2012) Govatati et al. (2012) Ying et al. (2011) Bianco et al. (2011) Ammendola et al. (2008) Vietri et al. (2007) Lattuada et al. (2004) Omori et al. (2004) Chang et al. (2002)
Latin American South Asian East Asian Latin American European European European East Asian East Asian
Ethnicity 98 720 180 198 129 104 151 105 118
Case 300 500 330 169 147 88 152 180 140
Control 50 206 34 103 59 64 84 37 12
GG
Ref.:reference a Assuming an odds ratio of 1.5 (small effect size) at a 0.05 level of significance.
Country
Author (Ref)
Numbers
Table 1. Characteristics of the individual studies included in the meta-analysis.
35 373 99 73 57 36 60 51 79
GC
Case
13 141 47 22 13 4 7 17 27
CC 158 141 107 81 68 48 91 71 43
GG 114 256 169 65 59 36 47 75 70
GC
Control
28 103 54 23 20 4 14 34 27
CC
0.455 0.728 0.000 0.336 0.708 0.372 0.962 0.859 0.006
Association P value
51.4 93.7 61.7 48.2 38.2 28.3 41.3 39.3 36.1
Power (%)a
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G. G. Song & Y. H. Lee Table 2. Prevalence of the C allele of the p53 codon 72 polymorphism. Numbers Population European East Asian Latin American South Asian Overall
C allele (%)
No. of studies
Case
Control
Case
Control
3 3 2 1 9
768 806 592 1,440 3,606
774 1,300 938 1,000 4,012
26.2 51.0 30.1 45.5 40.1
28.2 41.8 30.0 46.2 37.5
polymorphism showed no association between endometriosis and the p53 C allele in all study subjects (OR ¼ 1.087, 95% CI ¼ 0.921–1.282, p ¼ 0.323; Figure 2, Table 3). Stratification by ethnicity indicated no association between the p53 C allele and endometriosis in Europeans and Latin Americans (OR ¼ 0.929, 95% CI ¼ 0.737–1.158, p ¼ 0.490; OR ¼ 0.974, 95% CI ¼ 0.771– 1.231, p ¼ 0.826; Figure 3, Table 3). However, association was found between the p53 C allele and endometriosis in East Asians (OR ¼ 1.405, 95% CI ¼ 1.065–1.854, p ¼ 0.016) (Figure 3, Table 3). Furthermore, association was found between the p53 polymorphism and endometriosis in East Asians using the dominant model (OR ¼ 2.046, 95% CI ¼ 1.123–3.730, p ¼ 0.019; Table 3). Analysis using the recessive model and the homozygote contrast showed the trend of the same p53 C allele pattern in East Asians (OR ¼ 1.359, 95% CI ¼ 0.995–1.854, p ¼ 0.054; OR ¼ 2.097, 95% CI ¼ 0.985–4.466, p ¼ 0.055; Table 3). Heterogeneity and Publication Bias There was no between-study heterogeneity in the meta-analyses of the p53 polymorphism in Europeans and Latin Americans, but some heterogeneity was found during meta-analyses of the p53 polymorphism in the East Asian groups and total populations. However, no evidence of heterogeneity was identified in the meta-analyses using the recessive model of the p53 polymorphism (Table 3). Publication bias causes a disproportionate number of positive studies and poses a problem for meta-analyses, but Egger’s regression test showed no evidence of publication bias in the studies analyzed (Egger’s regression test p values were 40.1) (Figure 4, Table 3).
DISCUSSION Although the multifactorial nature of endometriosis is well recognized, genetic factors are considered strong determinants of these diseases, and therefore, researchers have been encouraged to search for the genes responsible. In this meta-analysis, we combined the results from previous studies to analyze the association between p53 codon 72 polymorphism and susceptibility to endometriosis. Our meta-analysis showed a significant association between the p53 codon 72 polymorphism and endometriosis in East Asians, but no association in Europeans and Latin Americans. The association observed between the p53 codon 72 polymorphism and the risks of endometriosis in this meta-analysis suggest that this polymorphism is a risk factor for
Overall European East Asian Latin American
Overall European East Asian Latin American
Overall European East Asian Latin American
CC vs. GC + CC (Recessive)
CC + GC vs. CC (Dominant)
CC vs. GG
9 3 3 2
9 3 3 2
9 3 3 2
9 3 3 2
No. of studies
OR, odds ratio; CI, confidence interval; F, fixed model; R, random model.
Overall European East Asian Latin American
Population
P53 C vs. G
Polymorphism
1.171 0.671 2.097 1.012
1.208 1.005 2.046 0.941
1.035 0.640 1.359 1.047
1.087 0.929 1.405 0.974
OR
0.784–1.748 0.384–1.171 0.985–4.466 0.622–1.647
0.929–1.571 0.755–1.337 1.123–3.730 0.693–1.277
0.864–1.239 0.373–1.096 0.995–1.854 0.657–1.669
0.921–1.282 0.737–1.158 1.065–1.854 0.771–1.231
95% CI
Test of association
Table 3. Meta-analysis of the associations between the p53 codon 72 polymorphism and endometriosis.
0.441 0.160 0.055 0.962
0.159 0.972 0.019 0.696
0.711 0.104 0.054 0.847
0.323 0.490 0.016 0.826
p Value
R F R F
R F R F
F F F F
R F R F
Model
0.002 0.864 0.027 0.181
0.002 0.467 0.026 0.463
0.122 0.746 0.138 0.190
0.009 0.793 0.099 0.231
p Value
Test of heterogeneity
67.2 0 72.2 43.9
67.7 0 73.5 0
37.1 0 48.5 41.6
60.5 0 56.6 30.2
I2
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Figure 2. Odds ratios and 95% confidence intervals of individual studies and pooled data for the association between the C allele of the p53 codon 72 polymorphism and endometriosis in all study subjects.
Figure 3. Odds ratios and 95% confidence intervals of individual studies and pooled data for the association between the C allele of the p53 codon 72 polymorphism and endometriosis in each ethnic group.
endometriosis in East Asians, but not in Europeans and Latin Americans. It is unclear why the association of this polymorphism differs among diverse ethnic groups. However, it may be explained by ethnic difference, because the frequency of the C allele of the p53 codon 72 polymorphism varies across different ethnicities. The p53 Pro allele had a frequency of 28.2% in the European, 30.0% in the Latin American, 41.8% in the East Asian, and 46.2% in the South Asian populations. Endometriosis could be associated with an imbalance between apoptosis and proliferation. It is known the Pro variant of the p53 codon 72 polymorphism is a less efficient inducer of apoptosis than the Arg variant (Dumont et al., 2003; Thomas et al., 1999), and the dysregulation of apoptosis could contribute to the pathogenesis of endometriosis (Taniguchi et al., 2011). In the present study, we observed an over-representation of the Pro allele in endometriosis as compared
p53Codon 72 Polymorphism and Endometriosis
Figure 4. Funnel plot of studies showing the association between the C allele of the p53 codon 72 polymorphism and endometriosis in all study subjects (Egger’s regression p value ¼ 0.898).
with controls. We suggest that the association between the Pro allele of the p53 codon 72 and endometriosis susceptibility might be due to less efficient apoptosis-induction by the Pro allele. However, our results should be interpreted with caution because of the limited number of studies included in this meta-analysis, which restricted further subgroup analyses. This meta-analysis differs from a previous meta-analysis analyzing the relationship between the p53 codon 72 polymorphism and endometriosis risk performed by Jia et al. (2012). Specifically, in the present report, 4 more studies (Bianco et al., 2011; Govatati et al., 2012; Paskulin et al., 2012; Ying et al., 2011), 1,196 more patients, and 1,299 more controls were included; and one study was excluded due to duplicate data (Hsieh & Lin, 2006). However, the result of this meta-analysis regarding the association of the p53 Pro allele with the development of endometriosis is in agreement with the previous study. Interactions between genes are common and may have an important role in determining the susceptibility to multifactorial disease (Ammendola et al., 2008). The possibility of interaction between p53 codon 72 and PTPN22 polymorphisms has been observed. The protective role of Arg/Arg against endometriosis observed in the Chinese population was present in the Italian population but only in subjects carrying the T allele of PTPN22 polymorphism (Ammendola et al., 2008; Gloria-Bottini et al., 2013). The interaction with PTPN22 suggests a possible explanation for the differences observed among populations (Ammendola et al., 2008). These systems may have different frequencies in Oriental as compared to European populations resulting in different strength of the association between p53 and endometriosis. The present study has some limitations that require consideration. First, heterogeneity and confounding factors might have distorted the meta-analysis. In addition, publication bias would have affected the results because studies that produced negative results may not have been published or may have been missed. Despite, our use of Egger’s regression test, we cannot eliminate the
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possibility of bias. Second, this meta-analysis included data from European, East Asian, and Latin American patients, and therefore, our results are only applicable to these ethnic groups. Third, the p53 codon 72 polymorphism may also be associated with the severity of endometriosis. However, the small amount of data available did not allow us to perform meta-analysis on the association between the p53 codon 72 polymorphisms and disease severity. Fourth, the number of studies was too small to conclude the association between the p53 polymorphism and endometriosis, especially in the different ethnic groups. Indeed, only 3 p53 polymorphism studies were conducted on East Asian and European patients and only 2 on Latin American patients. The meta-analysis suggests that the p53 codon 72 polymorphism is associated with susceptibility to endometriosis in Asians, but not in Europeans and Latin Americans. In addition, the mean frequency of the C allele of the p53 codon 72 polymorphism varied across ethnicity. These findings suggest that further investigations are needed to determine the associations between p53 polymorphisms and endometriosis susceptibility in different ethnic groups. Specifically, larger scale studies in different ethnic populations are required to explore the roles of polymorphisms of the p53 gene in the pathogeneses of endometriosis.
DECLARATION OF INTEREST The authors have no financial and non-financial conflicts of interest to declare. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. The authors alone are responsible for the content and writing of the paper.
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