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Hum. Reprod. Advance Access originally published online on January 7, 2008
Human Reproduction 2008 23(3):525-529; doi:10.1093/humrep/dem407
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© The Author 2008. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Association of cyclin D1 G870A polymorphism with uterine leiomyoma in women whose body mass index values are above 25 kg/m2

S.S. Han, J.H. No, Y.T. Jeon, J.W. Kim1, N.H. Park, Y.S. Song, S.B. Kang and H.P. Lee

Department of Obstetrics and Gynecology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea

1Correspondence address. Tel: +82-2-2072-3511; Fax: +82-2-762-3599; E-mail: kjwksh{at}snu.ac.kr


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
 References
 
BACKGROUND: Many studies have shown that a polymorphism (G870A) in cyclin D1 (CCND1) is associated with carcinogenesis in a variety of cancers. Our aim was to determine if an association exists between the CCND1 G870A polymorphism and uterine leiomyoma in Korean women.

METHODS: Blood samples of 331 cases and 204 controls aged 47.4 ± 7.6 and 46.8 ± 10.4 years (mean ± SD), respectively, were collected. CCND1 genotyping was determined by PCR and restriction fragment length polymorphism.

RESULTS: Allelic frequencies of cases (A, 0.53; G, 0.47) were not significantly different from those of controls (A, 0.49; G, 0.51) (P = 0.22). After adjustment for menarche age and BMI, multivariate logistic regression analysis showed that the AA genotype was not associated with increased risk for uterine leiomyoma [odds ratio (OR) = 1.38, 95% confidence interval (CI); 0.85–2.26, P = 0.19]. However, in stratification analysis of cases and controls with BMI >25 kg/m2, allelic frequencies of cases (A, 0.56; G, 0.44) were significantly different from controls (A, 0.36; G, 0.64) (P = 0.005), and the AA genotype was associated with increased risk for uterine leiomyoma (OR = 3.61, 95% CI; 1.02–12.73, P = 0.046). Furthermore, the OR for AA compared with combined GG and AG genotypes was 3.16 (95% CI 1.01–9.92, P = 0.048).

CONCLUSIONS: The A allele and AA genotype of CCND1 G870A polymorphism have a significant association with an increased risk of the uterine leiomyoma in obese Korean women.

Key words: cyclin D1 polymorphism/uterine leiomyoma/obesity


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Acknowledgements
 References
 
Uterine leiomyoma, the most common indication for hysterectomy, occurs in ~20–40% of all women in their lifetime (Day Baird et al., 2003Go). In addition, fine serial sectioning of uteri from 100 consecutive women who underwent hysterectomy found myomas in 77% (Cramer and Patel, 1990Go). Uterine leiomyomas are often asymptomatic, but may cause symptoms ranging in severity from mild abdominal discomfort to uterine bleeding, menometrorrhagia, severe dysmenorrhea, pelvic pain and infertility (Sell et al., 2005Go). Despite this high prevalence and the associated morbidity, the research on myoma has been underfunded compared with that on other malignant diseases.

Although the precise causes of myomas are unknown, several risk factors have been identified, such as age, endogeneous hormones (estrogen, progesterone), family history, ethnicity (African-American), obesity and nulliparity (Parker, 2007Go). Myomas are most prevalent during the reproductive years, due to estrogen-dependence, and regress after menopause (Parker, 2007Go). Estrogen is known to induce cell proliferation in target tissues, such as breast and uterus, by stimulating progression through the G1 phase of the cell cycle. The mitogenic action of estrogen induces cyclin D1 (CCND1) mRNA expression and translation (Sabbah et al., 1999Go).

The CCND1 gene is located at 11q13 and encoded by five exons. CCND1 is involved in integrating mitogenic stimulation with cellular proliferation and plays a key role in the G1/S checkpoint of the cell cycle. The ability of CCND1 to activate cyclin-dependent kinase (CDK) 4 or 6 mediates phosphorylation of the retinoblastoma tumor suppressor gene protein, resulting in the release of E2F transcription factors to allow cells to enter into S phase (Sherr and Roberts, 2004Go). Therefore, excessive CCND1 expression is a hallmark of several tumor types and is common in human cancers (Sherr, 2000Go, Knudsen et al., 2006Go). Furthermore, CCND1 has cell cycle-independent functions through its ability to modulate transcription factor action (Coqueret, 2002Go). Intragenic somatic mutations of CCND1 are rare, but many studies showed that a single base pair polymorphism (G870A) in CCND1 that affects splicing is associated with carcinogenesis and clinical outcome in a variety of cancers (Kong et al., 2000Go; Zheng et al., 2001Go; Wang et al., 2003Go; Knudsen, 2006Go).

We hypothesized that the CCND1 G870A polymorphism may be associated with the development of uterine leiomyoma, which is affected by estrogen. To evaluate the hypothesis, we undertook this hospital-based case–control study to investigate the association between the CCND1 G870A polymorphism and risk of uterine leiomyoma in Korean women.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Acknowledgements
 References
 
Subjects
All patients (n = 331) who had experienced myomectomy or hysterectomy due to uterine leiomyoma at the Department of Obstetrics and Gynecology, Seoul National University Hospital in 1999, were enrolled in this study. The histopathological results of all surgical specimens were leiomyoma. The non-tumor control group (n = 204) was composed of healthy Korean women who visited our hospital to participate in a routine gynecological cancer detection program. Control women had no evidence of leiomyoma by transvaginal ultrasonography and a normal cervical cytology in at least two consecutive annual examinations. To eliminate any selection bias, women with any malignant disease, those who had received blood transfusion and those with any systemic problem, such as chronic liver disease, were also excluded from the control group. The cases and controls were all Korean, meaning that they belonged to the same ethnic group. Before beginning this study, informed consent was obtained from all participants and the study protocol was approved by the Institutional Review Board of Seoul National University Hospital.

Genotyping
DNA was extracted from the 10 ml peripheral blood samples collected from all study participants. The 167 bp fragment encompassing the G–A polymorphism site in the CCND1 exon 4 terminal region was amplified using the specific forward primer 5'-GTGAAGTTCATTTCCAATCCGC-3' in exon 4 and reverse primer 5'-GGGACATCACCCTCACTTAC-3' in intron 4. PCR was carried out using 0.1 µg of DNA, 1 unit of Taq polymerase (Perkin-Elmer, Branchburg, NJ, USA), 10 mM of Tris–HCl (pH 8.3), 50 mM KCl, 1.0 mM MgCl2, 20 µM of each dNTP and 20 pM of each primer. The PCR conditions were as follows; 5 min of incubation at 50°C, 1 min at 95°C (denaturation), 35 amplification cycles [1 min at 61°C (annealing), 2 min at 72°C (extension)] and a final 7 min at 72°C final extension in a thermal cycler (GeneAmp PCR System 9700: Perkin-Elmer). After confirming a successful of PCR by 1.5% agarose gel electrophoresis, each PCR product was digested overnight with 5 units of ScrFI enzyme (New England Biolabs Inc., Beverly, MA, USA) at 37°C, and electrophoresed in 3.0% agarose gel. The 167 bp PCR fragment obtained was cut into 145 and 22 bp fragments when the ScrFI site was present. Genotypes were designated as G or A when the ScrFI restriction site was present or absent, respectively (Betticher et al., 1995Go). Direct DNA sequencing was performed in each genotype sample and they were used as positive controls. To test assay reliability, 50 randomly selected samples were re-tested and identical results were obtained.

Statistical analysis
Statistical analyses were carried out using the Statistical Package for the Social Sciences (SPSS) version 12.0 for Windows (SPSS Inc., Chicago, IL, USA). The {chi}2-test and the t-test were used to compare variables. A multivariate logistic regression model was used to calculate odds ratios (OR) with 95% confidence intervals (CIs) and corresponding P-values for each genotype after adjustment for age at menarche and BMI. A P-value of <0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Acknowledgements
 References
 
Table I includes the selected clinical characteristics of cases and controls. The mean age and parity of the two groups were similar. However, age at menarche and BMI were significantly different in the two groups (both P < 0.001).


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  		Table I. Clinical characteristics of cases and controls in the study group of Korean women

 
Allele frequencies and genotype distributions in the case and control subjects are included in Table II. The allelic frequencies of the case subjects (A, 0.53; G, 0.47) were not significantly different from those of the control subjects (A, 0.49; G, 0.51) (P = 0.22). The genotype distributions of the control and case groups were in Hardy–Weinberg equilibrium. On univariate logistic regression analysis, AA genotype had a borderline association with uterine leiomyoma (OR 1.49; 95% CI 0.97–2.28; P = 0.07). However, on multivariate logistic regression analysis after adjusting for BMI and age at menarche, there was no significant correlation between the CCND1 AA genotype and the risk of uterine leiomyoma (P = 0.19). When we used GG and AG genotypes as a reference genotype, we found that the OR for AA genotype was 1.41 on multivariate logistic regression analysis adjusted for BMI and age at menarche (95% CI 0.89–2.24; P = 0.14).


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  		Table II. Cyclin D1 (CCND1) G870A allele frequency and genotype distribution in leiomyoma cases and controls

 
Allelic frequencies and genotype distributions in the case and control subjects whose BMI values are >25 kg/m2 are represented in Table III. The allelic frequencies of the case subjects (A, 0.56; G, 0.44) were significantly different from those of the control subjects (A, 0.36; G, 0.64) (P = 0.005). On univariate logistic regression analysis, AA genotype had a significant association with the increased risk of uterine leiomyoma (OR, 4.5; 95% CI, 1.39–14.57; P = 0.01). There was also a significant correlation between the AA genotype and the risk of uterine leiomyoma on multivariate logistic regression analysis after adjusting for BMI and age at menarche (OR, 3.6; 95% CI, 1.02–12.73; P = 0.04). When we used GG and AG genotypes as a reference genotype, we found that the OR for AA genotype was 3.16 on multivariate logistic regression analysis adjusted for BMI and age at menarche (95% CI, 1.01–9.92; P = 0.048). There was no significant association between the allele frequencies and genotype distributions in the case and control subjects with BMI ≤25 kg/m2 (data not shown).


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  		Table III. CCND1 G870A allele frequency and genotype distribution in cases and controls with BMI >25 kg/m2

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Acknowledgements
 References
 
To the best of our knowledge, this is the first study that has attempted to evaluate the association between the CCND1 G870A polymorphism and uterine leiomyoma. This study shows that the CCND1 polymorphism (A allele, AA genotype) has a significant association with the increased risk of uterine leiomyoma in obese Korean women (BMI >25 kg/m2).

The CCND1 expression is stringently regulated, as would be expected based on its powerful role in proliferative control (Knudsen et al., 2006Go). However, CCND1 expression is deregulated in cancer. Recently, the G->A polymorphism at nucleotide 870, codon 242 in exon 4 of CCND1 gene that occurs in a splice donor site has been known to be linked to increased cancer risk or poor prognosis (Knudsen et al., 2006Go). It has been known that the G allele creates the well-described CCND1, whereas the A allele mainly produces a variant product of CCND1b (Betticher et al., 1995Go). The CCND1b lacks both the C-terminal PEST sequence and thr286 residue. Therefore, it was predicted that the CCND1b would reside in the nucleus and be more stable than full-length CCND1 (Knudsen, 2006Go). The constitutive nuclear localization of CCND1b could promote oncogenic transformation. Solomon et al. (2003Go) demonstrated that CCND1b harbors increased transforming capability.

The majority of many epidemiological studies showed that for CCND1 the A allele and AA genotype has a significant association with the increased cancer risk or poor disease outcome in a number of types of cancer (Knudsen et al., 2006Go), such as prostate cancer (Wang et al., 2003Go), larynx cancer (Rydzanicz et al., 2006Go), lung cancer (Qiuling et al., 2003Go; Sobti et al., 2006Go) and breast cancer (Shu et al., 2005Go). Results of the present study correspond with the earlier studies which reported that A allele and AA genotype have a significant association with cellular proliferation. In contrast to our results, some studies suggested that the G allele increase the cancer risk (Catarino et al., 2005Go, 2006Go), and others have ascribed no significant value to any allele of the CCND1 G870A polymorphism (Jeon et al., 2005Go; Kruger et al., 2006Go). These results mean that the G or A allele of the CCND1 G870A polymorphism may harbor differential effects in distinct tumor types. However, there have been inconsistent conclusions regarding the G/A allele type, even within a specific tumor type, such as colorectal cancer (Le Marchand et al., 2003Go; Hong et al., 2005Go). In fact, in our study, the CCND1 G870A polymorphism had no association with the increased risk of leiomyoma in total population irrespective of BMI. However, in obese group with BMI >25 kg/m2, the CCND1 G870A polymorphism had a significant association with the increased risk of leiomyoma on multivariate logistic regression analysis after adjustment for menarche age and BMI. The BMI threshold for assessing obesity for the Asians, such as the Koreans, is lower than those in Western populations (25.0 versus 30.0 kg/m2, respectively) (Kupelian et al., 1993Go).

A large prospective study of registered nurses in the USA found an increased leiomyoma risk with increasing adult BMI (Marshall et al., 1998Go). In our study, BMI was also significantly different between the case and control groups. Obesity could elevate the level of estrogen by various mechanisms, such as an increased conversion of circulating adrenal androgen to estrone, decreased hepatic production of sex hormone-binding globulin (Parker, 2007Go) and decreased metabolism of estradiol (E2) by the 2-hydroxylation route (Schneider et al., 1983Go). Therefore, elevated level of E2 by obesity may accelerate the induction of CCND1 mRNA expression and translation (Sabbah et al., 1999Go), resulting in the increase of leiomyoma.

Furthermore, estrogen is known to increase the mRNA for insulin-like growth factor-I (IGF-I) (Norstedt et al., 1989Go). IGF-I is increased in obese women. Increased expression of IGF-I was found in leiomyoma compared with adjacent myometrium (Kovacs et al., 2001Go). Jiang et al. (2006Go) suggested that IGF-I activates the CCND1 expression. The elevation of IGF-I and estrogen levels in obese women who have A allele and AA genotype of CCND1 G870A polymorphism may increase the risk of leiomyoma through the direct activation and production of CCND1b.

Although it is known that there is an inverse relationship between parity and the risk of leiomyomas, parity was similar between the two groups in this study. A possible explanation for this finding is that women in Korea with nulliparity or low parity are usually unwilling to have an operation on the uterus, resulting in an insufficient number of women with nulliparity or low parity in the case group. Early onset of menarche increases duration of estrogen exposure and may lead to increased chance of mutation in genes controlling myometrial proliferation, resulting in high susceptibility to leimyomas (Marshall et al., 1998Go). In contrast to our expectations, menarche age was 0.7 years older in case group. Maybe age would have been considerably affected by recall bias. Considering the small difference (0.7 years) and the size of this study, we think that it has minimal, if any, biological significance.

The limitations of our study are as follows. First, this study is a retrospective hospital-based, case–control study at a single institution. Although a selection bias may have occurred, the CCND1 G870A genotype frequencies of control and case groups in this study were in Hardy–Weinberg equilibrium. Second, we did not check the level of CCND1b according to the CCND1 G870A genotype. Although the A allele mainly facilitate production of CCND1b, individuals with the AA genotype can still produce the CCND1 (Holley et al., 2001Go). Therefore, further study of both genotype and cyclin D1b expression would clarify the relationship between the two parameters. Finally, the sample size of obese women was small. However, given that the increased risk of uterine leiomyoma was associated with increasing adult BMI (Marshall et al., 1998Go), CCND1 G870A polymorphism detected in obese women may explain the increase of uterine leiomyoma. A larger-scale study is warranted to confirm the association between the CCND1 G870A polymorphism and uterine leiomyoma in obese women.

In conclusion, this study suggests that cellular proliferation of myometrium related to CCND1 polymorphism in obese women could be one of the important steps in the genesis of uterine leiomyoma.


   Acknowledgements
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
References
 
The authors thank Seo-kyung Hahn, Medical Research Collaborating Center, Seoul National University Hospital for her assistance with the statistical analysis.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
 References
 
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Submitted on July 26, 2007; resubmitted on November 24, 2007; accepted on December 4, 2007.


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