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Association of vitamin D receptor polymorphisms with the risk of prostate cancer in the Han population of Southern China
- Yongheng Bai†1,
- Yaping Yu†2,
- Bin Yu2,
- Jianrong Ge2,
- Jingzhang Ji4,
- Hong Lu3,
- Jia Wei1,
- Zhiliang Weng1,
- Zhihua Tao3 and
- Jianxin Lu1Email author
© Bai et al; licensee BioMed Central Ltd. 2009
Received: 8 April 2009
Accepted: 4 December 2009
Published: 4 December 2009
Molecular epidemiological studies have shown that gene polymorphisms of vitamin D receptor (VDR) are associated with prostate cancer risks. However, previous results from many molecular studies remain inconsistent.
Blood samples were collected from 122 prostate cancer patients and 130 age-matched control subjects in the Han population of Southern China. The differences of VDR gene polymorphism between cancer cases and controls were determined by PCR-RFLP, examiming FokI (exon 2), BsmI, Tru9I, ApaI (intron 9), and TaqI (exon 9). Associations between the VDR gene polymorphism and prostate cancer risk were calculated in an unconditional logistic regression model. Linkage disequilibrium and haplotypes were analyzed with the SHEsis software.
Of five polymorphisms, BsmI was shown to associate with prostate cancer, while FokI, Tru9I, ApaI, and TaqI did not show any significant association. After adjustment for age, the BsmI 'B' allele was associated with an almost 1/3-fold risk (OR = 0.35, 95%CI: 0.15-0.80) of the occurrence of prostate cancer, a 1/5-fold risk (OR = 0.20, 95%CI: 0.06-0.68) of poorly differentiated prostate cancer, and a 1/10-fold risk (OR = 0.10, 95%CI: 0.01-0.78) of aggressive prostate cancer compared with the 'b' allele, especially among older men (>71 years). In addition, haplotype analysis revealed that the 'F-b-U-A-T' was more frequent found in cases than in controls (3.4% vs 0.0%, P = 0.0035), while the frequency of haplotype 'F-B-U-a-T' was 0.8% in cases, significantly lower than in controls (3.9%, P = 0.019).
Our experiments provide evidences that genetic polymorphisms in the VDR gene may be potential risk factors for prostate cancer in the Han population of southern China and the susceptibility to prostate cancer is associated with ethnicity and geographic location.
Prostate cancer is the most common type of tumor in old men throughout the world. In 2003, about 220,900 new cases of prostate cancer were diagnosed in the United States . Although epidemiological studies showed that the incidence of prostate cancer in Asians is much lower than that in African-Americans , the occurrence of this disease has rapidly increased among Chinese men . In the Shanghai population, the incidence was 1.9/10 million in 1983, but it increased to 21.08/10 million in 2005 . The incidence rate in Beijing was similar to that of Shanghai . Age, race, and geographical factors are well-established risk factors of prostate cancer . However, these factors may not completely explain the differences between different ethnic groups in prostate cancer rates. Therefore, genetic variation in certain genes, including genes controlling vitamin D activity, could play a role in determination of susceptibility to prostate cancer.
Based on investigations of the differences in prostate cancer incidence at different latitudes in the United States, Schwartz et al. [7, 8] hypothesized that low ultraviolet exposure may be a risk factor for prostate cancer. After exposure to UV radiation, vitamin D is produced in the skin and then hydroxylated in the liver to 25-hydroxyvitamin D3, and in the kidneys to the more physiologically active metabolite 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3]. The biological activity of 1,25(OH)2D3 is mediated primarily by vitamin D receptor (VDR). In addition to kidney and bone cells, VDR  is also expressed in human prostatic cells, and a series of experiments revealed that VDR mediates the influence of 1,25(OH)2D3 on the growth, differentiation [10, 11], and apoptosis  of prostatic cells. These findings indicated that 1,25(OH)2D3 and its specific nuclear receptor protein, VDR, may be closely associated with prostate cancer risk.
In this report, we carried out a population-based, case-control study to evaluate the association between VDR gene polymorphisms and prostate cancer risk in the Han population of Southern China because one salient characteristic of China's population has a large base with diverse genetic backgrounds. The present study can provide a platform to help explain the pathological mechanism of prostate cancer and to a better understanding of the geographic and ethnic differences associated with disease incidence and mortality.
In the present study, 122 prostate cancer patients and 130 age-matched male controls were enrolled in four hospitals in southern China between March 2007 and August 2008. All prostate cancer cases were confirmed by pathological examination. The pathologic grades were classified according to the Gleason score as well and moderately differentiated (Gleason 2-6) and poorly differentiated (Gleason 7-10) . Based on the TNM classification system promulgated by the American Joint Committee on Cancer, the disease stage was divided into localized and aggressive cancer, as determined by transrectal ultrasound, magnetic resonance imaging (MRI) and emission computed tomography (ECT). Localized prostate cancer can be detectable clinically or felt (palpated) on examination, but has not spread outside the prostate. Aggressive cancer means the cancer has spread through the prostatic capsule (eg, bladder neck, external sphincter, rectum, and levator muscles) and even has invaded other nearby structures (eg, bone and pancreas).
The age-matched control subjects were individuals recruited from retired employees at the First Affiliated Hospital of Wenzhou Medical College. The controls were screened to ensure that there had never been diagnosed with cancer and had low plasma prostate-specific antigen (PSA) levels (total PSA<4.00 ng/ml). The controls were also checked for cancer history based on their past medical records and/or asked directly for their cancer history.
All subjects were informed about the contents of the study and gave their informed consent. This study was approved by the Ethics Committee of Wenzhou Medical College.
PCR-RFLP conditions for VDR gene polymorphisms (GenBank AY342401)
FokI, BsmI, Tru9I, ApaI, and TaqI, are reported according to the standard nomenclature in which lowercase and uppercase letters indicate the presence or absence of a restriction site, respectively. The FokI T and C alleles are represented by f and F, the BsmI G and A alleles by b and B, the Tru9I G and A alleles by U and u, the ApaI T and G alleles by A and a, and the TaqI T and C alleles by T and t, respectively.
Tests for Hardy-Weinberg equilibrium were performed separately for each SNP among case and control subjects. The Independent-Samples T test was used to determine differences according to age, and the chi-square or Fisher's exact test was performed to calculate the clinical parametric distributions. Unconditional logistic regression analysis models were used to evaluate the relationships between different genotypes and disease risk [Odds ratios (OR), 95% confidence intervals (95% CI)] adjusted by age. Linkage disequilibrium and haplotypes were analyzed with the SHEsis software . A p-value of less than 0.05 was considered as statistically significant.
Results and Discussion
The worldwide incidence of clinical prostate cancer shows a strong dependence on age, race, and geography. For example the incidence in African-Americans was significantly higher than that in Asians, especially in the Chinese population. Recent epidemiological studies in different populations have indicated that difference in VDR genotype frequencies may play an important role in the risk of prostate cancer. In the present study, we evaluated the association between five polymorphisms in the VDR gene and prostate cancer risk in the southern Chinese Han population.
Clinic and demographic characteristics of the subjects
Cases (n = 122)
Controls (n = 130)
Ages at diagnosis (year)a
71.77 ± 8.12
71.28 ± 7.86
Smoking status b
Alcohol intake b
Distribution of VDR genotypes and alleles between prostate cancer cases and controls
Age-adjusted ORs and P value in different kinds of patients compared with controls by BsmI polymorphisms
Age stratification (years)*
Based on observations of the distribution difference between prostate cancer cases and controls, we here hypothesize the BsmI 'B' allele might have a protective effect against tumorigenesis. Previous studies also found that the BsmI 'BB+Bb' genotype was associated with one-third the risk of prostate cancer in a Japanese population  and one-fifth the risk in advanced stages and in poorly differentiated disease in a Taiwanese population . Although Ma et al.  reported no significant association between the BsmI polymorphism and prostate cancer risk, they did find a 57% reduction in the risk of prostate cancer with the BsmI 'BB' genotype compared with the 'bb' genotype in American men. These data also support our findings concerning the protective effect of the BsmI 'B' allele. However, there are still some studies failed to show such a result. For example, studies such as Liu et al.  in Beijing population and Ingles et al.  in African-Americans. In addition to ethnic characteristics, geographical differences and living habits, the factors, including the study sample size, the choice of the control group (BPH or healthy people), might be the important reasons for these inconsistent results.
Linkage disequilibrium test between five VDR gene polymorphisms
Distance between two polymorphisms
Haplotype frequencies for VDR five polymorphisms between prostate cancer cases and controls
The distribution of polymorphisms in the 3'UTR region of the VDR gene may be relavant with VDR mRNA stability and gene transcription . Alterations in the ability of VDR protein to bind 1,25(OH)2D3 or activate the VDRE gene would ultimately result in changes in the expression of regulatory genes, such as CDK, which can directly or indirectly control prostatic cell division. If the protective action of the BsmI 'B' allele is confirmed experimentally, the pathological mechanism of prostate cancer would be better understand. In addition, we observed the genotype and allelic frequencies of VDR gene varied from race to race. For example, the allelic frequency of TaqI 'T' in the southern Chinese Han population (96.5%, in control) was significantly higher than that in white Americans (55.2%)  and Portuguese (57.8%) . Thus, the distribution of VDR gene polymorphisms may help explain the difference in incidence of prostate cancer in different populations.
In conclusion, the present study indicated that VDR gene polymorphisms may be associated with prostate cancer risk in the southern Chinese Han population, and these associations may largely depend on population characteristics and geographic location.
All abbreviations are defined in the text.
We thank Dr. Luhu Shan (Zhejiang Cancer Hospital) and Dr. Guiqin Sun (Shaoxing People's Hospital) for their contributions to the subject assistance. This study was sponsored by Zhejiang Provincial Program for the Cultivation of High-level Innovative Health talents and Zhejiang Provincial Top Key Discipline of Laboratory Medicine, and supported by the Shaoxing Scientific Planning Key Project (Grant 2006A23014).
- American Cancer Society: Cancer Facts and Figures. 2003, [http://www.cancer.org/docroot/home/index.asp]Google Scholar
- Quinn M, Babb P: Patterns and trends in prostate cancer incidence, survival, prevalence and mortality. Part I: international comparisons. BJU Int. 2002, 90: 162-173. 10.1046/j.1464-410X.2002.2822.x.View ArticlePubMedGoogle Scholar
- Ostrander EA, Stanford JL: Genetics of prostate cancer: too many loci, too few genes. Am J Hum Genet. 2000, 67: 1367-1375. 10.1086/316916.View ArticlePubMedPubMed CentralGoogle Scholar
- The incidence of cancer in Shanghai city in 1983-2005. Tumor. 2008, 28: 571-Google Scholar
- Gu FL: Changing constituents of genitourinary cancer in recent 50 years in Beijing. Chin Med J (Eng l). 2003, 116: 1391-1393.Google Scholar
- Zhang HF, Wang HL, Xu N, Li SW, Ji GY, Li XM, Pang YZ, Zhang L, Zhao XJ, Gao HW: Mass screening of 12027 elderly men for prostate carcinoma by measuring serum prostate specific antigen. Chin Med J (Eng l). 2004, 117: 67-70.Google Scholar
- Schwartz GG, Hulka BS: Is vitamin D deficiency a risk factor for prostate cancer? (hypothesis). Anticancer Res. 1990, 10: 1307-1311.PubMedGoogle Scholar
- Hanchette CL, Schwartz GG: Geographic patterns of prostate cancer mortality: evidence for a protective effect of ultraviolet radiation. Cancer (Phila.). 1992, 70: 2861-2869. 10.1002/1097-0142(19921215)70:12<2861::AID-CNCR2820701224>3.0.CO;2-G.View ArticleGoogle Scholar
- Miller GJ, Stapleton GE, Ferrara JA, Lucia MS, Pfister S, Hedlund TE, Upadhya P: The human prostatic carcinoma cell line LNCaP expresses biologically active, specific receptors for 1a,25 dihydroxyvitamin D3. Cancer Res. 1992, 52: 515-520.PubMedGoogle Scholar
- Peehl DM, Skowronski RJ, Leung GK, Wong ST, Stamey TA, Feldman D: Antiproliferative effects of 1,25-dihydroxyvitamin D3 on primary cultures of human prostatic cells. Cancer Res. 1994, 54: 805-810.PubMedGoogle Scholar
- Schwartz GG, Wang MH, Zang M, Singh RK, Siegal GP: 1a,25-Dihydroxyvitamin D (calcitriol) inhibits the invasiveness of human prostate cancer cells. Cancer Epidemiol Biomarkers Prev. 1997, 6: 727-732.PubMedGoogle Scholar
- Guzey M, Kitada S, Reed JC: Apoptosis induction by 1alpha, 25-dihydroxyvitamin D3 in prostate cancer. Mol Cancer Ther. 2002, 1: 667-677.PubMedGoogle Scholar
- Morrison NA, Qi JC, Tokita A, Kelly PJ, Crofts L, Nguyen TV, Sambrook PN, Eisman JA: Prediction of bone density from vitamin D receptor alleles. Nature. 1994, 367: 284-287. 10.1038/367284a0.View ArticlePubMedGoogle Scholar
- Saijo T, Ito M, Takeda E, Huq AH, Naito E, Yokota I, Sone T, Pike JW, Kuroda Y: A unique mutation in the vitamin D receptor gene in three Japanese patients with vitamin D-dependent rickets type II: utility of single-strand conformation polymorphism analysis for heterozygous carrier detection. Am J Hum Genet. 1991, 49: 668-673.PubMedPubMed CentralGoogle Scholar
- Miyamoto K, Kesterson RA, Yamamoto H, Taketani Y, Nishiwaki E, Tatsumi S, Inoue Y, Morita K, Takeda E, Pike JW: Structural organization of the human vitamin D receptor chromosomal gene and its promoter. Mol Endocrinol. 1997, 11: 1165-1179. 10.1210/me.11.8.1165.View ArticlePubMedGoogle Scholar
- Arai H, Miyamoto K, Taketani Y, Yamamoto H, Iemori Y, Morita K, Tonai T, Nishisho T, Mori S, Takeda E: A vitamin D receptor gene polymorphism in the translation initiation codon: effect on protein activity and relation to bone mineral density in Japanese women. J Bone Miner Res. 1997, 12: 915-921. 10.1359/jbmr.19188.8.131.525.View ArticlePubMedGoogle Scholar
- Taylor JA, Hirvonen A, Watson M, Pittman G, Mohler JL, Bell DA: Association of prostate cancer with vitamin D receptor gene polymorphism. Cancer Res. 1996, 56: 4108-4110.PubMedGoogle Scholar
- Ingles SA, Ross RK, Yu MC, Irvine RA, La Pera G, Haile RW, Coetzee GA: Association of prostate cancer risk with genetic polymorphisms in vitamin D receptor and androgen receptor. J Natl Cancer Inst (Bethesda). 1997, 89: 166-170. 10.1093/jnci/89.2.166.View ArticleGoogle Scholar
- Xu Y, Shibata A, McNeal JE, Stamey TA, Feldman D, Peehl DM: Vitamin D receptor start codon polymorphism (FokI) and prostate cancer progression. Cancer Epidemiol Biomarkers Prev. 2003, 12: 23-27.PubMedGoogle Scholar
- Habuchi T, Suzuki T, Sasaki R, Wang L, Sato K, Satoh S, Akao T, Tsuchiya N, Shimoda N, Wada Y, Koizumi A, Chihara J, Ogawa O, Kato T: Association of vitamin D receptor gene polymorphism with prostate cancer and benign prostatic hyperplasia in a Japanese population. Cancer Res. 2000, 60: 305-308.PubMedGoogle Scholar
- Cheteri MB, Stanford JL, Friedrichsen DM, Peters MA, Iwasaki L, Langlois MC, Feng Z, Ostrander EA: Vitamin D receptor gene polymorphisms and prostate cancer risk. Prostate. 2004, 59: 409-418. 10.1002/pros.20001.View ArticlePubMedGoogle Scholar
- Medeiros R, Morais A, Vasconcelos A, Costa S, Pinto D, Oliveira J, Lopes C: The role of vitamin D receptor gene polymorphisms in the susceptibility to prostate cancer of a southern European population. J Hum Genet. 2002, 47: 413-418. 10.1007/s100380200060.View ArticlePubMedGoogle Scholar
- John EM, Schwartz GG, Koo J, Den Berg, Ingles SA: Sun Exposure, Vitamin D Receptor Gene Polymorphisms, and Risk of Advanced Prostate Cancer. Cancer Res. 2005, 65: 5470-5479. 10.1158/0008-5472.CAN-04-3134.View ArticlePubMedGoogle Scholar
- Patiyan A, Eberhard V, Peter S: Androgen receptor and vitamin D receptor gene polymorphisms and prostate cancer risk. Eur J Cancer. 2006, 42: 2833-2837. 10.1016/j.ejca.2006.06.030.View ArticleGoogle Scholar
- Oakley-Girvan I, Feldman D, Eccleshall TR, Gallagher RP, Wu AH, Kolonel LN, Halpern J, Balise RP, West DW, Paffenbarger Jr, Whittemore AS: Risk of early-onset prostate cancer in relation to germ line polymorphisms of the vitamin D receptor. Cancer Epidemiol Biomarkers Prev. 2004, 13: 1325-1330.PubMedGoogle Scholar
- Correa-Cerro L, Berthon P, Haussler J, Bochum S, Drelon E, Mangin P, Fournier G, Paiss T, Cussenot O, Vogel W: Vitamin D receptor polymorphisms as markers in prostate cancer. Hum Genet. 1999, 105: 281-287. 10.1007/s004390051102.View ArticlePubMedGoogle Scholar
- Cicek MS, Liu X, Schumacher FR, Casey G, Witte JS: Vitamin D Receptor Genotypes/Haplotypes and Prostate Cancer Risk. Cancer Epidemiol Biomarkers Prev. 2006, 15: 2549-2552. 10.1158/1055-9965.EPI-06-0409.View ArticlePubMedGoogle Scholar
- Ingles SA, Coetzee GA, Ross RK, Henderson BE, Kolonel LN, Crocitto L, Wang W, Haile RW: Association of prostate cancer with vitamin D receptor haplotype in African-Americans. Cancer Res. 1998, 58: 1620-1623.PubMedGoogle Scholar
- Hayes VM, Severi G, Padilla EJ, Eggleton SA, Southey MC, Sutherland RL, Hopper JL, Giles GG: Genetic variants in the vitamin D receptor gene and prostate cancer risk. Cancer Epidemiol Biomarkers Prev. 2005, 14: 997-999. 10.1158/1055-9965.EPI-04-0660.View ArticlePubMedGoogle Scholar
- Berndt SI, Dodson JL, Huang WY, Nicodemus KK: A systematic review of vitamin D receptor gene polymorphisms and prostate cancer risk. J Urol. 2006, 175: 1613-1623. 10.1016/S0022-5347(05)00958-4.View ArticlePubMedGoogle Scholar
- Yang Y, Wang S, Ye Z, Yang W: Association of single nucleotide polymorphism of vitamin D receptor gene start codon and the susceptibility to prostate cancer in the Han nationality in Hubei area. Zhonghua Nan Ke Xue. 2004, 10: 411-414.PubMedGoogle Scholar
- Liu JH, Li HW, Wang JQ, Li M, Xin DQ, Na X, Zhang M, Ye SY, Na YQ: Vitamin D receptor gene BsmI polymorphism and the susceptibility to prostate cancer in northern Chinese Han population. Zhonghua Nan Ke Xue. 2003, 9: 413-416.PubMedGoogle Scholar
- Chokkalingam AP, McGlynn KA, Gao YT, Pollak M, Deng J, Sesterhenn IA, Mostofi FK, Fraumeni JF, Hsing AW: Vitamin D receptor gene polymorphisms, insulin-like growth factors, and prostate cancer risk: a population-based case-control study in China. Cancer Res. 2001, 61: 4333-4336.PubMedGoogle Scholar
- Gleason DF, Mellinger GT: Prediction of prognosis for prostatic adenocarcinoma by combined histologic grading and clinical staging. J Urol. 1974, 111: 58-64.PubMedGoogle Scholar
- Shi YY, He L: SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res. 2005, 15: 97-98. 10.1038/sj.cr.7290286.View ArticlePubMedGoogle Scholar
- Huang SP, Chou YH, Wayne Chang, Wu MT, Chen YY, Yu CC, Wu TT, Lee YH, Huang JK, Wu WJ, Huang CH: Association between vitamin D receptor gene polymorphisms and prostate cancer risk in a Taiwanese population. Cancer Lett. 2004, 207: 69-77. 10.1016/j.canlet.2003.12.006.View ArticlePubMedGoogle Scholar
- Ma J, Stampfer MJ, Gann PH, Hough HL, Giovannucci E, Kelsey KT, Hennekens CH, Hunter DJ: Vitamin D receptor polymorphisms, circulating vitamin D metabolites and risk of prostate cancer in United States physicians. Cancer Epidemiol Biomark Prev. 1998, 7: 385-390.Google Scholar
- Morrison NA, Yeoman R, Kelly PJ, Eisman J: Contribution of trans-acting factor alleles to normal physiological variability: vitamin D receptor gene polymorphisms and circulating osteocalcin. Proc Nail Acad Sci USA. 1992, 89: 6665-6669. 10.1073/pnas.89.15.6665.View ArticleGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/10/125/prepub
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