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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

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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 Published OnlineFirst January 19, 2010; DOI: 10.1158/1055-9965.EPI-09-0662 Cancer Research Article Epidemiology, Biomarkers & Prevention 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 Jenny N. Poynter1,2, Elizabeth T. Jacobs3, Jane C. Figueiredo1, Won H. Lee1, David V. Conti1, Peter T. Campbell4,5, A. Joan Levine1, Paul Limburg6, Loic Le Marchand7, Michelle Cotterchio8, Polly A. Newcomb5, John D. Potter5, Mark A. Jenkins9, John L. Hopper9, David J. Duggan10, John A. Baron11, and Robert W. Haile1 Abstract Epidemiologic evidence supports a role for vitamin D in colorectal cancer (CRC) risk. Variants in vitamin D–related genes might modify the association between vitamin D levels and CRC risk. In this analysis, we did a comprehensive evaluation of common variants in the vitamin D receptor (VDR) and the vitamin D–binding protein (GC; group-specific component) genes using a population-based case–unaffected sibling control de- sign that included 1,750 sibships recruited into the Colon Cancer Family Registry. We also evaluated whether any associations differed by calcium supplement use, family history of CRC, or tumor characteristics. Het- erogeneity by calcium and vitamin D intake was evaluated for a subset of 585 cases and 837 sibling controls who completed a detailed food frequency questionnaire. Age- and sex-adjusted associations were estimated using conditional logistic regression. Overall, we did not find evidence for an association between any single- nucleotide polymorphism (SNP) in VDR or GC and risk for CRC (range of unadjusted P values 0.01-0.98 for VDR and 0.07-0.95 for GC). None of these associations was significant after adjustment for multiple compar- isons. We also found no evidence that calcium or vitamin D intake (food and supplement) from the food frequency questionnaire modified the association estimates between VDR and GC SNPs and CRC. We did observe associations between SNPs in GC and microsatellite unstable CRC, although these results should be confirmed in additional studies. Overall, our results do not provide evidence for a role of common genetic variants in VDR or GC in susceptibility to CRC. Cancer Epidemiol Biomarkers Prev; 19(2); 525–36. ©2010 AACR. Introduction because both cohort (2-5) and case-control studies (6-8) have reported an inverse relationship between vitamin Sunlight and vitamin D were first hypothesized to re- D intake and CRC, although the association did not reach duce risk for colorectal cancer (CRC) in 1980 (1). The ep- statistical significance in all studies. An inverse associa- idemiologic evidence has supported this relationship tion between serum levels of 25-hydroxyvitamin D, a bio- marker of vitamin D status, and CRC risk has been also Authors' Affiliations: 1Department of Preventive Medicine, University of shown in epidemiologic studies (5, 9-15). In addition, Southern California, Los Angeles, California; 2Division of Pediatric high plasma 25-hydroxyvitamin D was associated with Epidemiology and Clinical Research, University of Minnesota, decreased proliferation in colonic tissue from subjects at Minneapolis, Minnesota; 3Arizona Cancer Center and Mel and Enid Zuckerman College of Public Health, University of Arizona, Tuscon, risk for colorectal neoplasms because they had a personal Arizona; 4Department of Epidemiology, American Cancer Society, history of adenomas (16). Atlanta, Georgia; 5Cancer Prevention Program, Fred Hutchinson Cancer The vitamin D receptor (VDR) is a member of the ste- Research Center, Seattle, Washington; 6Mayo Clinic, Rochester, Minnesota; 7Cancer Research Center of Hawaii, University of Hawaii, roid superfamily of nuclear receptors and plays a key Honolulu, Hawaii; 8Cancer Care Ontario, Toronto, Ontario, Canada; role in regulating the transcriptional activity of the vita- 9Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Melbourne, Australia; min D metabolite, 1,25-dihydroxyvitamin D3 (17). Poly- 10Translational Genomics Research Institute, Phoenix, Arizona; and morphisms in VDR have been studied extensively in 11Department of Medicine, Dartmouth Medical School, Lebanon, New epidemiologic studies on CRC (18-26). These studies Hampshire have mostly focused on a few selected variants, includ- Note: Supplementary data for this article are available at Cancer Epidemi- Fok Taq ology, Biomarkers and Prevention Online (http://cebp.aacrjournals.org/). ing the I (rs2228570, previously rs10735810), I (rs731236), BsmI (rs1544410), and ApaI (rs7975232) re- Corresponding Author: Jenny N. Poynter, Division of Pediatric Epidemi- CDX2 ology and Clinical Research, University of Minnesota, 420 Delaware striction sites; a polymorphism in the -binding ele- Street Southeast, Moos 1-117, Minneapolis, MN 55455. Phone: 612- ment in VDR (rs11568820); and a poly-A microsatellite. 625-4232; Fax: 612-624-7147. E-mail: [email protected] Overall, the results have been mixed for studies on indi- doi: 10.1158/1055-9965.EPI-09-0662 vidual variants in CRC (18-22, 24-28). Several studies ©2010 American Association for Cancer Research. have suggested that haplotypes of these selected variants www.aacrjournals.org 525 Downloaded from cebp.aacrjournals.org on September 30, 2021. © 2010 American Association for Cancer Research. Published OnlineFirst January 19, 2010; DOI: 10.1158/1055-9965.EPI-09-0662 Poynter et al. are associated with risk for CRC (22, 23, 29) and that the (n = 1,815) and unaffected sibling controls (n = 2,889) association with these variants may be modified by die- were genotyped for this analysis. Most discordant sib- tary factors (18, 20, 21, 30, 31), physical activity (32), and ships had only one case (96.3%), and the remaining sib- BMI (32). ships included one or more affected relatives. In addition, The gene for the vitamin D–binding protein (GC) is also we also genotyped a random set of unrelated population- a logical candidate in the vitamin D pathway because its based controls (n = 447) from one of the Colon CFR sites major function is to transport vitamin D metabolites in the (Fred Hutchinson Cancer Research Center). blood. Variants in this gene have been shown to alter plas- We obtained informed consent from all participants. ma concentrations of 25-hydroxyvitamin D (33, 34). Se- The study was approved by the Institutional Review lected variants in GC have been evaluated in studies on Board(s) at each Colon CFR site. breast (35, 36) and prostate cancers (37); however, to date, no studies have been reported with colorectal neoplasia. Data Collection Despite the large number of studies that have evaluat- A core risk-factor questionnaire, administered to all ed the association between selected genetic variants in participants at the time of recruitment, was used to col- VDR and CRC, a comprehensive analysis of VDR and lect information on personal and family history of GC has not yet been published. In this analysis, we used polyps, colorectal cancer, and other cancers, as well as data from a multisite family-based case-control study other risk factors, including demographic information, conducted by the Colon Cancer Family Registry (Colon medication use, reproductive history (females only), CFR) to evaluate associations between common single- physical activity, alcohol consumption, tobacco use, and nucleotide polymorphisms (SNP) in VDR and GC and a brief section on diet. In addition, a well-validated food CRC. In addition, we evaluated heterogeneity by calcium frequency questionnaire, developed at the Cancer Re- supplement use, dietary vitamin D and calcium intake, search Center of Hawaii (39), was administered to all par- family history of CRC, tumor subsite in the colon or rec- ticipants at baseline for three of the Colon CFR sites tum, and presence/absence of tumor microsatellite insta- (University of Southern California consortium, Ontario, bility (MSI). and Hawaii), representing 32% of the overall study pop- ulation. The food frequency questionnaire included ques- Materials and Methods tions on dietary and supplemental intake of calcium and vitamin D. Calcium and vitamin D intake from food and Study Population supplements were evaluated as nutrient densities (per Participants were recruited for the Colon CFR from six 1,000 kcal/d). Individuals were asked to report expo- registry centers: the University of Hawaii (Honolulu, HI), sures at a reference time of 2 y before diagnosis for cases Fred Hutchinson Cancer Research Center (Seattle, WA), and 2 y before recruitment for unaffected siblings. Mayo Clinic (Rochester, MN), University of Southern Ca- lifornia Consortium (Los Angeles, CA), Cancer Care On- Genotyping tario (Toronto, Ontario, Canada), and the University of TagSNPs were selected using Haploview Tagger (40) Melbourne (Victoria, Australia). Families were ascer- with the following criteria: minor allele frequency > tained through population-based cancer registries (popu- 5%; pairwise r2 > 0.95; and distance from closest SNP > lation based) and high-risk clinics (clinic based). Some 60 bp. Linkage disequilibrium blocks were determined centers recruited all incident cases of CRC, whereas using data from HapMap data release 16c.1, June 2005, others oversampled cases with a family history of CRC on NCBI B34 assembly, dbSNP b124. For each gene, we or young age at diagnosis of CRC. Standardized proce- extended examination of the 5′- and 3′-untranslated re- dures were used to collect epidemiologic
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