The online version of this article (doi:10.1186/bcr3162) contains supplementary material, which is available to authorized users.
The authors declare that they have no competing interests.
SY helped to develop the hypothesis, design the study, and perform the data analysis and interpretation. CBA helped to develop the hypothesis, design the study, provide the data and biospecimen from the WCHS, perform the data analysis and interpretation, and provide financial support for the study. GZ helped to provide the data and biospecimen from the WCHS and to perform the data analysis and interpretation. DHB, LJ, MR, GC, WD, KSP, and EVB helped to provide the data and biospecimen from the WCHS. HH provided pathological data of tumor samples. C-CH, LES, LT, CSJ, DLT, SEM and FA helped to perform the data analysis and interpretation. HZ helped to provide financial support for the study. All authors read and approved the final draft of the manuscript.
American women of African ancestry (AA) are more likely than European Americans (EA) to have estrogen receptor (ER)-negative breast cancer. 25-hydroxyvitamin D (25OHD) is low in AAs, and was associated with ER-negative tumors in EAs. We hypothesized that racial differences in 25OHD levels, as well as in inherited genetic variations, may contribute, in part, to the differences in tumor characteristics.
In a case (n = 928)-control (n = 843) study of breast cancer in AA and EA women, we measured serum 25OHD levels in controls and tested associations between risk and tag single nucleotide polymorphisms (SNPs) in VDR, CYP24A1 and CYP27B1, particularly by ER status.
More AAs had severe vitamin D deficiency (< 10 ng/ml) than EAs (34.3% vs 5.9%), with lowest levels among those with the highest African ancestry. Associations for SNPs differed by race. Among AAs, VDR SNP rs2239186, associated with higher serum levels of 25OHD, decreased risk after correction for multiple testing (OR = 0.53, 95% CI = 0.31-0.79, p by permutation = 0.03), but had no effect in EAs. The majority of associations were for ER-negative breast cancer, with seven differential associations between AA and EA women for CYP24A1 (p for interaction < 0.10). SNP rs27622941 was associated with a > twofold increased risk of ER-negative breast cancer among AAs (OR = 2.62, 95% CI = 1.38-4.98), but had no effect in EAs. rs2209314 decreased risk among EAs (OR = 0.38, 95% CI = 0.20-0.73), with no associations in AAs. The increased risk of ER-negative breast cancer in AAs compared to EAs was reduced and became non-significant (OR = 1.20, 95% CI = 0.80-1.79) after adjusting for these two CYP24A1 SNPs.
These data suggest that genetic variants in the vitamin D pathway may be related to the higher prevalence of ER-negative breast cancer in AA women.
Additional file 1: Supplementary Tables S1-S5. The file contains the following five supplementary tables. Table S1. Breast cancer risk associated with SNPs in VDR, CYP27B1, and CYP24A1 in African American and European American women. Table S2. Haplotypes of VDR and CYP24A1 in significant association with breast cancer risk in African American and European American women. Table S3. Risk of estrogen receptor positive breast cancer associated with SNPs in VDR, CYP27B1, and CYP24A1 in African Americana and European American women. Table S4. Risk of estrogen receptor negative breast cancer associated with SNPs in VDR, CYP27B1, and CYP24A1 in African Americana and European American women. Table S5. SNPs in VDR that show differential associations with breast cancer stratified by menopausal status in African American and European American women. (DOC 704 KB)13058_2011_2955_MOESM1_ESM.DOC
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Fumagalli M, Sironi M, Pozzoli U, Ferrer-Admettla A, Pattini L, Nielsen R: Signatures of environmental genetic adaptation pinpoint pathogens as the main selective pressure through human evolution. PLoS Genet. 2011, 7: e100235- CrossRef
Jablonski NG: The evolution of human skin and skin color. Ann Rev Anthropol. 2004, 33: 585-623. 10.1146/annurev.anthro.33.070203.143955. CrossRef
Nesby-O'Dell S, Scanlon KS, Cogswell ME, Gillespie C, Hollis BW, Looker AC, Allen C, Doughertly C, Gunter EW, Bowman BA: Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: third National Health and Nutrition Examination Survey, 1988-1994. Am J Clin Nutr. 2002, 76: 187-192. PubMed
Wejse C, Olesen R, Rabna P, Kaestel P, Gustafson P, Aaby P, Andersen PL, Glerup H, Sodemann M: Serum 25-hydroxyvitamin D in a West African population of tuberculosis patients and unmatched healthy controls. Am J Clin Nutr. 2007, 86: 1376-1383. PubMed
Nejentsev S, Godfrey L, Snook H, Rance H, Nutland S, Walker NM, Lam AC, Guja C, Ionescu-Tirgoviste C, Undlien DE, Ronningen KS, Tuomilehto-Wolf E, Tuomilehto J, Newport MJ, Clayton DG, Todd JA: Comparative high-resolution analysis of linkage disequilibrium and tag single nucleotide polymorphisms between populations in the vitamin D receptor gene. Hum Mol Genet. 2004, 13: 1633-1639. 10.1093/hmg/ddh169. CrossRefPubMed
Zinser G, Packman K, Welsh J: Vitamin D(3) receptor ablation alters mammary gland morphogenesis. Development. 2002, 129: 3067-3076. PubMed
Welsh J: Vitamin D and breast cancer: insights from animal models. Am J Clin Nutr. 2004, 80: 1721S-1724S. PubMed
International Agency for Research on Cancer: Vitamin D and cancer. IACR Working Group Reports. 2008, Lyon, France: International Agency for Research on Cancer, 5:
Chlebowski RT, Johnson KC, Kooperberg C, Pettinger M, Wactawski-Wende J, Rohan T, Rossouw J, Lane D, O'Sullivan MJ, Yasmeen S, Hiatt RA, Shikany JM, Vitolins M, Khandekar J, Hubbell FA: Calcium plus vitamin D supplementation and the risk of breast cancer. J Natl Cancer Inst. 2008, 100: 1581-1591. 10.1093/jnci/djn360. CrossRefPubMedPubMedCentral
Yao S, Sucheston LE, Millen AE, Johnson CS, Trump DL, Nesline MK, Davis W, Hong CC, McCann SE, Hwang H, Kulkarni S, Edge SB, O'Connor TL, Ambrosone CB: Pretreatment serum concentrations of 25-hydroxyvitamin D and breast cancer prognostic characteristics: a case-control and a case-series study. PLoS One. 2011, 6: e17251-10.1371/journal.pone.0017251. CrossRefPubMedPubMedCentral
Ambrosone CB, Ciupak GL, Bandera EV, Jandorf L, Bovbjerg DH, Zirpoli G, Pawlish K, Godbold J, Furberg H, Fatone A, Valdimarsdottir H, Yao S, Li Y, Hwang H, Davis W, Roberts M, Sucheston L, Demissie K, Amend KL, Tartter P, Reilly J, Pace BW, Rohan T, Sparano J, Raptis G, Castaldi M, Estabrook A, Feldman S, Weltz C, Kemeny M: Conducting molecular epidemiological research in the age of HIPAA: a multi-institutional case-control study of breast cancer in African-American and European-American women. J Oncol. 2009, 2009: 871250- CrossRefPubMedPubMedCentral
The International HapMap Consortium: The International HapMap Project. Nature. 2003, 426: 789-796. 10.1038/nature02168. CrossRef
SeattleSNPs Genome Variation Server. [ http://gvs.gs.washington.edu/GVS/]
Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D: The structure of haplotype blocks in the human genome. Science. 2002, 296: 2225-2229. 10.1126/science.1069424. CrossRefPubMed
Zhang W, Duan S, Kistner EO, Bleibel WK, Huang RS, Clark TA, Chen TX, Schweitzer AC, Blume JE, Cox NJ, Dolan ME: Evaluation of genetic variation contributing to differences in gene expression between populations. Am J Hum Genet. 2008, 82: 631-640. 10.1016/j.ajhg.2007.12.015. CrossRefPubMedPubMedCentral
Arai H, Miyamoto KI, Yoshida M, Yamamoto H, Taketani Y, Morita K, Kubota M, Yoshida S, Ikeda M, Watabe F, Kanemasa Y, Takeda E: The polymorphism in the caudal-related homeodomain protein Cdx-2 binding element in the human vitamin D receptor gene. J Bone Miner Res. 2001, 16: 1256-1264. 10.1359/jbmr.2001.16.7.1256. CrossRefPubMed
Fang Y, van Meurs JB, Bergink AP, Hofman A, van Duijn CM, van Leeuwen JP, Pols HA, Uitterlinden AG: Cdx-2 polymorphism in the promoter region of the human vitamin D receptor gene determines susceptibility to fracture in the elderly. J Bone Miner Res. 2003, 18: 1632-1641. 10.1359/jbmr.2003.18.9.1632. CrossRefPubMed
Trabert B, Malone KE, Daling JR, Doody DR, Bernstein L, Ursin G, Marchbanks PA, Strom BL, Humphrey MC, Ostrander EA: Vitamin D receptor polymorphisms and breast cancer risk in a large population-based case-control study of Caucasian and African-American women. Breast Cancer Res. 2007, 9: R84-10.1186/bcr1833. CrossRefPubMedPubMedCentral
Poynter JN, Jacobs ET, Figueiredo JC, Lee WH, Conti DV, Campbell PT, Levine AJ, Limburg P, Le Marchand L, Cotterchio M, Newcomb PA, Potter JD, Jenkins MA, Hopper JL, Duggan DJ, Baron JA, Haile RW: Genetic variation in the vitamin D receptor (VDR) and the vitamin D-binding protein (GC) and risk for colorectal cancer: results from the Colon Cancer Family Registry. Cancer Epidemiol Biomarkers Prev. 2010, 19: 525-536. 10.1158/1055-9965.EPI-09-0662. CrossRefPubMedPubMedCentral
- Variants in the vitamin D pathway, serum levels of vitamin D, and estrogen receptor negative breast cancer among African-American women: a case-control study
Dana H Bovbjerg
Chi Chen Hong
Lara E Sucheston
Candace S Johnson
Donald L Trump
Susan E McCann
Karen S Pawlish
Elisa V Bandera
Christine B Ambrosone
- BioMed Central
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