Polymorphisms in the 3 ′ UTR Region of ESR2 and CYP19A1 Genes and Its Influence on Allele-Specific Gene Expression in Endometriosis
Open accessAbstract
Objectives. Endometriosis is supported by hormonal, immunological, and environmental factors. No specific marker for endometriosis has yet been identified. ESR2 and CYP19A1 genes play a major role in the hormonal control of endometriosis women, the development of which largely depends on steroid hormones. Aim. An analysis of ESR2 and CYP19A1 allele-specific gene expressions in the context of the risk for endometriosis occurrence. Methods. The study material included paraffin-embedded tissue specimens, collected from patients ( n = 100 ) with endometriosis. Blood samples from age-matched, endometriosis-free women ( n = 100 ) served as a control. the RT-PCR technique was performed to observe the expression of ESR2 and CYP19A1 genes. Moreover, Sanger’s sequencing method was applied for polymorphism analysis. Results. A set of 4 single-nucleotide polymorphisms (SNPs) was determined; all of them most significantly associated with endometriosis: rs4986938 (G>A)(chromosome 14), rs928554 (A>G) (chromosome 14), rs10046 (C>T) (chromosome 15), and rs4646 (C>A) (chromosome 15). There were no differences in the distribution of genotypes and alleles in the studied groups, taking into account ESR2 and CYP19A1 gene expressions. Conclusion. The ESR2 and CYP19A1 polymorphisms may not be correlated with endometriosis susceptibility. Further analysis is needed to specify the role of these polymorphisms in the pathogenesis of endometriosis.
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Written from the paper’s full text.
TL;DR
This case-control study examined four 3′ UTR SNPs in ESR2 (rs4986938, rs928554) and CYP19A1 (rs10046, rs4646) and allele-specific expression in 100 endometriosis patients and 100 controls. It found no statistically significant association between these polymorphisms and ESR2/CYP19A1 expression or endometriosis susceptibility.
Key findings
- Four SNPs were identified as most associated with endometriosis: rs4986938 (G>A), rs928554 (A>G), rs10046 (C>T), and rs4646 (C>A).
- In endometriosis cases, genotype frequencies were: rs4986938 GG 73%, GA 25%, AA 2%; rs928554 AA 48%, AG 52%, GG 0%; rs10046 CC 37%, CT 63%, TT 0%; rs4646 CC 48%, CA 51%, AA 1%. In controls: rs4986938 GG 61%, GA 32%, AA 7%; rs928554 AA 51%, AG 49%, GG 0%; rs10046 CC 41%, CT 59%, TT 0%; rs4646 CC 56%, CA 44%, AA 0%.
- No statistically significant differences were found in ESR2 expression by rs4986938 (Kruskal-Wallis p=0.46) or rs928554 (Mann-Whitney p=0.11), nor in CYP19A1 expression by rs10046 (p=0.23) or rs4646 (p=0.18).
- No relationship was found between ESR2/CYP19A1 polymorphisms and rASRM classification, age, BMI, menopausal status, or number of pregnancies.
Methods
- Case-control study: 100 paraffin-embedded tissue specimens from patients with endometriosis and 100 blood samples from age-matched endometriosis-free women as controls; clinical staging used rASRM.
- RT-PCR measured ESR2 and CYP19A1 expression; Sanger sequencing analyzed polymorphisms in the 3′ UTR.
- Statistical analysis used STATISTICA 11 with nonparametric tests (Mann-Whitney U, Kruskal-Wallis), Spearman correlation, Hardy-Weinberg equilibrium, and significance at p<0.05.
Limitations
- The paper states the study is limited by sample size and may lack statistical power to detect smaller expression differences; larger samples are needed.
- Evident from the text: some genotype groups had zero individuals (rs928554 GG, rs10046 TT, rs4646 AA in controls), so expression comparisons for those genotypes were not possible.
- Evident from the text: cases were paraffin-embedded tissue specimens while controls were blood samples, and the text does not specify whether expression analyses used comparable sample types.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
0 of 11 cited sources checked · 0 supported · 0 flagged
- Findingown data
In control women, CYP19A1 rs4646 genotypes CC, CA, and AA occurred at frequencies 56%, 44%, and 0%, respectively.
“Regarding rs4646, the CC, CA, and AA were observed in 56% (56/100), 44% (44/100), and 0% (0/100) of the studied individuals, respectively.”
Quote in the paperNot a substantial claim - Findingown data
In control women, ESR2 rs928554 genotypes AA, AG, and GG occurred at frequencies 51%, 49%, and 0%, respectively.
“Regarding rs928554, the AA, AG, and GG genotypes were observed in 51 (51/100), 49% (49/100), and 0% (0/100) of the studied individuals, respectively.”
Quote in the paperNot a substantial claim - Findingown data
There was no statistically significant correlation between CYP19A1 rs4646 polymorphisms and CYP19A1 expression (Mann-Whitney p = 0.18).
“Our data did not demonstrate any statistically significant correlation between CYP19A1 rs4646 polymorphisms and CYP19A1 expression (Mann-Whitney test p = 0:18) (Table 5).”
Quote in the paperSubstantial claim - Findingown data
In control women, CYP19A1 rs10046 genotypes CC, CT, and TT occurred at frequencies 41%, 59%, and 0%, respectively.
“Taking into account the nonendometriosis control females, the CC, CT, and TT in rs10046 polymorphism were found in 41% (41/100), 59% (59/100), and 0% (0/100) of the patients, respectively.”
Quote in the paperNot a substantial claim - Findingown data
There were no differences in the distribution of genotypes and alleles between endometriosis and control groups for ESR2 and CYP19A1.
“There were no differences in the distribution of genotypes and alleles in the studied groups, taking into account ESR2 and CYP19A1 gene expressions.”
Quote in the paperSubstantial claim
- Findingown data
In endometriosis patients, CYP19A1 rs4646 genotypes CC, CA, and AA occurred at frequencies 48%, 51%, and 1%, respectively.
“In the case of rs4646, CC, CA, and AA genotypes were found in 48% (48/100), 51% (51/100), and 1% (1/100) of the studied patients, respectively (Table 7).”
Quote in the paperNot a substantial claim - Findingown data
There were no statistically significant differences in CYP19A1 gene expression in relation to the occurrence of rs10046 polymorphism genotypes (Mann-Whitney p = 0.23).
“There were no statistically significant differences in the CYP19A1 gene expression in relation to the occurrence of rs10046 polymorphism genotypes (Mann-Whitney test p = 0:23) (Table 4).”
Quote in the paperSubstantial claim - Findingown data
In endometriosis patients, ESR2 rs928554 genotypes AA, GA, and GG occurred at frequencies 48%, 52%, and 0%, respectively.
“In the case of rs928554, AA, GA, and GG genotypes were found in 48% (48/100), 52% (52/100), and 0% (0/100) of the studied patients, respectively (Table 5).”
Quote in the paperNot a substantial claim - Findingown data
No relationship was revealed between ESR2 and CYP19A1 polymorphisms and rASRM classification scores in the study group.
“No relationship was revealed between ESR2 and CYP19A1 polymorphisms and rASRM (revised American Society for Reproductive Medicine) classification scores in the study group.”
Quote in the paperNot a substantial claim - Findingown data
In endometriosis patients, CYP19A1 rs10046 genotypes CC, CT, and TT occurred at frequencies 37%, 63%, and 0%, respectively.
“In the females with endometriosis, CC, CT, and TT genotypes within CYP19A1 rs10046 SNP were observed in 37% (37/100), 63% (63/100), and 0% (0/100) of the studied individuals, respectively (Table 6).”
Quote in the paperNot a substantial claim - Findingown data
In control women, ESR2 rs4986938 genotypes GG, GA, and AA occurred at frequencies 61%, 32%, and 7%, respectively.
“Taking into account the nonendometriosis control females, the GG, GA, and AA genotypes in rs4986938 polymorphism were found in 61% (61/100), 32% (32/100), and 7% (7/100) of the patients, respectively.”
Quote in the paperNot a substantial claim - Findingown data
In endometriosis patients, ESR2 rs4986938 genotypes GG, GA, and AA occurred at frequencies 73%, 25%, and 2%, respectively.
“In the females with endometriosis, GG, GA, and AA genotypes within ESR2 rs4986938 SNP were observed in 73% (73/100), 25% (25/100), and 2% (2/100) of the studied individuals, respectively (Table 4).”
Quote in the paperNot a substantial claim - Findingown data
A set of four SNPs (rs4986938, rs928554, rs10046, rs4646) was most significantly associated with endometriosis risk.
“A set of 4 single-nucleotide polymorphisms (SNPs) was determined; all of them most significantly associated with endometriosis: rs4986938 (G>A)(chromosome 14), rs928554 (A>G) (chromosome 14), rs10046 (C>T) (chromosome 15), and rs4646 (C>A) (chromosome 15).”
- Also stated in: § 3. Results · plain
“A pool of 4 SNPs mostly correlated with endometriosis risk was determined: rs4986938 (G>A) (chromosome 14), rs928554 (A>G) (chromosome 14), rs10046 (C>T) (chromosome 15), and rs4646 (C>A) (chromosome 15).”
Quote in the paperSubstantial claim - Also stated in: § 3. Results · plain
- Findingown data
There were no statistically significant differences in ESR2 gene expression in relation to the occurrence of rs4986938 polymorphism (Kruskal-Wallis p = 0.46).
“There were no statistically significant differences in the ESR2 gene expression in relation to the occurrence of rs4986938 polymorphism (Kruskal-Wallis test p = 0:46).”
Quote in the paperSubstantial claim - Premisecitation
Previous studies of associations between various CYP19A1 polymorphisms and endometriosis have been inconsistent.
“While SNPs in CYP19A1 have been associated with sexsteroid hormone levels and other oestrogen-dependent diseases including endometriosis, the results of previous studies of the associations between various CYP19A1 polymorphisms and endometriosis have been inconsistent up to a certain degree.”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
SNPs in CYP19A1 have been associated with sex-steroid hormone levels and other oestrogen-dependent diseases including endometriosis.
“While SNPs in CYP19A1 have been associated with sexsteroid hormone levels and other oestrogen-dependent diseases including endometriosis, the results of previous studies of the associations between various CYP19A1 polymorphisms and endometriosis have been inconsistent up to a certain degree.”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationown data
The two genes ESR2 and CYP19A1 do not play significant roles in the pathogenesis of endometriosis.
“There are no statistically significant differences in the ESR2 and CYP19A1 allele-specific gene expressions based on the comparisons of the 100 cases vs. the 100 controls, which lead us to conclude that the two genes do not play significant roles in the pathogenesis of endometriosis.”
Quote in the paperSubstantial claim - Premisecitation
Endometriosis lesions, unlike eutopic endometrium, demonstrate some activity of aromatase.
“Endometriosis lesions, unlike the eutopic endometrium, demonstrate some activity of the aromatase [6].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [6] source
Not checked in the free run.
- Interpretationown data
ESR2 and CYP19A1 polymorphisms may not be correlated with endometriosis susceptibility.
“The ESR2 and CYP19A1 polymorphisms may not be correlated with endometriosis susceptibility.”
Quote in the paperSubstantial claim - Premisecitation
Different expression levels of aromatase were determined in endometriosis foci compared to eutopic endometrium.
“Different expression levels of aromatase were determined in the endometriosis foci in comparison to the eutopic endometrium.[9].”
Quote in the paperSubstantial claim0 of 2 sources checked
- May combine two claims. 4
- Classified as probably not a substantial claim. 6
May combine two claims.
Findingown dataThe SNPs in the study group did not correlate with age, BMI, menopausal status, or number of pregnancies in history.
“The SNPs in the study group did not correlate with either the age of the patients or with their BMI, menopausal status, or with the number of pregnancies in history.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThere were no statistically significant differences in genotype frequencies of ESR2 rs928554 polymorphism and ESR2 expression (Mann-Whitney p = 0.11).
“No statistically significant differences were observed in genotype frequencies of ESR2 rs928554 polymorphism and ESR2 expression (Mann-Whitney test p = 0:11) (Table 3).”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductnone givenThe study is limited by sample sizes, and statistical power may not be enough to detect smaller expression differences among the comparison groups.
“This study is limited by the sample sizes, and it is possible statistical power may be not enough to detect smaller expression differences among the comparison groups.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll study participants gave written informed consent.
“All the study participants gave a written informed consent.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe study protocol was approved by the Bioethical Committee of the Polish Mother's Memorial Institute (approval number 8/2016).
“The study protocol was approved by the Bioethical Committee of the Polish Mother's Memorial Institute (approval number: 8/2016).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThe genotype and allele distributions were confirmed to be in Hardy-Weinberg equilibrium before statistical analysis.
“Statistical analysis of the distribution of genotypes and alleles in the test and control group was carried out after prior confirmation that the obtained systems remain in a state of equilibrium according to the rules of Hardy and Weinberg.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationSpecific SNPs in the 3′ UTR regions have structural consequences that may result in phenotypic manifestations in the form of disease.
“The literature data showed that a number of specific SNPs in the 3 ′ UTR regions have structural consequences that may result in the emergence of phenotypic manifestations in the form of the disease [13].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationERβ is the predominant isoform in patients with endometriosis.
“ERβ is the predominant isoform in patients with endometriosis [7,8].”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationBoth ERs are expressed in human endometriotic tissues, with significantly increased ERβ and decreased ERα in endometriotic lesions compared with eutopic endometrium.
“Previous studies have been demonstrated that both ERs are expressed in human endometriotic tissues but it has been shown that there are significantly increased levels of oestrogen receptor ERβ and decreased levels of ERα in the endometriotic lesions in comparison with the eutopic endometrium.[10][11][12].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [10][11][12]
Not checked in the free run.
The paper relies on this without support.
No specific marker for endometriosis has yet been identified.
“No specific marker for endometriosis has yet been identified.”
The paper relies on this without support.
The 3′ UTR region is important because it attaches to miRNA, which regulates gene expression.
“Regarding studies of CYP17 and ESR2 gene polymorphisms, there are few reports concerning the 3 ′ UTR region, which is important, because it attaches to the miRNA, which regulates gene expression.”
The paper relies on this without support.
The 3′ UTR region is important for phenotypic changes that may trigger development of endometriosis.
“This region is therefore important for phenotypic changes that may trigger development of endometriosis”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Studies draw attention to the significant role of estrogen receptor genes, especially the ESR2 gene and the CYP19A1 gene, for the susceptibility and occurrence of endometriosis.
“Literature data indicate that studies draw attention to the significant role of estrogen receptor genes, especially the ESR2 gene and the CYP19A1 gene for the susceptibility and occurrence of endometriosis [199,200,201].”
From Endometriosis: Epidemiology, Classification, Pathogenesis, Treatment and Genetics (Review of Literature) (2021) · cites this paper as [201]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
SNPs are described as both significantly associated and not associated with endometriosis
MajorThe abstract says all four SNPs were significantly associated with endometriosis, but its conclusion says the ESR2 and CYP19A1 polymorphisms may not be correlated with susceptibility. These statements give opposing interpretations of the study's central result.
“A set of 4 single-nucleotide polymorphisms (SNPs) was determined; all of them most significantly associated with endometriosis: rs4986938 (G>A)(chromosome 14), rs928554 (A>G) (chromosome 14), rs10046 (C>T) (chromosome 15), and rs4646 (C>A) (chromosome 15).”
“The ESR2 and CYP19A1 polymorphisms may not be correlated with endometriosis susceptibility.”
The rs4986938 expression result cites the nucleotide-sequence table
MinorThe text directs readers to Table 2 for rs4986938 expression, but Table 2 is labeled as nucleotide sequences and primers, not expression results.
“The genotype frequency of the ESR2 rs4986938 polymorphism in relation to its expression is summarized in Table 2.”
“Table: 2 Table 2 : The nucleotide sequence of the amplified 3′UTR region of the ESR2 and CYP19A1 genes.”
The rs4646 expression result cites the rs928554 table
MinorThe rs4646 result cites Table 5, but Table 5 is labeled as ESR2 expression by rs928554 genotype. The supplied rs4646 expression table is Table 7.
“Our data did not demonstrate any statistically significant correlation between CYP19A1 rs4646 polymorphisms and CYP19A1 expression (Mann-Whitney test p = 0:18) (Table 5).”
“Table: 5 Table 5 : Relative ESR2 gene expression with regard to the polymorphism rs928554.”
The stated 63% does not match 63/1000
MinorThe discussion gives 63/1000 alongside 63%; that fraction is 6.3%. The earlier Results section gives the corresponding count as 63/100.
Reported 63 · recomputed 6.3
“37% (37/100), 63% (63/1000, and 0% of the studied individuals, respectively (Table 6).”
The rs928554 expression result cites the SNP-coordinate table
MinorThe rs928554 expression result cites Table 3, which is labeled as SNP coordinates; the supplied expression table for rs928554 is Table 5.
“No statistically significant differences were observed in genotype frequencies of ESR2 rs928554 polymorphism and ESR2 expression (Mann-Whitney test p = 0:11) (Table 3).”
“Table: 3 Table 3 : The chromosomal coordinates of the four studied SNPs.(https://www.ncbi.nlm.nih.gov/genome/guide/human/).”
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Smolarz, B., Szyłło, K., & Romanowicz, H. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms221910554 · Cited by 560 · see citing works
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- Authors
- Smolarz, B., Szaflik, T., Romanowicz, H., & Szyłło, K.
- Affiliations
- Polish Mother’s Memorial Hospital Research Institute (PL)
- Corresponding author
- Smolarz, Beata
- Venue
- Disease Markers
- Publisher
- Wiley
- Published
- 2020-12-01
- Volume
- 2020
- Pages
- 1-7
- ISSN
- 0278-0240 (ISSN-L)
- 1875-8630
- OpenAlex
- W3107852625
- Semantic Scholar
- 733a56f86451d210e08bdc4bd963dba83ddf5094
- Cited by
- 27
- References
- 31
- Citations by year
- 2021: 25 · 2020: 2
- FWCI
- 5.94
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Disease Markers (publishedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Ministerstwo Nauki i Szkolnictwa Wyzszego (2016/VI/13-MN)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- endometriosis, ESR2, CYP19A1, estrogen receptor beta, aromatase, 3'UTR polymorphism, single nucleotide polymorphisms, allele-specific expression, genetic risk markers, steroid hormones
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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