- Research article
- Open Access
- Open Peer Review
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
- Prostate Cancer Patient
- Prostate Cancer Risk
- Prostate Cancer Case
- Wenzhou Medical College
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.
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).
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