Catechol-O-methyltransferase 158G/A polymorphism and endometriosis/adenomyosis susceptibility: A meta-analysis in the Chinese population

Endometriosis and adenomyosis are two common gynecological disorders. Both diseases are characterized by the presence of endometrial glands and stroma outside their normal locations. Endometriosis is defined as the presence of endometrial tissue outside the uterine cavity, whereas adenomyosis refers to the condition when endometrial tissues invade the myometrium with smooth muscle hyperplasia.[] The prevalence of endometriosis has been reported to be 2–22% in women of childbearing age, whereas adenomyosis has a prevalence of 20–35% in the infertility clinic, and varies by ethnic groups.[] Despite extensive research on endometriosis and adenomyosis, our current knowledge of its etiology and pathogenesis is quite limited.[] A growing body of evidence has indicated that both diseases are likely to be determined by multifactorial factors. Susceptibility to endometriosis and adenomyosis depends on complex interactions between immunologic, hormonal, environmental, and genetic factors.[] In recent years, several common low-penetrant genes have been identified as potential endometriosis and adenomyosis susceptibility genes. An important one is catechol-O-methyltransferase (COMT), the G/A nonsynonymous single-nucleotide polymorphism at codon 158 in the COMT gene leads to valine-to-methionine substitution, which apparently influences the enzyme activity.[] An association between COMT 158G/A polymorphism and endometriosis was first reported by Wieser et al. in 2002 in Australian.[] As a consequence, many studies analyzed the influence of COMT 158G/A polymorphism on endometriosis and adenomyosis risk; however, no clear consensus was reached. To lessen the impact of different genetic background, we performed this meta-analysis to assess the relationship of COMT 158G/A polymorphism with risk of endometriosis and adenomyosis in the Chinese population.

Search strategy and study selection A systematic literature search was conducted for published articles concerning the association of COMT 158G/A polymorphism and endometriosis/adenomyosis risk. The search included PubMed, Springer Link, Chinese Biomedical Database, Chinese National Knowledge Infrastructure, Chinese VIP, and Wanfang databases for articles published through December 2015 using the Mesh terms: (endometriosis or adenomyosis) and (COMT). The search was performed without any restrictions on language and focused on studies conducted in humans. All reference lists of retrieved articles were manually reviewed to identify the additional articles. Criteria for inclusion in the meta-analysis were (1) case–control or cohort studies describing the association of COMT 158G/A polymorphism and endometriosis/adenomyosis; (2) availability of data on genotype distribution in both cases and controls; (3) all participants were Chinese. The reasons for exclusion of the studies were (1) duplicate publications, (2) incomplete data, (3) lack of controls, and (4) meta-analyses, letters, reviews, or editorial articles. Data extraction We conducted this meta-analysis in accordance with the guidelines provided by the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement.[] The title and abstract of all potentially relevant articles were screened to determine their relevance. Full articles were also scrutinized if the title and abstract were ambiguous. Information from all eligible publications was independently extracted by two authors. Discrepancies between the two authors were resolved by discussion, and if a consensus was not achieved, a decision was made by all the reviewers. Data extracted from identified studies included first author's name, publication year, geographic area(s), study population ethnicities, source of controls, sample size, and number of subjects with COMT 158G/A genotypes. If data from any category were not reported in the primary study, we did not contact the author to request the information. The categorization of ethnicity comprised Han and other ethnic Chinese. Statistical analysis Statistical analysis was conducted using Stata 14 software.[] Odds ratios (ORs) with 95% confidence intervals (CIs) were used to determine the strength of associations between the COMT 158G/A polymorphism and risk for endometriosis and adenomyosis. The significance of pooled ORs was determined by a Z-test. Cochran's Q-statistic was used to assess between-study heterogeneity. A significant Q-statistic (P < 0.10) indicated heterogeneity across studies. In cases of heterogeneity, the random-effects model was chosen to pool ORs with 95% CIs; otherwise, the fixed-effects model was used. Hardy–Weinberg equilibrium for controls was calculated using the goodness-of-fit test; deviation was considered when P < 0.05. Sensitivity analyses were performed using fixed- and random-effects models. All P values were two-sided. P <0.05 was considered statistically significant. Subgroup analyses stratified by source of controls, ethnicity, and disease groups were also performed.

Description of included studies A total of 86 articles that examined the association between COMT 158G/A polymorphism and risk of endometriosis/adenomyosis were identified. After screening the titles and abstracts of these articles, 75 were excluded from the study. Of the remaining 11 potentially relevant articles,[] one article[] were excluded due to a lack of genotype data, and three[] articles were excluded because they concerned subjects included in an expanded series.[] The flow chart of the study selection is shown in Figure 1. Finally, seven case-control studies[] published between 2006 and 2013 comprising 782 cases, and 700 controls met the inclusion criteria. The characteristics of the included studies are summarized in Table 1. Overall analysis The main results of this meta-analysis and the heterogeneity test were shown in Table 2. There was no evidence of between-study heterogeneity among all included studies. Therefore, the fixed-effects model was used in the overall analysis. A significant association between COMT 158G/A polymorphism and the risk of endometriosis and adenomyosis was found in allele and homozygous models (A vs. G, OR = 1.21, 95% CI: 1.02–1.42; AA vs. GG, OR = 1.47, 95% CI: 1.01–2.14; AA vs. GG + GA, OR = 1.42, 95% CI: 0.99–2.03; AA + GA vs. GG, OR = 1.20, 95% CI: 0.97–1.49) [Figure 2]. Subgroup and sensitivity analyses In the subgroup analyses based on the ethnicity and source of controls, the results showed that the association between COMT 158G/A polymorphism and risk for endometriosis and adenomyosis is statistically significant among Chinese not mentioned the ethnicity and population-based (PB) studies (A vs. G, OR = 1.31, 95% CI: 1.08–1.60; AA vs. GG, OR = 1.94, 95% CI: 1.25–3.03; AA vs. GG + GA, OR = 1.88, 95% CI: 1.23–2.86), but not among Chinese Han and hospital-based (HB) studies [Table 2]. In addition, we also performed stratified analysis based on the disease groups, it revealed the significant results for adenomyosis in all genetic models (A vs. G, OR = 1.42, 95% CI: 1.11–1.82; AA vs. GG, OR = 2.08, 95% CI: 1.15–3.75; AA vs. GG + GA, OR = 1.78, 95% CI: 1.01–3.16; AA + GA vs. GG, OR = 1.49, 95% CI: 1.08–2.04), but not for endometriosis [Table 2]. To compare the difference and evaluate the sensitivity of the meta-analyses, we used both models (the fixed- and random-effects models) to evaluate the stability of the meta-analysis. Most of the results were not materially altered in the overall and subgroup analyses [Table 2]. Hence, results of the sensitivity analysis suggest that the data in this meta-analysis are relatively stable and credible.

This meta-analysis aimed to systematically summarize the epidemiological evidence for the association between COMT 158G/A polymorphism and risk of endometriosis and adenomyosis in Chinese. Seven case–control studies with 782 cases and 700 controls were finally included in the meta-analysis. The results showed a significant association between COMT 158G/A polymorphism and endometriosis and adenomyosis in overall analysis. Individuals with the variant AA genotype were found to be at approximately 47% higher risk of endometriosis and adenomyosis (AA vs. GG, OR = 1.47, 95% CI: 1.01–2.14) in China. The findings from this meta-analysis provide new and strong epidemiological evidence for the association between COMT 158G/A polymorphism and risk of endometriosis and adenomyosis. Till date, only one meta-analysis was published to assess the association between the COMT 158G/A polymorphism and endometriosis and adenomyosis risk, but the existing evidence was still weak due to limited sample size and ethnic difference in Chinese.[] Therefore, the present meta-analysis of all available case–control studies was conducted to shed some light on those previous results. Although the precise mechanism(s) accounting for ethnic discrepancy is uncertain, differences in both genetic backgrounds and social, environmental factors among various populations may be significant. In the subgroup analyses by ethnicity source of controls, the variant allele and genotype of COMT 158G/A were found to increase the risk of endometriosis and adenomyosis in Chinese not mentioned the ethnicity and PB studies. We did not perform subgroup analyses on other ethnicity history, because of the lack of sufficient data. The different results based on the source of controls may be due to biases within HB studies as the controls represent an ill-defined reference population, rather than the general population. The results stratified by disease groups of this meta-analysis also indicate a significant association for adenomyosis in all genetic models, but not for endometriosis. The different results between adenomyosis and endometriosis with regard to the COMT 158G/A can be partially attributed to their different pathogeneses. Although adenomyosis might be considered a special form of endometriosis, distinct processes have been found in the two diseases.[] In addition, adenomyosis and endometriosis differ with respect to clinical symptoms and treatment, which may further support different pathophysiological mechanisms between two diseases. Some limitations of this meta-analysis should be acknowledged. First, the number of studies and the number of subjects included in our meta-analysis were relatively small. Second, due to the limitations of funnel plotting, which requires a range of studies, we did not evaluate publication bias in this meta-analysis. Third, the present meta-analysis was based primarily on unadjusted effect estimates and CIs, and the confounding factors were not controlled. In spite of these limitations, our meta-analysis also had some advantages. First, we have followed the inclusion and exclusion criteria strictly to reduce possible selection bias. Second, our inclusion of non-English language reports was important in minimizing a major potential threat to the validity of any meta-analysis-publication bias and the related threat of a language bias. Third, the sensitivity analysis had been performed to confirm the reliability and stability of this meta-analysis. Most of the important, impact of the different genetic background was minimized by including the studies performed in the Chinese population only, which suggested that there was almost no significantly different genetic background among the subjects. Therefore, the seven studies would appear to be comparable in all respects relevant to our meta-analysis.

The present meta-analysis indicated that the COMT 158G/A polymorphism may be associated with the risk of endometriosis and adenomyosis in the Chinese population. Considering the limitations of the meta-analysis; further, larger studies in selected populations are needed to confirm these results. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

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