Polymorphisms in CYP19A1, HSD17B1 and HSD17B2 genes and serum sex hormone level among postmenopausal Japanese women
Introduction
Postmenopausal women with higher circulating levels of sex hormones are at increased risk of developing estrogen-dependent malignant tumors, such as breast, endometrial and ovarian cancer [1], [2], [3], [4], [5]. Accumulated exposure to elevated sex steroid hormones, especially estrogens, leads to the inhibition of apoptosis and proliferation of mammary and endometrial epithelial cells [6]. After menopause, production of endogenous estrogen ceases in the ovaries, but continues in extragonadal sites, including peripheral adipose tissue, via the cytochrome P450 enzyme aromatase [7]. As shown in Fig. 1, aromatase, which is encoded by the CYP19A1 gene, converts androstenedione to estrone and testosterone to estradiol in peripheral adipose tissue [8], [9]. 17B-hydroxysteroid dehydrogenase type 1 (HSD17B1), which is encoded by the HSD17B1 gene, catalyzes the reduction of estrone to estradiol. In premenopausal women, HSD17B1 is mainly expressed in ovary and placenta, which secrete estradiol into the circulation. In postmenopausal women, in contrast, HSD17B1 is involved in the conversion of estrone to estradiol in certain local tissues, such as breast or endometrial epithelial cells. Conversely, 17B-hydroxysteroid dehydrogenase type 2 (HSD17B2), which is encoded by HSD17B2, contributes to the opposite reaction to HSD17B1, converting estradiol to estrone. HSD17B2 is expressed in epithelial cells of various tissues, such as breast, endometrium, prostate, placenta, liver, intestine and kidney in postmenopausal women. HSD17B2 may limit the entry of active sex steroids into the circulation [10].
Given the important role of these enzymes in estrogen synthesis in postmenopausal women, many epidemiological studies have investigated the association between single nucleotide polymorphisms (SNPs) in CYP19A1, HSD17B1, and HSD17B2 and the risk of sex hormone-dependent cancers [9], [11], [12], [13], [14], [15], [16]. However, few studies have evaluated the association between these polymorphisms and circulating sex hormone levels, particularly in Asian populations [8], [14], [15], [16], [17], [18], [19].
Here, we examined the impact of SNPs in CYP19A1, HSD17B1, and HSD17B2 on serum sex hormone levels among postmenopausal Japanese women, using cross-sectional data from the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study [20]. We also explored the interaction between current obesity and these polymorphisms.
Section snippets
Subjects
The J-MICC study has been described in detail elsewhere [20]. Briefly, this cohort study was launched in 2005 to investigate gene–environment interactions in lifestyle-related diseases. Participants aged 35–69 years from 10 geographically dispersed areas of Japan were asked to complete a questionnaire and provide a blood sample. From a total of about 60,000 participants during 2004–2008, 4519 subjects were arbitrarily selected, which consisted of about 500 subjects from each area, and
Results
The 785 study subjects are characterized in Table 1. Median age at enrollment was 61 years, and median age at menopause was 51 years. Half of the participants had been in menopause for more than 10 years. Median current BMI was 22.4 kg/m2 and 18.6% of participants had a BMI ≥25 kg/m2. 8.3% of participants had a history of any hormone therapy use. Women with a short menopausal period were likely to have a higher androstenedione level (P value = 0.0031). Although the differences in mean estrone and
Discussion
In this study, we found significant differences in serum estrone and estradiol level according to current BMI and serum SHBG level. We also found that rs4441215 and rs936306 in CYP19A1 were associated with a difference in serum estrone and estradiol levels, whereas rs4888202 and rs2955160 in the HSD17B2 genotype were associated with a difference in serum estrone level. Although obese women are more likely to have higher sex hormone levels than those of normal weight, none of these polymorphisms
Conclusions
We found significant differences in serum estrone and estradiol level by CYP19A1 and HSD17B2 genotype, after adjustment for multiple comparisons. These polymorphisms might be associated with serum estradiol level among postmenopausal Japanese women, independent of current BMI. This is the first report that a polymorphism in HSD17B2 affects circulating sex hormone levels. Long-term accumulation of estrogen exposure is associated with an increased risk of estrogen-dependent cancer, such as breast
Conflict of interest
The authors declare no conflicts of interest.
Contributors
Contributions of the authors:
Study concept and design: Hosono, Ito, and Tanaka.
Acquisition of data: All authors.
Analysis and interpretation of data: Hosono, Ito, and Tanaka.
Writing, review and/or revision of the manuscript: All authors.
Administrative, technical, or material support: Hosono, Ito, Kubo, Nagata, Naito, Hamajima, and Tanaka.
Study supervision: Ito and Tanaka.
Competing interest
None.
Funding
This study was supported in part by a Grant-in-Aid for Scientific Research on Priority Areas of Cancer (No. 17015018) and on Innovative Areas (No. 221S0001) from the Japanese Ministry of Education, Science, Sports, Culture and Technology.
Ethical approval
The study was approved by the ethics committees of Nagoya University School of Medicine (Ref. 253/2010) and participating institutions.
Acknowledgements
The authors are grateful to the assistant staff at the Laboratory for Genotyping Development, Center for Genomic Medicine, RIKEN, for their support with genotyping. The authors also would like to thank all of participants and staffs who took part in the Japan Multi-Institutional Collaborative Cohort Study.
References (30)
- et al.
Hormonal changes during menopause
Maturitas
(2009) - et al.
Structure and function of 17beta-hydroxysteroid dehydrogenase type 1 and type 2
Mol. Cell. Endocrinol.
(2001) - et al.
Gene variants in PPARD and PPARGC1A are associated with timing of natural menopause in the general Japanese population
Maturitas
(2012) - et al.
Some statistical methods for multiple endpoints in clinical trials
Control. Clin. Trials
(1997) - et al.
Global analysis of DNA methylation variation in adipose tissue from twins reveals links to disease-associated variants in distal regulatory elements
Am. J. Hum. Genet.
(2013) - et al.
Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies
J. Natl. Cancer Inst.
(2002) - et al.
Postmenopausal serum androgens, oestrogens and breast cancer risk: the European prospective investigation into cancer and nutrition
Endocr. Relat. Cancer
(2005) - et al.
Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review
Cancer Epidemiol. Biomark. Prev.: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
(2002) - et al.
Endogenous sex hormones and endometrial cancer risk in women in the European Prospective Investigation into Cancer and Nutrition (EPIC)
Endocr. Relat. Cancer
(2008) - et al.
Endogenous hormones and ovarian cancer: epidemiology and current hypotheses
Cancer Epidemiol. Biomark. Prev.: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
(2005)
Hormonal carcinogenesis
Carcinogenesis
Association between CYP19A1 polymorphisms and sex hormones in postmenopausal Japanese women
J. Hum. Genet.
Interaction between CYP19A1 polymorphisms body mass index in the risk of endometrial cancer in postmenopausal Japanese and women
Asian Pac. J. Cancer Prev.: APJC. P.
Association between CYP19 polymorphisms and breast cancer risk: results from 10,592 cases and 11,720 controls
Breast Cancer Res Treat.
Genetic polymorphisms of estrogen metabolizing enzyme and breast cancer risk in Thai women
Int. J. Cancer – J. Int. Cancer
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