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. Author manuscript; available in PMC: 2009 Dec 29.
Published in final edited form as: J Toxicol Environ Health A. 2008;71(6):367–372. doi: 10.1080/15287390701798685

Vitamin D Receptor Polymorphisms and Renal Cancer Risk in Central and Eastern Europe

S Karami 1, P Brennan 2, RJ Hung 2,3, P Boffetta 2, J Toro 1, RT Wilson 1, D Zaridze 4, M Navratilova 7, N Chatterjee 1, D Mates 9, V Janout 5, H Kollarova 5, V Bencko 6, N Szeszenia-Dabrowska 8, I Holcatova 6, A Moukeria 4, R Welch 10, S Chanock 10, N Rothman 1, W-H Chow 1, LE Moore 1
PMCID: PMC2799224  NIHMSID: NIHMS162532  PMID: 18246496

Abstract

Previous studies investigated the role of vitamin D intake and cancer risk. The kidney is a major organ for vitamin D metabolism, activity, and calcium homeostasis, therefore, it was hypothesized that dietary vitamin D intake and polymorphisms in the vitamin D receptor (VDR) gene may modify renal cell carcinoma (RCC) risk. Three common VDR gene polymorphisms (BsmI, FokI, TaqI) were evaluated among 925 RCC cases and 1,192 controls enrolled in a hospital-based case-control study conducted in Central and Eastern Europe. Overall associations with RCC risk were not observed, however subgroup analyses revealed associations after stratification by median age of diagnosis and family history of cancer. Among subjects over 60 years, reduced risks were observed among carriers of the f alleles in the FokI SNP (OR = 0.61 for Ff and OR = 0.74 for ff genotypes) compared to subjects with the FF genotype (P-trend = 0.04; P-interaction = 0.004). Subjects with the BB BsmI genotype and a positive family history of cancer had lower risk compared to subjects with the bb allele (OR=0.60; 95% CI: 0.33-1.1; P trend = 0.05). Genotype associations with these subgroups were not modified when dietary sources of vitamin D or calcium were considered. Additional studies of genetic variation in the VDR gene are warranted.

Keywords: VDR polymorphisms, FokI, BsmI, TaqI, RCC, renal cancer, kidney

Introduction

The kidney is a major organ for vitamin D metabolism, activity and calcium homeostasis (Klassen and Watkins, 2001). The anti-carcinogenic properties of vitamin D include inhibition of clonal tumor cell proliferation, hematopoieses, induction of immune cell differentiation and apoptosis (Valdivielso and Fernandez, 2006; Walters, 1992). Vitamin D activity is mediated through binding to vitamin D receptors (VDR), transcriptional factors that are part of the nuclear hormone receptor family which influence the behavior of genes involved in cell regulation, growth, and immunity (Valdivielso and Fernandez, 2006; Walters, 1992; Thibault et al, 2006).

Several epidemiologic studies of breast, prostate and colorectal cancer examined the relationship between cancer risk and dietary vitamin D intake (Kim et al, 2001; Slattery et al, 2004(b); Tseng et al, 2005; Divisier al, 2006; Lin et al, 2007; Shin et al, 2002) but the direction of risk has not been consistent. There are currently no studies that investigated the association between dietary vitamin D intake and renal cancer given that the kidney is the major organ of vitamin D metabolism and activity. However, dietary intake of vitamin D may not be a good measure of vitamin D exposure since sunlight exposure induces synthesis of vitamin D. Yet, since vitamin D activity is mediated by the vitamin D receptor, analysis of genetic variation in VDR may elucidate the role of vitamin D in RCC etiology. Three VDR polymorphisms have been commonly investigated. Each polymorphism is named by the restriction sites that were initially used to identify them. The FokI (Ex4+4T>C) polymorphism is located at the 5′ end of the VDR gene. This polymorphism alters the transcription initiation site of the VDR protein.

The protein associated with the FokI f variant is three amino acids shorter than the F allele and functions with higher activity as a transcription factor than the wild-type (FF) protein (Arai et al, 1997; Jurutka et al, 2000); evidence from previous epidemiological studies indicate the FokI f polymorphism to be associated with decreased cancer risk (Huang et al, 2006; Liu et al, 2005). Furthermore, BsmI (IVS10+283G>A) and TaqI (Ex11+32T>C) polymorphisms are highly correlated to each other and are both located near the 3′ end of the gene. Like many tagging SNPs, BsmI and TaqI polymorphisms are not known to have functional relevance yet they are thought to be in linkage disequilibrium with functional variants in the 3'UTR which modify mRNA stability (Uitterlinden et al, 2004).

In this study, the role of common VDR polymorphisms within one of the largest RCC studies with biological samples to date was examined to evaluate whether genetic variants were associated with RCC risk overall or within particular case subgroups. In addition, interactions between VDR polymorphisms and dietary intake frequency of vitamin D and calcium rich foods were assessed.

Materials and Methods

Details regarding this study population were previously described (Moore et al, 2007). Briefly, a hospital-based case-control study of renal cell cancer was conducted between 1999 and 2003 in 7 centers in 4 Central and Eastern European countries (Moscow, Russia; Bucharest, Romania; Lodz, Poland; and Prague, Olomouc, Ceske-Budejovice, and Brno, Czech Republic). This is an area with the highest incidence of RCC in the world (Hung et al, 2007). A total of 1,097 newly diagnosed and histologically confirmed RCC (IDC-O-2 codes C64) cases, aged 20-88 years were recruited for this study. Controls were selected among individuals admitted as in-patients or out-patients from the same hospitals as cases. Eligible controls (N=1,476) were recruited with non-tobacco related conditions and frequency-matched to cases on gender, age (+/- 3 years), center and place of residence. No single disease made up more than 20% of the control group. All participants were of Caucasian decent. Using lifestyle and food frequency questionnaires, consumption of food-specific items were categorized into: never, low (<1 a month), medium (≥1 a month but <1 a week), and high (≥1 a week). Dietary sources of vitamin D were estimated based on intake frequency of liver, fish and egg. Dietary sources of calcium were estimated based on intake frequency of yogurt, milk and cheese. Additional details on the dietary questionnaire were previously reported (Hsu et al, 2006).

Laboratory Analysis

Genotyping of VDR polymorphisms was conducted at IARC and at NCI's Core Genotyping Facility (CGF). Blood samples were stored at -80°C and shipped to the NCI on dry ice. DNA for genotyping assays were extracted from buffy coat and whole blood samples using phenol-chloroform extraction. Methods for all genotype assays can be found at: http://snp500cancer.nci.nih.gov/home.cfm (Packer, 2004). DNA from RCC cases and controls were blinded and randomized on PCR plates for genotyping analyses. Genotyping of a randomly selected 5% duplicate samples was conducted for quality control. A total of 925 (84.2%) cases and 1,192 (80.7%) controls were genotyped. All three VDR variants were in Hardy-Weinberg Equilibrium (p<0.05), and duplicates were highly concordant. Call rates for BsmI IVS10+283G>A (94%), FokI Ex4+4T>C (98%), and TaqI Ex11+32T>C (92%) were similar for RCC cases and controls.

VDR genotypes are expressed using nomenclature derived from restriction-fragment length polymorphism (RFLP) analysis studies. Upper-case letters (i.e. B, F, T) specify alleles coded for the restriction polymorphisms previously observed that also refers to a specific base change. Specifically, the BsmI (IVS10+283G>A) polymorphism A allele is equivalent to “B” using the RFLP nomenclature. The FokI (Ex4+4T>C) C allele is equivalent to “F” allele from the RFLP nomenclature, and the TaqI (Ex11+32T>C) T allele is equivalent to “T” allele using RFLP nomenclature.

Statistical Analysis

Hardy-Weinberg equilibrium was tested by the goodness of fit χ2 test. Pairwise linkage disequilibrium (LD) between SNP was estimated based on D′ and r2 values using Haploview (http://www.broad.mit.edu/mpg/haploview/index.php). Of the 3 SNP genotyped, BsmI and TaqI were highly correlated (r2 <0.95). Haplotype analysis for BsmI and TaqI, which reside within a region of high linkage disequilibrium (Uitterlinden Ag, 2004), were estimated in R, adjusted for age, gender and center (version 2.4.0; http://www.r-project.org). Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using unconditional logistic regression models adjusting for gender, age, center, self-reported hypertension (yes, no), smoking status (never, ever) and body mass index (BMI). Interactions were tested comparing regression models with and without interaction terms using a likelihood ratio test (LRT). Polytomous logistic regression was used to estimate OR and 95% CI for histologically defined case subgroups. Heterogeneity between risk factor OR for case subgroups was assessed using logistic regression analyses restricted to cases. An extension of the polytomous logistic regression model was used to evaluate heterogeneity in risk factor ORs by multiple tumor characteristics simultaneously (Chatterjee, 2004). This method allowed simultaneous evaluation of several correlated tumor features (i.e. histopathologic subtype, stage, and grade) as determinants of risk. All analyses were conducted in STATA 8.0 unless otherwise specified (STATA Corporation, College Station, TX).

Results

A description of study subjects is presented in Table 1. Cases and controls were comparable in age; however, cases had a higher prevalence of hypertension, having a first degree relative with cancer, and high BMI. Overall, none of the VDR polymorphisms investigated were significantly associated with RCC risk (Table 2). After stratification by mean age (60 years), reduced RCC risk was observed among older subjects with the f allele in the FokI SNP (OR = 0.61 for Ff; OR = 0.74 for ff genotypes) compared to those with the FF genotype (P trend = 0.04; P interaction = 0.004). Among subjects with a familial history of cancer, risks were lower among carriers of the B allele in the BsmI SNP (OR = 0.72 for Bb; OR = 0.60 for the BB genotypes) compared with the bb genotype (P trend = 0.05). Lower risk was observed among subjects with the t allele in the TaqI SNP (OR = 0.79 for Tt; OR = 0.62 for the tt genotypes) compared to the TT genotype (P trend = 0.07). VDR polymorphisms did not modify associations between RCC and known risk factors such as hypertension, BMI, or tobacco. Genotype associations overall or within subgroups were not modified when dietary vitamin D or calcium intake frequencies were considered (data not shown). Results did not differ after stratification by tumor histology, stage or grade (data not shown).

Table 1. General characteristics of participants genotyped in the Central and Eastern European Renal Cell Carcinoma Study.

Variables Cases Controls


n % n % P-value
Participants Genotyped 925 43.7 1,192 56.3
Gender
Male 550 59.5 766 64.3
Female 375 40.5 426 35.7 0.02
Age at Interview (years)
≤60 472 51.0 620 52.0
>60 453 49.0 572 48.0 0.65
Mean Age (std) 59.5 years (10.4) 59.3 years (10.4)
Center
Romania-Bucharest 90 9.7 125 10.5
Poland-Lodz 80 8.7 195 16.4
Russia-Moscow 288 31.1 366 30.7
*Czech Republic 467 50.5 506 42.4 <.001
BMI at Interview
<25 267 28.9 432 36.2
25-29.9 404 43.7 493 41.4
30+ 254 27.5 267 22.4 <.001
Tobacco Status
Never 433 46.9 486 40.8
Ever 490 53.1 705 59.2 0.01
Hypertension
No 507 54.9 737 61.8
Yes 417 45.1 455 38.2 0.001
Familial History of Cancer
No 1st degree relative with cancer 623 67.4 861 72.2
1st degree relative with cancer 302 32.6 331 27.8 0.02
Dairy Intake
Low: <1/mo 264 29.3 403 33.2
Medium: < 1/week 324 36.0 405 33.4
High: ≥1/week 312 34.7 406 33.4 0.15
Yogurt Intake
Low: <1/mo 361 39.1 537 43.1
Medium: < 1/week 182 19.7 212 17.0
High: ≥1/week 381 41.2 498 39.9 0.18
Milk Intake
Low: <1/mo 203 22.0 292 23.4
Medium: < 1/week 133 14.4 157 12.6
High: ≥1/week 588 63.6 798 64.0 0.76
Egg Intake
Low: <1/mo 33 3.6 92 7.4
Medium: < 1/week 297 32.1 314 25.2
High: ≥1/week 594 64.3 841 67.4 0.80
Fish Intake
Low: <1/mo 244 27.1 355 29.2
Medium: < 1/week 356 39.6 444 36.6
High: ≥1/week 300 33.3 415 34.2 0.71
Liver Intake
Low: <1/mo 406 43.9 508 40.7
Medium: < 1/week 373 40.4 487 39.1
High: ≥1/week 145 15.7 252 20.2 0.02
*

Brno, Olomouc, Prague, Ceske

Dietary sources of calcium intake

Dietary sources of vitamin D intake

Table 2. Risk of renal cell carcinoma by: Main Effects, Age, and Familial History of Cancer.

Main Effects Age: 20-60 Years Age: > 60 Years No Familial History of Cancer Familial History of Cancer





SNP Polymorphisms *Cases *Controls OR (95%CI) *Cases *Controls OR (95%CI) *Cases *Controls OR (95%CI) P-int§ *Cases *Controls OR (95%CI) *Cases *Controls OR (95%CI) P-int§
rs1544410 (IVS10+283G>A)
(Bsm I) bb 324 407 1.00 174 216 1.00 150 191 1.00 204 296 1.00 120 111 1.00
Bb 370 474 0.97 (0.79-1.18) 182 256 0.85 (0.64-1.13) 188 218 1.13 (0.84-1.53) 263 347 1.11 (0.87-1.41) 107 127 0.72 (0.49-1.06)
BB 81 112 0.85 (0.61-1.18) 39 60 0.70 (0.44-1.12) 42 52 1.05 (0.65-1.70) 55 78 0.97 (0.65-1.44) 26 34 0.60 (0.33-1.11)
P-trend 0.38 0.10 0.59 0.28 0.79 0.05 0.16
rs10735810 (M1T)
(FoK I) FF 286 338 1.00 129 190 1.00 157 148 1.00 198 249 1.00 88 89 1.00
Ff 376 492 0.90 (0.73-1.11) 212 253 1.27 (0.95-1.71) 164 239 0.61 (0.45-0.83) 246 359 0.87 (0.67-1.12) 130 133 0.93 (0.62-1.39)
ff 149 199 0.91 (0.69-1.19) 72 105 1.11 (0.76-1.62) 77 94 0.74 (0.50-1.09) 100 138 0.97 (0.70-1.34) 49 61 0.79 (0.48-1.30)
P-trend 0.41 0.41 0.04 0.004 0.66 0.37 0.56
rs731236 (I352I)
(Taq I) TT 320 402 1.00 173 214 1.00 147 188 1.00 206 295 1.00 114 107 1.00
Tt 361 438 1.00 (0.82-1.24) 176 225 0.93 (0.70-1.24) 185 213 1.12 (0.83-1.51) 254 319 1.12 (0.87-1.44) 107 119 0.79 (0.53-1.16)
tt 97 137 0.87 (0.64-1.18) 45 74 0.70 (0.45-1.07) 52 63 1.10 (0.71-1.70) 67 95 1.00 (0.69-1.44) 30 42 0.62 (0.35-1.08)
P-trend 0.49 0.14 0.55 0.35 0.73 0.07 0.20

Main effects adjusted for gender, age (continuous), center, self reported hypertension (yes, no), BMI (continuous), and smoking status (ever never)

Age effect adjusted for gender, center, self reported hypertension (yes, no), BMI (continuous), and smoking status (ever never)

Familial history of cancer effect adjusted for gender, age (continuous), center, self reported hypertension (yes, no), BMI (continuous), and smoking status (ever never)

*

Differences between total number of cases and controls are due to missing data

Highly correlated with Bsm I (r2<0.95)

First degree relative

§

P-interaction calculated by likelihood ratio test

Discussion

In this study, RCC risk was not associated with the BsmI, FokI, or TaqI VDR polymorphic variants evaluated. However, after subgroup analysis by age, lower risks were observed among subjects older than 60 years of age with the FokI f allele compared to those with the F allele. Among subjects with a familial history of cancer, lower risks were observed among subjects the BsmI B and TaqI t allele.

The FokI f polymorphism results in a protein that is three amino acids shorter and with higher transcriptional activity than the wild-type protein (Arai et al, 1997; Jurutka et al, 2000; Uitterlinden et al, 2004; Hu et al, 2003). Epidemiological studies showed FokI F polymorphism is associated with elevated risk among older prostate and head and neck cancer cases compared to carriers of the ff allele (Huang et al, 2006; Liu et al, 2005). Among the elderly, vitamin D levels tend to decrease due to reduced dermal production of vitamin D, reduced solar exposure and outdoor activity, and reduced intake of vitamin D rich foods (Holick, 1989; Lips, 2001). While most epidemiological studies show an association between the FokI F polymorphism and increase cancer risk, the relationship may be modified with age. Because vitamin D levels generally decrease with age, genetic contributions may provide greater protection among the elderly than among younger populations with adequate intake levels (Mosekilde, 2005).

No significant associations among VDR variant genotypes among subjects with a positive family history of cancer were observed in previous colon and prostate cancer studies (Cheteri et al, 2004; Slattery ML, 2004(a)), however, a case-control study of 483 breast cancer patients in Finland found significantly lower cancer risk among women with a family history of breast cancer, among women with an a allele in the VDR ApaI SNP compared with carriers of the AA genotype (Sillanpaa et al, 2004). The authors of this study speculated that a novel interaction between the VDR ApaI genotype and breast cancer 1 (BRCAI) or breast cancer 2 (BRCA2) genes exist (Sillanpaa et al, 2004). Similarly, significant association with the BsmI genotype and RCC among those with a familial history of cancer may reflect an association with other genes predisposing to family renal cancer, such as the von Hipple-Lindau (VHL) gene.

A Japanese study observed higher RCC risk among subjects with the TaqI TT polymorphism, particularly among RCC cases with rapid compared to slow-growth tumors (Ikuyama et al, 2002). In our study, prevalence of VDR polymorphisms did not differ by tumor stage or grade.

Strengths of this study include (1) high rates for participation and biological specimen collection, (2) inclusion of histologically confirmed cancer cases, and (3) a large sample size. This study also had sufficient statistical power to detect relatively small genotype associations overall and within subgroups, although power to detect multiplicative interactions was limited. Furthermore, the assessment of vitamin D and calcium intake was evaluated using a food frequency questionnaire of specific food items which limited the ability to accurately assess intake.

In conclusion, the data showed that the FokI f polymorphism was associated with lower RCC risk among older subjects and that BsmI B and TaqI t polymorphisms were associated with lower risk among individuals with a family history of cancer. Additional studies are warranted to elucidate the role of genetic variation in VDR and RCC risk.

Acknowledgments

This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health and by European Commission INCO-COPERNICUS Grant IC15-CT96-0313. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government.

References

  1. 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. doi: 10.1359/jbmr.1997.12.6.915. [DOI] [PubMed] [Google Scholar]
  2. 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. doi: 10.1002/pros.20001. [DOI] [PubMed] [Google Scholar]
  3. Chatterjee N. A two-stage regression model for epidemiological studies with multivariate disease classification data. Jam Stat Assoc. 2004;99:127–138. [Google Scholar]
  4. Divisi D, Di Tommaso S, Salvemini S, Garramone M, Crisci R. Diet and cancer. Acta Biomed. 2006;77:118–123. [PubMed] [Google Scholar]
  5. Holick MF, Matsuoka LY, Wortsman J. Age, vitamin D, and solar ultraviolet radiation. Lancet. 1989;4:1104–1105. doi: 10.1016/s0140-6736(89)91124-0. [DOI] [PubMed] [Google Scholar]
  6. Hsu CC, Chow WH, Boffetta P, Moore L, Zaridze D, Moukeria A, Janout V, Kollarova H, Bencko V, Navratilova M, Szeszenia-Dabrowska N, Mates D, Brennan P. Dietary risk factors of renal cell carcinoma in eastern and central Europe. Am J Epidemiol. 2007;166:62–70. doi: 10.1093/aje/kwm043. [DOI] [PubMed] [Google Scholar]
  7. Hu J, Mao Y, White K, Canadian Cancer Registries Epidemiology Research Group Diet and vitamin or mineral supplements and risk of renal cell carcinoma in Canada. Cancer Causes Control. 2003;14:705–714. doi: 10.1023/a:1026310323882. [DOI] [PubMed] [Google Scholar]
  8. Huang SP, Huang CY, Wu WJ, Pu YS, Chen J, Chen YY, Yu CC, Wu TT, Wang JS, Lee YH, Huang JK, Huang CH, Wu MT. Association of vitamin D receptor FokI polymorphism with prostate cancer risk, clinicopathological features and recurrence of prostate specific antigen after radical prostatectomy. Int J Cancer. 2006;119:1902–1907. doi: 10.1002/ijc.22053. [DOI] [PubMed] [Google Scholar]
  9. Hung RJ, Moore L, Boffetta P, Feng BJ, Toro JR, Rothman N, Zaridze D, Navratilova M, Bencko V, Janout V, Kollarova H, Szeszenia-Dabrowska N, Mates D, Chow WH, Brennan P. Family history and the risk of kidney cancer: a multicenter case-control study in Central Europe. Cancer Epidemiol Biomarkers Prev. 2007;16:1287–1290. doi: 10.1158/1055-9965.EPI-06-0963. [DOI] [PubMed] [Google Scholar]
  10. Ikuyama T, Hamasaki T, Inatomi H, Katoh T, Muratani T, Matsumoto T. Association of vitamin D receptor gene polymorphism with renal cell carcinoma in Japanese. Endocr J. 2002;49:433–438. doi: 10.1507/endocrj.49.433. [DOI] [PubMed] [Google Scholar]
  11. Jurutka PW, Remus LS, Whitfield GK, Thompson PD, Hsieh JC, Zitzer H, Tavakkoli P, Galligan MA, Dang HT, Haussler CA, Haussler MR. The polymorphic N terminus in human vitamin D receptor isoforms influences transcriptional activity by modulating interaction with transcription factor IIB. Mol Endocrinol. 2000;14:401–420. doi: 10.1210/mend.14.3.0435. [DOI] [PubMed] [Google Scholar]
  12. Kim HS, Newcomb PA, Ulrich CM, Keener CL, Bigler J, Farin FM, Bostick RM, Potter JD. Vitamin D receptor polymorphism and risk of colorectal adenomas: evidence of interaction with dietary vitamin D and calcium. Cancer Epidemiol Biomarkers Prev. 2001;10:869–874. [PubMed] [Google Scholar]
  13. Klassen CD, Watkins JB., III . Casarett & Doull's Essentials of Toxicology. 6th. NY: McGraw Hill; 2001. pp. 208–219. [Google Scholar]
  14. Lin J, Manson JE, Lee IM, Cook NR, Buring JE, Zhang SM. Intakes of calcium and vitamin D and breast cancer risk in women. Arch Intern Med. 2007;167:1050–1059. doi: 10.1001/archinte.167.10.1050. [DOI] [PubMed] [Google Scholar]
  15. Lips P. Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. Endocrine Reviews. 2001;22:477–501. doi: 10.1210/edrv.22.4.0437. [DOI] [PubMed] [Google Scholar]
  16. Liu Z, Calderon JI, Zhang Z, Sturgis E, Spitz MR, Wei Q. Polymorphisms of vitamin D receptor gene protect against the risk of head and neck cancer. Pharmacogenet Genomics. 2005;15:159–165. doi: 10.1097/01213011-200503000-00004. [DOI] [PubMed] [Google Scholar]
  17. Moore LE, Brennan P, Karami S, Hung RJ, Hsu C, Boffetta P, Toro J, Zaridze D, Janout V, Bencko V, Navratilova M, Szeszenia-Dabrowska N, Mates D, Mukeria A, Holcatova I, Welch R, Chanock S, Rothman N, Chow WH. Glutathione S-transferase polymorphisms, cruciferous vegetable intake, smoking, and cancer risk in the Central and Eastern European Kidney Cancer Study. Carcinogenesis. 2007 doi: 10.1093/carcin/bgm151. Epub ahead of print. [DOI] [PubMed] [Google Scholar]
  18. Mosekilde L. Vitamin D and the elderly. Clin Endocrinol (Oxf) 2005;62:265–281. doi: 10.1111/j.1365-2265.2005.02226.x. [DOI] [PubMed] [Google Scholar]
  19. Parker BR, Yeager M, Stats B, Welch R, Crenshaw A, Kiley M, Eckert A, Beerman M, Miller E, Bergen A, Rothman N, Strausberg R, Chanock SJ. SNP500Cancer: a public resource for sequence validation and assay development for genetic variation in candidate genes. Nucleic Acids Res. 2004;32:D528–D532. doi: 10.1093/nar/gkh005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Shin MH, Holmes MD, Hankinson SE, Wu K, Colditz GA, Willett WC. Intake of diary products, calcium and vitamin D and risk of breast cancer. J Natl Cancer Inst. 2002;94:1301–1311. doi: 10.1093/jnci/94.17.1301. [DOI] [PubMed] [Google Scholar]
  21. Sillanpaa P, Hirvonen A, Kataja V, Eskelinen M, Kosma VM, Uusitupa M, Vainio H, Mitrunen K. Vitamin D receptor gene polymorphism as an important modifier of positive family history related breast cancer risk. Pharmacogenetics. 2004;14:239–245. doi: 10.1097/00008571-200404000-00003. [DOI] [PubMed] [Google Scholar]
  22. Slattery ML, Murtaugh M, Caan B, Ma KN, Wolff R, Samowitz W. Associations between BMI, energy intake, energy expenditure, VDR genotype and colon and rectal cancers (United States) Cancer Causes Control. 2004a;15:863–872. doi: 10.1007/s10552-004-1048-6. [DOI] [PubMed] [Google Scholar]
  23. Slattery ML, Neuhausen SL, Hoffman M, Caan B, Curtin K, Ma KN, Samowitz W. Dietary calcium, vitamin D, VDR genotypes and colorectal cancer. Int J Cancer. 2004b;111:750–756. doi: 10.1002/ijc.20330. [DOI] [PubMed] [Google Scholar]
  24. Thibault F, Cancel-Tassin G, Cussenot O. Low penetrance genetic susceptibility to kidney cancer. Br J Urul Int. 2006;98:735–738. doi: 10.1111/j.1464-410X.2006.06351.x. [DOI] [PubMed] [Google Scholar]
  25. Tseng M, Breslow RA, Graubard BI, Ziegler RG. Dairy, calcium, and vitamin D intakes and prostate cancer risk in the National Health and Nutrition Examination Epidemiologic Follow-up Study cohort. Am J Clin Nutr. 2005;81:1147–1154. doi: 10.1093/ajcn/81.5.1147. [DOI] [PubMed] [Google Scholar]
  26. Uitterlinden AG, Fang Y, van Meurs JB, Pols HA, Van Leeuwen JP. Genetics and biology of vitamin D receptor polymorphisms. Gene. 2004;338:143–156. doi: 10.1016/j.gene.2004.05.014. [DOI] [PubMed] [Google Scholar]
  27. Valdivielso JM, Fernandez E. Vitamin D receptor polymorphisms and diseases. Clin Chim Acta. 2006;371:1–12. doi: 10.1016/j.cca.2006.02.016. [DOI] [PubMed] [Google Scholar]
  28. Walters MR. Newly Identified actions of the vitamin D endocrine system. Endocr Rev. 1992;13:719–764. doi: 10.1210/edrv-13-4-719. [DOI] [PubMed] [Google Scholar]

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