Elizabeth L Barry1, Janet L Peacock2, Judy R Rees1, Roberd M Bostick3, Douglas J Robertson4, Robert S Bresalier5, John A Baron6. 1. Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire. 2. Division of Health and Social Care Research, King's College London, London, England. 3. Rollins School of Public Health, Winship Cancer Institute, Emory University, Atlanta, Georgia. 4. VA Medical Center, White River Junction, Vermont. 5. Department of Gastroenterology, The University of Texas MD Anderson Cancer Center, Houston. 6. Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire6Department of Medicine, University of North Carolina School of Medicine, Chapel Hill.
Abstract
IMPORTANCE: Despite epidemiological and preclinical evidence suggesting that vitamin D and calcium inhibit colorectal carcinogenesis, daily supplementation with these nutrients for 3 to 5 years was not found to significantly reduce the risk of recurrent colorectal adenomas in a recent randomized clinical trial. OBJECTIVE: To investigate whether common variants in 7 vitamin D and calcium pathway genes (VDR, GC, DHCR7, CYP2R1, CYP27B1, CYP24A1, and CASR) modify the effects of vitamin D3 or calcium supplementation on colorectal adenoma recurrence. DESIGN, SETTING, AND PARTICIPANTS: We examined 41 candidate single-nucleotide polymorphisms (SNPs) in 2259 participants in a randomized, double-blind, placebo-controlled trial conducted at 11 clinical centers in the United States. Eligibility criteria included a recently diagnosed adenoma and no remaining colorectal polyps after complete colonoscopy. The study's treatment phase ended on August 31, 2013, and the analysis for the present study took place from July 28, 2014, to October 19, 2016. INTERVENTIONS: Daily oral supplementation with vitamin D3 (1000 IU) or calcium carbonate (1200 mg elemental calcium) or both or neither. MAIN OUTCOMES AND MEASURES: The outcomes assessed were the occurrence of 1 or more adenomas or advanced adenomas (estimated diameter, ≥1 cm; or with villous histologic findings, high-grade dysplasia, or cancer) during follow-up. Treatment effects and genotype associations and interactions were estimated as adjusted risk ratios (RRs) and 95% confidence intervals (CIs). The effective number of independent SNPs was calculated to correct for multiple testing. RESULTS: Among the 2259 participants randomized, 1702 were non-Hispanic whites who completed the trial and had genotype data for analysis (1101 men; mean [SD] age 58.1 [6.8] years). The effect of vitamin D3 supplementation on advanced adenomas, but not on adenoma risk overall, significantly varied according to genotype at 2 VDR SNPs (rs7968585 and rs731236) in linkage disequilibrium (D' = 0.98; r2 = 0.6). For rs7968585, among individuals with the AA genotype (26%), vitamin D3 supplementation reduced risk by 64% (RR, 0.36; 95% CI, 0.19-0.69; P = .002; absolute risk decreased from 14.4% to 5.1%). Among individuals with 1 or 2 G alleles (74%), vitamin D3 supplementation increased risk by 41% (RR, 1.41; 95% CI, 0.99-2.00; P = .05; absolute risk increased from 7.7% to 11.1%; P < .001 for interaction). There were no significant interactions of genotypes with calcium supplementation. CONCLUSIONS AND RELEVANCE: Our findings suggest that benefits from vitamin D3 supplementation for the prevention of advanced colorectal adenomas may vary according to vitamin D receptor genotype. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00153816.
IMPORTANCE: Despite epidemiological and preclinical evidence suggesting that vitamin D and calcium inhibit colorectal carcinogenesis, daily supplementation with these nutrients for 3 to 5 years was not found to significantly reduce the risk of recurrent colorectal adenomas in a recent randomized clinical trial. OBJECTIVE: To investigate whether common variants in 7 vitamin D and calcium pathway genes (VDR, GC, DHCR7, CYP2R1, CYP27B1, CYP24A1, and CASR) modify the effects of vitamin D3 or calcium supplementation on colorectal adenoma recurrence. DESIGN, SETTING, AND PARTICIPANTS: We examined 41 candidate single-nucleotide polymorphisms (SNPs) in 2259 participants in a randomized, double-blind, placebo-controlled trial conducted at 11 clinical centers in the United States. Eligibility criteria included a recently diagnosed adenoma and no remaining colorectal polyps after complete colonoscopy. The study's treatment phase ended on August 31, 2013, and the analysis for the present study took place from July 28, 2014, to October 19, 2016. INTERVENTIONS: Daily oral supplementation with vitamin D3 (1000 IU) or calcium carbonate (1200 mg elemental calcium) or both or neither. MAIN OUTCOMES AND MEASURES: The outcomes assessed were the occurrence of 1 or more adenomas or advanced adenomas (estimated diameter, ≥1 cm; or with villous histologic findings, high-grade dysplasia, or cancer) during follow-up. Treatment effects and genotype associations and interactions were estimated as adjusted risk ratios (RRs) and 95% confidence intervals (CIs). The effective number of independent SNPs was calculated to correct for multiple testing. RESULTS: Among the 2259 participants randomized, 1702 were non-Hispanic whites who completed the trial and had genotype data for analysis (1101 men; mean [SD] age 58.1 [6.8] years). The effect of vitamin D3 supplementation on advanced adenomas, but not on adenoma risk overall, significantly varied according to genotype at 2 VDR SNPs (rs7968585 and rs731236) in linkage disequilibrium (D' = 0.98; r2 = 0.6). For rs7968585, among individuals with the AA genotype (26%), vitamin D3 supplementation reduced risk by 64% (RR, 0.36; 95% CI, 0.19-0.69; P = .002; absolute risk decreased from 14.4% to 5.1%). Among individuals with 1 or 2 G alleles (74%), vitamin D3 supplementation increased risk by 41% (RR, 1.41; 95% CI, 0.99-2.00; P = .05; absolute risk increased from 7.7% to 11.1%; P < .001 for interaction). There were no significant interactions of genotypes with calcium supplementation. CONCLUSIONS AND RELEVANCE: Our findings suggest that benefits from vitamin D3 supplementation for the prevention of advanced colorectal adenomas may vary according to vitamin D receptor genotype. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00153816.
Authors: John A Baron; Elizabeth L Barry; Leila A Mott; Judy R Rees; Robert S Sandler; Dale C Snover; Roberd M Bostick; Anastasia Ivanova; Bernard F Cole; Dennis J Ahnen; Gerald J Beck; Robert S Bresalier; Carol A Burke; Timothy R Church; Marcia Cruz-Correa; Jane C Figueiredo; Michael Goodman; Adam S Kim; Douglas J Robertson; Richard Rothstein; Aasma Shaukat; March E Seabrook; Robert W Summers Journal: N Engl J Med Date: 2015-10-15 Impact factor: 91.245
Authors: Mark R Haussler; G Kerr Whitfield; Ichiro Kaneko; Carol A Haussler; David Hsieh; Jui-Cheng Hsieh; Peter W Jurutka Journal: Calcif Tissue Int Date: 2012-07-11 Impact factor: 4.333
Authors: N A Morrison; J C Qi; A Tokita; P J Kelly; L Crofts; T V Nguyen; P N Sambrook; J A Eisman Journal: Nature Date: 1994-01-20 Impact factor: 49.962
Authors: Urszula Dougherty; Reba Mustafi; Haider I Haider; Abdurahman Khalil; Jeffrey S Souris; Loren Joseph; John Hart; Vani J Konda; Wei Zhang; Joel Pekow; Yan Chun Li; Marc Bissonnette Journal: Cancer Prev Res (Phila) Date: 2019-05-14
Authors: David Corley Gibbs; Roberd M Bostick; Marjorie L McCullough; Caroline Y Um; W Dana Flanders; Mazda Jenab; Elisabete Weiderpass; Björn Gylling; Inger T Gram; Alicia K Heath; Sandra Colorado-Yohar; Christina C Dahm; Bas Bueno-de-Mesquita; Aurora Perez-Cornago; Antonia Trichopoulou; Rosario Tumino; Tilman Kühn; Veronika Fedirko Journal: Int J Cancer Date: 2020-05-25 Impact factor: 7.396
Authors: Samir Gupta; David Lieberman; Joseph C Anderson; Carol A Burke; Jason A Dominitz; Tonya Kaltenbach; Douglas J Robertson; Aasma Shaukat; Sapna Syngal; Douglas K Rex Journal: Gastroenterology Date: 2020-02-07 Impact factor: 22.682
Authors: Samir Gupta; David Lieberman; Joseph C Anderson; Carol A Burke; Jason A Dominitz; Tonya Kaltenbach; Douglas J Robertson; Aasma Shaukat; Sapna Syngal; Douglas K Rex Journal: Gastrointest Endosc Date: 2020-02-07 Impact factor: 9.427