NAT2 gene polymorphisms and endometriosis risk: A PRISMA-compliant meta-analysis

Zhangming Wei, Mengmeng Zhang, Xinyue Zhang, Mingyu Yi, Xiaomeng Xia, Xiaoling Fang
PloS one · 2019 · vol. 14(12) , pp. e0227043 · doi:10.1371/journal.pone.0227043 · PMID:31881062 · PMC6934289 · W2998637692
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This meta-analysis found that the NAT2 slow acetylation phenotype increases endometriosis risk in Asians, while the rs1799930 polymorphism decreases risk across all populations.

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This PRISMA-compliant meta-analysis evaluated associations between NAT2 acetylation phenotypes and specific NAT2 SNPs (rs1799929, rs1799930, rs1208, rs1799931) and endometriosis risk using odds ratios and 95% confidence intervals pooled across nine case-control studies, with subgroup analyses by ethnicity. In the Asian subgroup, the slow acetylation phenotype versus intermediate+fast acetylation phenotype showed an increased endometriosis risk (OR 2.30, 95% CI 1.61–3.28), and the rs1799930 mutant genotype was associated with decreased risk (OR 0.74, 95% CI 0.59–0.92), while no statistically significant associations were found for rs1799931, rs1208, or rs1799929. The paper’s main limitation is that its conclusions rely on the included case-control studies and the available phenotype/genotype data extracted from them, and it does not indicate any additional prospective validation. This paper is centrally about endometriosis — it specifically meta-analyzes NAT2 polymorphisms and acetylation phenotypes as risk biomarkers for endometriosis.

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Abstract

OBJECTIVE: Endometriosis is a common chronic, gynecological disease. Despite many studies on the role of N-acetyltransferase 2 (NAT2) in endometriosis, its clinical significance is unclear. In this study, associations between NAT2 phenotypes as well as single nucleotide polymorphisms (SNPs) within NAT2 (i.e. rs1799929, rs1799930, rs1208, and rs1799931) and endometriosis risk were evaluated using a meta-analysis approach. METHODS: Embase, PubMed, ClinicalTrials.gov, CNKI (China National Knowledge Infrastructure), Wanfang databases, Cochrane Library for clinical trials, and Web of Science were searched to identify relevant articles. ORs (odds ratios) and 95% CIs (95% confidence intervals) were used to estimate the associations between NAT2 polymorphisms and endometriosis risk. Heterogeneity among included studies was also assessed. In addition, a subgroup analysis of NAT2 phenotypes and endometriosis risk based on ethnicity was performed. RESULTS: Nine case-control studies met the inclusion criteria. The odds ratio was 2.30 (95% CI: 1.61-3.28) for the NAT2 slow acetylation phenotype versus the intermediate + fast acetylation phenotype in the Asian population. These results suggest that Asian individuals with the NAT2 slow acetylation phenotype have a 130% increased risk of endometriosis. A significant association was also found for rs1799930 (OR = 0.74; 95% CI, 0.59-0.92), suggesting that individuals with this mutant genotype have a 26% decreased risk of endometriosis. CONCLUSIONS: The rs1799930 mutant genotypes are associated with a decreased risk of endometriosis. No statistically significant associations were found between rs1799931, rs1208, or rs1799929 and endometriosis. Based on a subgroup analysis based on ethnicity, the NAT2 slow acetylation phenotype was found to increase the risk of endometriosis in Asians. No statistically significant associations were found between the NAT2 slow acetylation phenotype and endometriosis risk in Caucasians. Accordingly, NAT2 phenotypes and SNPs are potential biomarkers for the diagnosis and treatment of endometriosis.
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Intro

Endometriosis is a common estrogen-dependent chronic gynecological disease affecting 5–10% of women of reproductive age[ 1 ]. It occurs when the endometrium grows outside of the uterine corpus, which causes inflammation, pelvic pain, dysmenorrhea, menstrual disorders, ectopic bleeding, bladder symptoms, infertility, and further malignant transformation [ 2 ]. It is strongly associated with significant social and physical debility. The etiology of this disease is unclear. However, the main hypotheses include classical theories of blood reflux, blood and lymphatic dissemination, coelomic metaplasia, immunology, endocrinology, and genetics, but none of these can satisfactorily explain the occurrence of endometriosis [ 3 ]. With increasing evidence for a role of genetic factors, many scholars are trying to find genes related to the pathogenesis of endometriosis [ 4 ]. Recently, toxic metabolic enzyme genes have been a focus of research. Genes encoding many metabolic enzymes such as cytochrome P4501A1 (CYP1A1), catechol- O -methyltransferase (COMT), N -acetyltransferase 2 (NAT2), and glutathione S -transferase P1 (GSTP1) are associated with polymorphisms that can distinguish between populations. Mutations might be related to the decreased function or changes in the function of these enzymes including enzymes involved in detoxification, resulting in differences in the risk of endometriosis and other diseases [ 5 ]. Recent meta-analysis-based studies have investigated the relationships between polymorphisms in GSTP1 [ 6 ], COMT [ 7 ], and CYP1A1 [ 8 ] and the risk of endometriosis. Here, we further analyzed the relationship among NAT2 phenotypes, genotypes, and endometriosis. NAT2 is the product of a single, intron-less gene comprising an 870-bp open reading frame that encodes 290 amino acids. The gene is located on chromosome 8p21.323.1 [ 9 ]. NAT2 nucleotide substitutions can change the protein structure and cause reductions in substrate affinity, protein stability, and/or catalytic activity for the recombinant N-acetyltransferase allozyme. Recombinant human NAT2 clusters catalyze N-, O-, and N, O-acetyltransferase activities at slow speeds compare to that with wild-type phenotype [ 10 , 11 ]. Extensive research has concretely established the correlation between NAT2 polymorphisms and susceptibility to a variety of complex diseases, particularly in lung cancer, bladder cancer, alimentary canal tumor, asthma, and other allergic disorders [ 12 ]. NAT2 has over 27 variants or combinations of single nucleotide polymorphisms (SNPs) [ 13 ]. The studied SNPs in NAT2 that affect its phenotype include rs1799930, also known as G590A, rs1799931, also known as G857A, rs1799929, also known as C481T, and rs1208, also known as A803G [ 14 – 17 ]. Like that in leukemia, different combinations of SNPs result in different alleles, producing the NAT2 slow, intermediate, or fast acetylation phenotypes, as summarized by the authoritative NAT2 organization websites “ http://nat2pred.rit.albany.edu/ ” and http://nat.mbg.duth.gr/Human%20NAT2%20alleles_2013.htm#_Footnotes [ 14 ]. Endometriosis is associated with a range of environmental factors (hormonal/reproductive, lifestyle) and genetic factors. It is well established that high levels of natural and man-made chemicals are present in the environment and play a role in the pathogenesis of endometriosis. For example, dioxin-like PCBs (polychlorinated biphenyls) promote the development of endometriosis through the stimulation of endocrine–inflammation interactions. Toxicant dioxins (dioxin and dioxin-like chemicals) have an adverse effect on growth factors, cytokines, hormones, and the immune system. Exposure to dioxins is a potential factor for the development of endometriosis [ 18 , 19 ]. Because endometriosis is a hormone-dependent disease, polymorphisms in genes encoding detoxification enzymes might contribute to its development [ 20 – 23 ]. NAT2 plays a key role in xenobiotic metabolism. Other xenobiotic metabolic enzymes like aromatase P450 family members CYP1A1 and CYP19A1 [ 24 ] also have a fundamental role in the pathogenesis of endometriosis [ 23 , 25 ], and have been widely studied and applied to endometriosis treatment. However, the role of NAT2 polymorphisms in endometriosis remains to be discovered. Specifically, previous studies have evaluated the relationship between NAT2 polymorphisms and the risk of endometriosis; however, contradictory results have been obtained [ 14 , 26 , 27 ]. Accordingly, in this study, a meta-analysis was performed to clarify whether different NAT2 phenotypes or the SNPs rs1799929, rs1799930, rs1208, and rs1799931 are associated with susceptibility to endometriosis worldwide.

Results

A total of 617 articles were retrieved from the electronic search. Among these, 604 were excluded based on titles and abstracts. The full texts of the remaining 13 articles were screened. One review article was excluded [ 25 ]. Two articles were excluded for not reporting exact genotypes [ 20 , 31 ]. One article was excluded for being a single-arm study [ 32 ]. Finally, nine case-control studies [ 14 , 17 , 26 , 27 , 33 – 37 ] met the inclusion criteria. The details of the study selection process are presented in Fig 1 . All article titles excluded—with reason—are shown in S1 File . The characteristics and quality of the included studies are summarized in Tables 1 and 2 . Nine case-control studies were included in this meta-analysis. Note: For NAT2 mm = slow acetylation phenotype, wm = intermediate acetylation phenotype, ww = fast acetylation phenotype. For each SNPs, m = mutation alleles, w = wild alleles, mm = mutation homozygote, mw = mutation heterozygote, ww = wild homozygote. for example: for G590A, m = A, w = G, mm = AA, mw = AG, ww = GG. In the primary model (slow vs. intermediate + fast), heterogeneity was high (χ 2 = 44.09, I 2 = 82%; Fig 2 ). Accordingly, we performed a subgroup analysis focusing on different ethnicities, mainly a Caucasian group and an Asian group. In the Asian group, the heterogeneity was low (χ 2 = 3.18, I 2 = 6%) and the OR was 2.30 (95% CI, 1.59–3.32; P < 0.001). This result suggests that individuals with the NAT2 slow acetylation phenotype have a 130% increased risk of endometriosis in the Asian population. Results for other ethnicity groups are summarized in Table 3 . The result indicates Asian individuals who present NAT2 slow acetylation phenotype might have a 130% increased endometriosis risk. Note OR = Odds ratio. CI = Confidence interval. Z = Z-value for Q statistic. P = P-value for Q statistic. I 2 = I statistic for heterogeneity. Phet = P-value for heterogeneity. F = Fixed model. R = Random model. Next, we investigated the relationships between rs1799930 (G590A), rs1799931 (G857A), rs1799929 (C481T), or rs1208 (A803G) and the risk of endometriosis. As shown in Fig 3 , in the G590A AA+GA vs. GG model, heterogeneity was low (χ 2 = 5.12, I 2 = 22%) and the OR was 0.74 (95% CI, 0.59–0.92; P < 0.001; P Adjust = 0.03), indicating that individuals who carry the G590A mutation have a 26% decreased risk of endometriosis compared to that of wild-type homozygotes. In the G857A AA vs. AG+GG model ( Fig 4 ), heterogeneity was low (χ 2 = 3.35, I 2 = 10%) and the OR was 0.42 (95% CI, 0.20–0.86; P = 0.02; P adjust = 0.10). For C481T and A803G, no statistically significant differences in risk were detected ( Table 4 ). All model comparisons and results are summarized in Table 4 . People who carry G590A mutation may have 26% decreased endometriosis risk compared with wild homozygotes. Note OR = Odds ratio. CI = Confidence interval. Z = Z-value for Q statistic. P = P-value for Q statistic. I 2 = I statistic for heterogeneity. Phet = P-value for heterogeneity. F = Fixed model. R = Random model. Begg’s funnel plot and Egger’s test were used to evaluate publication bias. The symmetry detected in Begg’s funnel plot indicated low publication bias in these statistically significant models ( Fig 5 ). (a) on NAT2 phenotype polymorphism in Asian group, (b) on G590A polymorphism, and (c) on G857A polymorphism. Begg's funnel plot indicates low publication bias of this study. By sequentially excluding individual studies, the outcomes were consistent with the overall study results, indicating that our results showed good stability and reliability. After excluding each study, the changes in OR with 95% CIs are presented in Table 5 . Note OR = Odds ratio. CI = Confidence interval. Z = Z-value for Q statistic. I 2 = I statistic for heterogeneity. F = Fixed model. R = Random model.

Conclusions

In summary, the rs1799930 mutant genotypes are associated with a decreased risk of endometriosis. No statistically significant results were found between rs1799931, rs1208, or rs1799929 and endometriosis. In a subgroup analysis based on ethnicity, the NAT2 slow acetylation phenotype was found to increase the risk of endometriosis in Asians. However, no statistically significant results were found between the NAT2 slow acetylation phenotype and endometriosis risk in Caucasians. These SNPs and NAT2 phenotype are potential biomarkers for the diagnosis and treatment of endometriosis. Further large-scale case-control studies are needed, with specific designs to account for the disease stage, for a more in-depth and thorough exploration of the relationship between NAT2 polymorphisms and endometriosis.

Materials|Methods

The detailed protocol, which followed the template of the Cochrane review is available in the PROSPERO registry (No. CRD42018111924). This meta-analysis was prepared according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Declaration of human rights: no formal consent was required for this type of study. PubMed, Embase, Web of science, Cochrane Library for clinical trials, ClinicalTrials.gov, CNKI (China National Knowledge Infrastructure), and Wanfang databases were searched extensively (the last search was updated on June 20, 2019). The search words and strategy included the following: (NAT2 OR "N-acetyltransferase 2" OR "Arylamine-N-acetyltransferase" OR "NAT" OR "dioxin detoxification enzymes") AND (mutation OR variant OR polymorphism) AND (endometriosis OR endometriosis OR Mulleriosis OR Mullerianosis OR EM OR EMT OR EMS OR Mullerianosis). Inclusion criteria were as follows. (1) The relationship between NAT2 polymorphisms and endometriosis risk was evaluated. (2) Only case-control studies that included both endometriosis cases and endometriosis-free controls were included. (3) Sufficient and procurable data for both cases and controls were required to estimate the odds ratio (OR) and 95% confidence interval (95% CI). (4) Endometriosis diagnosis in accordance with the Revised American Society for Reproductive Medicine classification was required. The exclusion criteria were as follows: (1) abstracts, case reports, letters, reviews, or single-arm studies; (2) phenotype/genotype frequency and endometriosis risk were not reported; (3) incomplete data for the calculation of ORs and 95% CIs. All potentially relevant studies were checked by two investigators (M-M.Z. and Z-M.W.) independently, and a third investigator (X-L.F.) resolved discrepancies. The following items were extracted: year of publication, first author, diagnostic standard, NAT2 phenotypes, target genotypes, diagnostic methods, genotyping methods, case age, ethnicity, features of the controls, endometriosis stage, genotype distributions in cases and controls, and the total number of cases and controls. The corresponding authors of the original studies were contacted when further data were needed. Subgroup analysis by ethnicity, χ 2 tests, Begg’s funnel plots, and Egger’s tests were performed. In addition, the Newcastle-Ottawa scale (NOS), OR, 95% CI, and I 2 statistic were estimated. The NOS criteria were used to assess the methodological quality of all studies. Studies with NOS scores ≥ 7 were regarded as good quality (range, 0–8) [ 28 ]. To determine whether genotypes were in accordance with the Hardy–Weinberg equilibrium, an internet-based program was used ( http://ihg.gsf.de/cgi-bin/hw/hwa1.pl ) [ 29 ]. The risk for the primary model (slow + intermediate phenotype versus fast phenotype) was first evaluated. Then, the recessive model (slow phenotype versus intermediate + fast phenotype) was evaluated. In addition, the risks of the intermediate phenotype versus the fast phenotype and the slow phenotype versus the fast phenotype were estimated. Moreover, a subgroup analysis by ethnicity (Asian or Caucasian) was performed. For each SNP, all combinations of genotypes were evaluated. The I 2 statistic was used to calculate heterogeneity. A value of P < 0.05 was regarded as statistically significant. The Bonferroni method was used to adjust P values for multiple testing. If heterogeneity was low ( I 2< 30%), a fixed effect model was used to calculate the combined OR for each study. Otherwise ( I 2 ≥ 30%), the random effect model was used. The publication bias was assessed by Begg’s and Egger’s tests. A sensitivity analysis was performed by sequentially excluding each study to assess the stability of the meta-analysis results. Environmental effects adjustments, like those for dioxin exposure, pollution exposure, life style, diabetes, smoking, coffee intake, breast feeding time, or other genetic factors were not conducted due to the insufficiency of available data. All analyses were implemented with Stata 12.0 (Stata, College Station, TX, USA) and RevMan 5.3 software (Cochrane Collaboration, Oxford, England) [ 30 ].

Supplementary Material

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endometriosis

MeSH descriptors

Arylamine N-Acetyltransferase Endometriosis Polymorphism, Single Nucleotide Arylamine N-Acetyltransferase Asian People Asian People Endometriosis Female Genetic Predisposition to Disease Humans Phenotype White People White People

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