Polymorphisms and haplotypes of the gene encoding the estrogen-metabolizing cyp19 gene in korean women: no association with advanced-stage endometriosis

ABSTRACT A variety of factors affect the development of endometriosis, including hormonal status and genetic factors. The growth of endometriosis is stimulated by local estrogen production

in conjunction with circulating estrogen. The CYP19 gene encodes a steroid aromatase that catalyses the conversion of C-19 androgens to estrogens. This study investigated whether

polymorphisms of the CYP19 gene are associated with the risk of advanced endometriosis in Korean women. Blood samples were collected from 224 female patients with endometriosis of stages III

and IV, as diagnosed by both pathologic and laparoscopic findings, and from a control group comprising of 188 women undergoing laparoscopic surgery or laparotomy for nonmalignant lesions.

Single-nucleotide polymorphisms, restriction fragment length polymorphisms, and tetranucleotide tandem repeat polymorphisms were discriminated by the polymerase chain reaction (PCR).

Haplotype analysis was also performed. CYP19 115T>C, 240G>A, and 1531C>T polymorphisms and [TTTA]_n_ tetranucleotide repeat polymorphisms in the CYP19 gene and their haplotypes were

not significantly associated with the risk of endometriosis. The risk of endometriosis also did not increase significantly with the number of higher risk alleles of the CYP19 gene. In

conclusion, our findings suggest that CYP19 genetic polymorphisms are not associated with advanced-stage endometriosis in Korean women. SIMILAR CONTENT BEING VIEWED BY OTHERS SIGNIFICANCE OF

_LHCGR_ POLYMORPHISMS IN POLYCYSTIC OVARY SYNDROME: AN ASSOCIATION STUDY Article Open access 21 December 2023 IMPACT OF RS2414096 POLYMORPHISM OF _CYP19_ GENE ON SUSCEPTIBILITY OF

POLYCYSTIC OVARY SYNDROME AND HYPERANDROGENISM IN KASHMIRI WOMEN Article Open access 21 June 2021 _CYP3A7*1C_ ALLELE: LINKING PREMENOPAUSAL OESTRONE AND PROGESTERONE LEVELS WITH RISK OF

HORMONE RECEPTOR-POSITIVE BREAST CANCERS Article Open access 26 January 2021 INTRODUCTION Endometriosis is one of the most common gynecologic disorders, but its etiology and pathogenesis

remain obscure. There is increasing evidence that endometriosis is inherited as a complex genetic trait, implying that multiple gene loci interact with both each other and the environment to

produce the phenotype disease (Kennedy 1997). Recent genetic studies have found an association between the development of endometriosis and the polymorphisms of several genes (Cramer et al.

1996; Baranova et al. 1997; Watanabe et al. 2001; Chang et al. 2002; Wieser et al. 2002; Hur et al. 2005), including the genes related to estrogen metabolism (Georgiou et al. 1999; Kitawaki

et al. 2001; Kado et al. 2002). The growth of endometriosis increases with the level of estrogen. Endometrial implants contain estrogen, progesterone, and androgen receptors (Lessey et al.

1989; Prentice et al. 1992; Bergqvist and Fernö 1993), as well as aromatase, an enzyme that catalyses the conversion of androgens to estrogens. Ectopic endometriotic implants respond to

ovarian hormonal changes. Local estrogen production in conjunction with circulating estrogen stimulates the growth of endometriosis, which is mediated by the estrogen receptor (Kitawaki et

al. 1997). Aromatase is a member of the cytochrome P450 enzyme family and is encoded by the CYP19 gene. CYP19 is one of the essential enzymes for the biosynthesis of estrogen, which converts

androgens into estrogens, androstenedione into estrone, and testosterone into estradiol. Although endometriotic implants express aromatase, endometrial tissue from uterine-disease-free

women does not exhibit aromatase activity (Kitawaki et al. 1999; Bulun et al. 2004). In contrast, aromatase enzyme activity and increased mRNA levels are readily detectable in endometriosis

(Bulun et al. 2005). We speculated that the onset or growth of endometriosis might be associated with an aberrant transcription of CYP19. The CYP19 gene has several polymorphisms: a

[TTTA]_n_ tetranucleotide repeat polymorphism in intron 4 (Healey et al. 2000; Kristensen et al. 2000), a 115T>C polymorphism in exon 2 (Trp39Arg) (Miyoshi et al. 2000), a silent

240A>G polymorphism at codon 80 in exon 3 (Siegelmann-Danieli and Buetow 1999), a 790C>T polymorphism in exon 8 (Arg264Cys) (Toda et al. 1990; Kristensen et al. 2000; Lee et al. 2003),

and a 1531C>T polymorphism in the 3′ untranslated region of exon 10 (Sourdaine et al. 1994). CYP19 gene polymorphisms are reportedly associated with estrogen-dependent diseases, such as

uterine myoma, endometriosis, breast cancer, and endometrial cancer (Hirose et al. 2004; Bulun et al. 2005; Paynter et al. 2005). The development of endometriosis depends on estrogen, and

several features of this disease can be explained by the overproduction of estrogen. Endometriosis is currently treated using hormones that aim to lower the circulation level of estrogen.

Genetic polymorphisms in the estrogen-synthesizing or estrogen-metabolizing enzymes may be responsible for interindividual variations in the levels and the activity of circulating estrogen,

and may play an important role in interindividual variations in endometriosis by altering the local estrogen production or circulation levels of estrogen. We evaluated whether the 115T>C,

240G>A, and 1531C>T polymorphisms and their haplotypes and also [TTTA]_n_ tetranucleotide repeat polymorphisms in CYP19 are associated with the risk of endometriosis. In this study,

we have investigated the potential influence of CYP19 polymorphisms in Korean women with and without endometriosis to assess the risk of individual genotypes or haplotypes that alter

metabolizing capabilities for estrogen in the development of endometriosis. MATERIAL AND METHODS SUBJECTS The study protocol was approved by the Institutional Review Board on the Use of

Human Subjects in Research at Ewha Womans University and informed consent was obtained from each patient. The endometriosis patients had undergone laparotomy or laparoscopy from the

Obstetrics and Gynecology Department at Ewha Womans University Hospital. The patients consisted of 224 unrelated Korean women and were diagnosed as advanced-stage endometriosis (stages III

and IV) by both pathological and laparoscopic findings according to the revised American Fertility Society classification of endometriosis (American Fertility Society 1985). The 188 women

undergoing laparoscopic surgery or laparotomy for nonmalignant lesions, such as benign ovarian cyst, were included in the control group. Blood samples were collected for DNA extraction.

115T>C GENOTYPING Polymerase chain reaction (PCR) with confronting two-pair primers (Hirose et al. 2004) was used for the 115T>C polymorphism, with the amplification for CYP19 being

achieved using primers forward 1: 5′-ATCTGTACTGTACAGCACC-3′ and reverse 1: 5′-ATGTGCCCTCATAATTCCG-3′ (Bioneer, Seoul, Korea) for the C (Arg) allele and forward 2: 5′-GGCCTTTTTCTCTTGGTGT-3′

and reverse 2: 5′-CTCCAAGTCCTCATTTGCT-3′ (Bioneer, Seoul, Korea) for the T (Trp) allele. Genomic DNA (30–100 ng) was added to 25 μl of reaction medium with 0.15 mM deoxynucleotide

triphosphates, 25 pmol of each primer, 5 units of AmpliTaq Gold, and 2.5 μl of GeneAmp 10× PCR buffer, including 15 mM MgCl2 (Perkin-Elmer, Foster City, CA, USA). All PCR amplifications were

carried out using a GeneAmp 9600 thermal cycler (Perkin-Elmer). Amplification conditions were 10 min of initial denaturation at 95°C, followed by 30 cycles of 1 min at 95°C, 1 min at 54°C,

and 1 min at 72°C and 5 min of final extension at 72°C. The amplified DNA was visualized on 2% agarose gel with ethidium bromide staining. The genotypes were distinguished as follows: a

200-bp band for the T allele, a 264-bp band for the C allele, and a 427-bp common band. 240A>G GENOTYPING For determination of the 240A>G polymorphism at position Val80 in CYP19, a

188-bp PCR product was generated. The PCR was carried out in a 25-μl reaction mixture containing 200 ng genomic DNA, 2.0 mM MgCl2, 250 μM deoxy-NTPs, 0.5 μM of each primer, and 0.5 U Taq DNA

polymerase. The primer sequences were as follows: forward, 5′-AGTAACACAGAACAGTTGCA-3′; reverse, 5′-TCCAGACTCGCATGAATTCTCCGTA-3′ (Bioneer). A mismatch (G instead of A) was introduced in the

reverse primer to create a restriction site for the Rsa1 enzyme. All PCR amplifications were carried out using a GeneAmp 9600 thermal cycler (Perkin-Elmer). After an initial denaturation at

95°C for 5 min, 35 cycles of amplification with denaturation at 95°C for 30 s, annealing at 56°C for 30 s, and extension at 72°C for 30 s were performed, followed by a final extension step

of 7 min at 7°C. The PCR product was digested overnight with 5 U Rsa1 followed by size separation and visualization of the restriction fragments by electrophoresis on 1% agarose gels stained

with ethidium bromide and viewed by UV illumination. The presence of the G variant in CYP19 resulted in digestion of the 188-bp amplicon to two smaller fragments of 164 bp and 24 bp. Only

one 188-bp fragment was seen in subjects with the AA genotype. In subjects with the GA genotype, two bands of 188 bp and 164 bp were seen, whereas in those subjects homozygous for the G

variant (GG), only one 164-bp PCR fragment was present. CYP19 1531C>T GENOTYPING CYP19 C1558-T genotyping for polymorphisms were carried out by PCR as described by Tofteng et al. (2004)

with minor modifications. A 190-bp DNA fragment, including the polymorphic site in exon 10, was amplified by PCR. Because there are no naturally occurring restriction sites capable of

discriminating the C to T transition, we introduced a recognition site in the wild-type allele for the restriction enzyme Bsp1286 I by altering one nucleotide (C to G) close to the 3′-end of

the forward primer. DNA samples were amplified with the forward primer: 5′-TAG AGA AGG CTG GTC AGT GCC-3′, reverse primer 5′-CTC TGG TGT GAA CAG GAG CA-3′ (Bioneer). PCR was performed in a

final volume of 50 μl, consisting of DNA (0.1 g) dNTP (0.2 mM each) (Perkin-Elmer) MgCl2 (2.5 mM), each primer (1.0 μM for CYP19 C1558-T), Taq polymerase (1.25 U) (Perkin-Elmer), reaction

buffer, and 2% DMSO. Amplification was performed with an initial denaturation at 9°C for 2 min, followed by 30 cycles of amplification performed at 95°C for 30 s, 61°C for 30 s, and 72°C for

30 s, and a final extension at 7°C for 7 min, using a GeneAmp 9600 thermal cycler (Perkin-Elmer). The PCR products were digested for 12 h at 37°C with Bsp1286 I (New England BioLabs Inc.,

Beverly, MA, USA), followed by size separation and the visualization of restriction fragments by electrophoresis on 2.5% agarose gels stained with ethidium bromide. Wild-type alleles with

the restriction site (cleavage to 169 bp+21 bp) were denoted C, variant alleles (uncleaved product) without the restriction site were denoted T (190 bp). TETRANUCLEOTIDE REPEAT POLYMORPHISM

[TTTA]_N_ GENOTYPING The CYP19 VNTR in intron 4 [TTTA]_n_ alleles were determined by introducing 100 ng of genomic DNA in a PCR reaction mixture containing 10× PCR buffer, 200 μM dNTPs, 2.0 

mM MgCl2, and 0.35 U Taq DNA polymerase (Life Technologies Ltd., Gaithersburg, Scotland, UK) to a 15-μl total reaction volume, using 0.3 μM of the following primers: forward 5′-GCA GGT ACT

TAG TTA GCT AC-3′, reverse 5′-TTA CAG TGA GCC AAG GTC GT-3′. All PCR amplifications were carried out using a GeneAmp 9600 thermal cycler (Perkin-Elmer). The amplification parameters were as

follows: 3 min for initial denaturation at 94°C, 30 s at 94°C, 35 s at 55°C, 7°C for 30 s—these steps were repeated for 30 cycles—final extension step at 72°C for 10 min. CYP19 were analyzed

in 8% and 10% polyacrylamide gels (29:1 ratio of acrylamide to bis-acrylamide), respectively, and were silver stained. Genotypes were identified by UV densitometry (Gel-Doc 2000 system,

Bio-Rad Laboratories Inc., Hercules, CA, USA). STATISTICAL ANALYSIS Among control subjects, the genotype frequencies for each CYP19 marker were examined for deviation from the Hardy-Weinberg

equilibrium (HWE) using the _X_ 2 test. The haplotype combination at CYP19 115T>C, 240A>G, and 1531C>T in the individuals was inferred using the maximum likelihood estimation

method with the Haplotype program (http://www.people.fas.harvard.edu/~junliu/Haplo/docMain.htm) (Niu et al. 2002). The differences in the distribution of the genotypes, haplotypes, and

diplotype distributions between the groups were assessed by a Chi-square test. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for CYP19

genotypes and to evaluate their interaction with endometriosis. The potential confounding factors that affect endometriosis risk, such as age and body mass index (BMI), was adjusted for

using logistic models in the estimation of ORs. Adjustments for these factors did not produce substantial changes in the results. We reported the results with and without adjustments for

these factors. All analyses were conducted using the Statistical Package for the Social Sciences version 12.0 (SPSS Inc., Chicago, IL, USA). Pairwise linkage disequilibrium (LD) between four

CYP1B1 polymorphic loci was assessed using the Haploview program (version 3.2, available at http://www.broad.mit.edu/mpg/haploview/index.php). RESULTS We determined the frequency of the

115T>C, 240A>G, and 1531C>T polymorphisms of the CYP19 gene among 188 healthy control subjects in the Korean women. The distributions of the 115T>C, 240A>G, and 1531C>T

genotypes were in Hardy-Weinberg equilibrium, and the genotype frequencies did not differ significantly between the endometriosis and control groups (Table 1). Using the homozygous wild

genotype as a reference group for each polymorphism, the ORs did not differ significantly between the homozygous variant genotype and the heterozygous-plus-homozygous variant genotype, even

after adjusting for age and BMI (Table 2). Individual haplotypes and diplotypes of single-nucleotide polymorphisms (SNPs) were determined using the Haplotyper program. Analysis of the

115T>C, 240A>G, and 1531C>T SNPs revealed only six of the eight possible haplotypes. The most common haplotype and diplotype were TGT and TAC/TGT, respectively. The distribution,

frequencies, and risks of the estimated haplotype combinations are listed in Table 3. The haplotype and diplotype combinations were not significantly associated with the risk of

endometriosis. Significant linkage disequilibrium among the three CYP19 SNPs is evident in Table 4. There were 8.85±2.29 repeats (mean±SD). The most frequent allele was [TTTA]11, followed by

[TTTA]7 and [TTTA]7–3 ([TTTA]7 with an additional 3-bp deletion) in both groups. We found no significant association between the [TTTA]_n_ repeat polymorphisms and endometriosis (Table 5).

Dividing the number of [TTTA]_n_ repeats into two groups (S, up to 7 repeats; L, 813 repeats) resulted in no significant differences between the S and L groups (Table 6). Strong linkage

disequilibrium was observed between the T genotype of 408C>T and [TTTA]_n_ with _n_=813 (correlation coefficient of 0.621, _p_<0.0001) (Table 7). DISCUSSION Estrogen is a sex steroid

that significantly affects the development of endometriosis, and, hence, genes controling the synthesis of estrogen, such as CYP19, are strong candidates for disorders associated with

estrogen exposure, including endometriosis. CYP19 polymorphisms can potentially change gene expression and, thereby, affect sex-steroid action. In the present study, which is the first to

investigate the association of CYP19 115T>C, 240A>G, and 1531C>T polymorphisms with endometriosis, we identified 115T>C, 240A>G, and 1531C>T polymorphisms and [TTTA]_n_

tetranucleotide repeat polymorphisms in the CYP19 gene, and found that none of these polymorphisms or their haplotypes were significantly associated with the risk of endometriosis. A

case–control study found that the CYP19 115T>C (Trp39Arg) polymorphism is significantly associated with breast cancer risk, in that this risk is significantly lower in carriers of the

variant Arg (C) allele than in noncarriers in premenopausal Japanese women (Miyoshi et al. 2000; Hirose et al. 2004). Functional genomic studies performed with the Trp39Arg variant and the

double variant Arg39Cys264 revealed a slight decrease in both the activity and quantity of allozyme protein for the Arg (C) allele, whereas double variant Arg39Cys264 allozymes showed

significant decreases in the activity and levels of immunoreactive protein when compared with the wild-type enzyme (Ma et al. 2005). The presence of Trp39Arg in a Japanese population

resulted in a less active aromatase protein (Miyoshi et al. 2000; Nativelle-Serpentini et al. 2002). In our study, the C genotype of the 115T>C polymorphism tended to decrease the risk of

endometriosis, but this did not reach statistical significance. Because the allele frequency of the C variant of the 115T>C polymorphism is only 4.5% (17 cases) in Koreans, we cannot

compare the effect of this allele with the results from studies performed on other ethnic groups. In our study, a synonymous polymorphism 240A>G (codon 80) in exon 3 (A genotype carrier)

did not affect the risk of endometriosis development. The 240A>G polymorphism was associated with breast cancer in postmenopausal Caucasian women, and the serum estradiol concentrations

were higher in women with the AA genotype than in those with the GG genotype. All of our subjects were premenopausal, whereas the other breast cancer and hormone studies involved

postmenopausal women, and, hence, the differing results might be due to the circumstances and role of the CYP19 enzyme in estrogen metabolism differing with the menopausal status. For the

CYP19 1531C>T transition in the 3′ untranslated region of exon 10, women with the T allele had significantly lower levels of testosterone, androstenedione, DHEA, and DHEAS. A

significantly greater estrone:androstenedione ratio supports the hypothesis that the T allele elevates aromatase activity (Haiman et al. 2002). The variant T allele was previously suggested

to be associated with a high estrogen profile because it was correlated with tumor aromatase mRNA levels. The variant T allele is associated with alternative promoter use (Somner et al.

2004), and Kristensen et al. (2000) found that it was more frequent in breast cancer cases than in their controls. Other studies have found no association between the 1531C>T polymorphism

and breast cancer risk, and the present study found that the CYP19 1531C>T polymorphism is not associated with the risk of endometriosis. Our results are consistent with the recent study

by Travis et al. (2004) suggesting the absence of an association between the CYP19 1531C>T polymorphism and plasma estradiol concentrations in postmenopausal women. We found a

tetranucleotide tandem repeat polymorphism that varies from 7 to 13 repeats in intron 4, and with an additional 3-bp deletion, although no data exist on the functionality of either the

tetranucleotide repeat or the deletion polymorphisms. The different genetic variants may lead to alternate splicing patterns and mRNA transcripts, which could, ultimately, modify the

activity of the resulting protein. On the other hand, the intratumoral aromatase activity tended to be higher in carriers of the longest CYP19 alleles than in carriers of all other CYP19

allele variants. The [TTTA]10 allele was found to be associated with endometriosis (Arvanitis et al. 2003), and several studies have failed to show associations between [TTTA]_n_ repeat

polymorphisms (including the 3-bp I/D polymorphism) and the risks of breast cancer and endometriosis (Probst-Hensch et al. 1999; Healey et al. 2000). A Japanese study found no significant

association between [TTTA]_n_ repeat polymorphisms and endometriosis, but patients carrying the D/D genotype were more frequent in the endometriosis group than in their control group (Kado

et al. 2002), especially in subgroups with a chocolate cyst. The present study found that advanced-stage endometriosis was not associated with [TTTA]_n_ repeat polymorphisms (including the

3-bp I/D polymorphism), despite the severity of endometriosis in our patients being similar to that in the Japanese study. Differences in the distributions of tetranucleotide repeats or

deletion polymorphisms might be responsible for different results in association studies. In present study, the CYP19 [TTTA]_n_ polymorphisms were in linkage disequilibrium with the

1531C>T polymorphism (correlation coefficient of 0.621, _p_<0.0001), and the number of repeats was highest in women with the TT genotype (11 repeats), which is consistent with a Danish

study (Tofteng et al. 2004). Our finding of the absence of an association between CYP19 polymorphisms and the risk of endometriosis is consistent with a Japanese study finding no

association between the Arg264Cys polymorphism and endometriosis (Tsuchiya et al. 2005). The CYP19 gene appears to have a limited number of common haplotypes and many very rare haplotypes.

The haplotype associated with the risk of endometrial cancer in postmenopausal women is also significantly associated with the ratios of estrone to androstenedione and estradiol to

testosterone, which are products and substrates of the enzyme aromatase that are encoded by CYP19 (Paynter et al. 2005). However, in our study, we found no association between haplotype and

the risk of endometriosis, which might be due to the different menstrual status of our subjects. The strengths of this study include the relatively large number of endometriosis cases and

the use of Korean female subjects, who are considered to be genetically homogenous. In conclusion, endometriosis does not appear to be associated with CYP19 polymorphisms, and, hence, the

genotypes and haplotype frequencies of these polymorphisms are probably not useful markers for predicting susceptibility to endometriosis. REFERENCES * American Fertility Society (1985)

Revised American Fertility Society classification of endometriosis: 1985. Fertil Steril 43:351–352 Article  Google Scholar  * Arvanitis DA, Koumantakis GE, Goumenou AG, Matalliotakis IM,

Koumantakis EE, Spandidos DA (2003) CYP1A1, CYP19, and GSTM1 polymorphisms increase the risk of endometriosis. Fertil Steril 79:702–709 Article  Google Scholar  * Baranova H, Bothorishvilli

R, Canis M, Albuisson E, Perriot S, Glowaczower E, Bruhat MA, Baranov V, Malet P (1997) Glutathione S-transferase M1 gene polymorphism and susceptibility to endometriosis in a French

population. Mol Hum Reprod 3:775–780 Article  CAS  Google Scholar  * Bergqvist A, Fernö M (1993) Oestrogen and progesterone receptors in endometriotic tissue and endometrium: comparison of

different cycle phases and ages. Hum Reprod 8:2211–2217 Article  CAS  Google Scholar  * Bulun SE, Fang Z, Imir G, Gurates B, Tamura M, Yilmaz B, Langoi D, Amin S, Yang S, Deb S (2004)

Aromatase and endometriosis. Semin Reprod Med 22:45–50 Article  CAS  Google Scholar  * Bulun SE, Imir G, Utsunomiya H, Thung S, Gurates B, Tamura M, Lin Z (2005) Aromatase in endometriosis

and uterine leiomyomata. J Steroid Biochem Mol Biol 95:57–62 Article  CAS  Google Scholar  * Chang CC, Hsieh YY, Tsai FJ, Tsai CH, Tsai HD, Lin CC (2002) The proline form of p53 codon 72

polymorphism is associated with endometriosis. Fertil Steril 77:43–45 Article  Google Scholar  * Cramer DW, Hornstein MD, Ng WG, Barbieri RL (1996) Endometriosis associated with the N314D

mutation of galactose-1-phosphate uridyl transferase (GALT). Mol Hum Reprod 2:149–152 Article  CAS  Google Scholar  * Georgiou I, Syrrou M, Bouba I, Dalkalitsis N, Paschopoulos M,

Navrozoglou I, Lolis D (1999) Association of estrogen receptor gene polymorphisms with endometriosis. Fertil Steril 72:164–166 Article  CAS  Google Scholar  * Haiman CA, Hankinson SE,

Spiegelman D, Brown M, Hunter DJ (2002) No association between a single nucleotide polymorphism in CYP19 and breast cancer risk. Cancer Epidemiol Biomarkers Prev 11:215–216 CAS  Google

Scholar  * Healey CS, Dunning AM, Durocher F, Teare D, Pharoah PD, Luben RN, Easton DF, Ponder BA (2000) Polymorphisms in the human aromatase cytochrome P450 gene (CYP19) and breast cancer

risk. Carcinogenesis 21:189–193 Article  CAS  Google Scholar  * Hirose K, Matsuo K, Toyama T, Iwata H, Hamajima N, Tajima K (2004) The CYP19 gene codon 39 Trp/Arg polymorphism increases

breast cancer risk in subsets of premenopausal Japanese. Cancer Epidemiol Biomarkers Prev 13:1407–1411 CAS  PubMed  Google Scholar  * Hur SE, Lee JY, Moon H-S, Chung HW (2005) Polymorphisms

of the genes encoding the GSTM1, GSTT1 and GSTP1 in Korean women: no association with endometriosis. Mol Hum Reprod 11:15–19 Article  CAS  Google Scholar  * Kado N, Kitawaki J, Obayashi H,

Ishihara H, Koshiba H, Kusuki I, Tsukamoto K, Hasegawa G, Nakamura N, Yoshikawa T, Honjo H (2002) Association of the CYP17 gene and CYP19 gene polymorphisms with risk of endometriosis in

Japanese women. Hum Reprod 17:897–902 Article  CAS  Google Scholar  * Kennedy SH (1997) Is there a genetic basis to endometriosis? Semin Reprod Endocrinol 5:309–318 Article  Google Scholar 

* Kitawaki J, Noguchi T, Amatsu T, Maeda K, Tsukamoto K, Yamamoto T, Fushiki S, Osawa Y, Honjo H (1997) Expression of aromatase cytochrome P450 protein and messenger ribonucleic acid in

human endometriotic and adenomyotic tissues but not in normal endometrium. Biol Reprod 57:514–519 Article  CAS  Google Scholar  * Kitawaki J, Kusuki I, Koshiba H, Tsukamoto K, Fushiki S,

Honjo H (1999) Detection of aromatase cytochrome P-450 in endometrial biopsy specimens as a diagnostic test for endometriosis. Fertil Steril 72:1100–1106 Article  CAS  Google Scholar  *

Kitawaki J, Obayashi H, Ishihara H, Koshiba H, Kusuki I, Kado N, Tsukamoto K, Hasegawa G, Nakamura N, Honjo H (2001) Oestrogen receptor-alpha gene polymorphism is associated with

endometriosis, adenomyosis and leiomyomata. Hum Reprod 16:51–55 Article  CAS  Google Scholar  * Kristensen VN, Harada N, Yoshimura N, Haraldsen E, Lonning PE, Erikstein B, Kåresen R,

Kristensen T, Borresen-Dale AL (2000) Genetic variants of CYP19 (aromatase) and breast cancer risk. Oncogene 19:1329–1333 Article  CAS  Google Scholar  * Lee KM, Abel J, Ko Y, Harth V, Park

WY, Seo JS, Yoo KY, Choi JY, Shin A, Ahn SH, Noh DY, Hirvonen A, Kang D (2003) Genetic polymorphisms of cytochrome P450 19 and 1B1, alcohol use, and breast cancer risk in Korean women. Br J

Cancer 88:675–678 Article  CAS  Google Scholar  * Lessey BA, Metzger DA, Haney AF, McCarty KS Jr (1989) Immunohistochemical analysis of estrogen and progesterone receptors in endometriosis:

comparison with normal endometrium during the menstrual cycle and the effect of medical therapy. Fertil Steril 51:409–415 Article  CAS  Google Scholar  * Ma CX, Adjei AA, Salavaggione OE,

Coronel J, Pelleymounter L, Wang L, Eckloff BW, Schaid D, Wieben ED, Adjei AA, Weinshilboum RM (2005) Human aromatase: gene resequencing and functional genomics. Cancer Res 65:11071–11082

Article  CAS  Google Scholar  * Miyoshi Y, Iwao K, Ikeda N, Egawa C, Noguchi S (2000) Breast cancer risk associated with polymorphism in CYP19 in Japanese women. Int J Cancer 89:325–328

Article  CAS  Google Scholar  * Nativelle-Serpentini C, Lambard S, Séralini GE, Sourdaine P (2002) Aromatase and breast cancer: W39R, an inactive protein. Eur J Endocrinol 146:583–589

Article  CAS  Google Scholar  * Niu T, Qin ZS, Xu X, Liu JS (2002) Bayesian haplotype inference for multiple linked single-nucleotide polymorphism. Am J Hum Genet 70:157–169 Article  CAS 

Google Scholar  * Paynter RA, Hankinson SE, Colditz GA, Kraft P, Hunter DJ, De Vivo I (2005) CYP19 (aromatase) haplotypes and endometrial cancer risk. Int J Cancer 116:267–274 Article  CAS 

Google Scholar  * Prentice A, Randall BJ, Weddell A, McGill A, Henry L, Horne CHW, Thomas EJ (1992) Ovarian steroid receptor expression in endometriosis and in two potential parent

epithelia: endometrium and peritoneal mesothelium. Hum Reprod 7:1318–1325 Article  CAS  Google Scholar  * Probst-Hensch NM, Ingles SA, Diep AT, Haile RW, Stanczyk FZ, Kolonel LN, Henderson

BE (1999) Aromatase and breast cancer susceptibility. Endocr Relat Cancer 6:165–173 Article  CAS  Google Scholar  * Siegelmann-Danieli N, Buetow KH (1999) Constitutional genetic variation at

the human aromatase gene (CYP19) and breast cancer risk. Br J Cancer 79:456–463 Article  CAS  Google Scholar  * Somner J, McLellan S, Cheung J, Mak YT, Frost ML, Knapp KM, Wierzbicki AS,

Wheeler M, Fogelman I, Ralston SH, Hampson GN (2004) Polymorphisms in the P450 c17 (17-hydroxylase/17,20-Lyase) and P450 c19 (aromatase) genes: association with serum sex steroid

concentrations and bone mineral density in postmenopausal women. J Clin Endocrinol Metab 89:344–351 Article  CAS  Google Scholar  * Sourdaine P, Parker MG, Telford J, Miller WR (1994)

Analysis of the aromatase cytochrome P450 gene in human breast cancers. J Mol Endocrinol 13:331–337 Article  CAS  Google Scholar  * Toda K, Terashima M, Kawamoto T, Sumimoto H, Yokoyama Y,

Kuribayashi I, Mitsuuchi Y, Maeda T, Yamamoto Y, Sagara Y (1990) Structural and functional characterization of human aromatase P-450 gene. Eur J Biochem 193:559–565 Article  CAS  Google

Scholar  * Tofteng CL, Kindmark A, Brändstrom H, Abrahamsen B, Petersen S, Stiger F, Stilgren LS, Jensen JEB, Vestergaard P, Langdahl BL, Mosekilde L (2004) Polymorphisms in the CYP19 and AR

genes—relation to bone mass and longitudinal bone changes in postmenopausal women with or without hormone replacement therapy: the Danish Osteoporosis Prevention Study. Calcif Tissue Int

74:25–34 Article  CAS  Google Scholar  * Travis RC, Churchman M, Edwards SA, Smith G, Verkasalo PK, Wolf CR, Wolf H, Key TJ (2004) No association of polymorphisms in CYP17, CYP19, and

HSD17-B1 with plasma estradiol concentrations in 1,090 British women. Cancer Epidemiol Biomarkers Prev 13:2282–2284 CAS  PubMed  Google Scholar  * Tsuchiya M, Nakao H, Katoh T, Sasaki H,

Hiroshima M, Tanaka T, Matsunaga T, Hanaoka T, Tsugane S, Ikenoue T (2005) Association between endometriosis and genetic polymorphisms of the estradiol-synthesizing enzyme genes HSD17B1 and

CYP19. Human Reprod 20:974–978 Article  CAS  Google Scholar  * Watanabe T, Imoto I, Kosugi Y, Fukuda Y, Mimura J, Fujii Y, Isaka K, Takayama M, Sato A, Inazawa J (2001) Human arylhydrocarbon

receptor repressor (AHRR) gene: genomic structure and analysis of polymorphism in endometriosis. J Hum Genet 46:342–346 Article  CAS  Google Scholar  * Wieser F, Schneeberger C, Tong D,

Tempfer C, Huber JC, Wenzl R (2002) PROGINS receptor gene polymorphism is associated with endometriosis. Fertil Steril 77:309–312 Article  Google Scholar  Download references ACKNOWLEDGMENT

This work was supported by a Korea Research Foundation Grant (KRF-2004-041-E00192). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Obstetrics and Gynecology, Konyang University

College of Medicine, Daejeon, South Korea Sung Eun Hur * Department of Obstetrics and Gynecology, Ewha Womans University Mokdong Hospital, 911-1 Yang-Cheon-Ku Mock-6-Dong, 158-710, Seoul,

South Korea Sara Lee, Hye-Sung Moon & Hye Won Chung * Department of Obstetrics and Gynecology, Konkuk University School of Medicine, Seoul, South Korea Ji Young Lee * Department of

Biochemistry, Ewha Womans University School of Medicine, Seoul, South Korea Hyung Lae Kim Authors * Sung Eun Hur View author publications You can also search for this author inPubMed Google

Scholar * Sara Lee View author publications You can also search for this author inPubMed Google Scholar * Ji Young Lee View author publications You can also search for this author inPubMed 

Google Scholar * Hye-Sung Moon View author publications You can also search for this author inPubMed Google Scholar * Hyung Lae Kim View author publications You can also search for this

author inPubMed Google Scholar * Hye Won Chung View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Hye Won Chung.

RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Hur, S.E., Lee, S., Lee, J.Y. _et al._ Polymorphisms and haplotypes of the gene encoding the

estrogen-metabolizing CYP19 gene in Korean women: no association with advanced-stage endometriosis. _J Hum Genet_ 52, 703–711 (2007). https://doi.org/10.1007/s10038-007-0174-x Download

citation * Received: 12 March 2007 * Accepted: 16 June 2007 * Published: 01 September 2007 * Issue Date: September 2007 * DOI: https://doi.org/10.1007/s10038-007-0174-x SHARE THIS ARTICLE

Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided

by the Springer Nature SharedIt content-sharing initiative KEYWORDS * CYP19 gene polymorphism * Haplotype * Estrogen-metabolizing gene * Advanced-stage endometriosis