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Instrumental Variable Estimation of the Causal Effect of Plasma 25-Hydroxy-Vitamin D on Colorectal Cancer Risk: A Mendelian Randomization Analysis

Author

Listed:
  • Evropi Theodoratou
  • Tom Palmer
  • Lina Zgaga
  • Susan M Farrington
  • Paul McKeigue
  • Farhat V N Din
  • Albert Tenesa
  • George Davey-Smith
  • Malcolm G Dunlop
  • Harry Campbell

Abstract

Vitamin D deficiency has been associated with several common diseases, including cancer and is being investigated as a possible risk factor for these conditions. We reported the striking prevalence of vitamin D deficiency in Scotland. Previous epidemiological studies have reported an association between low dietary vitamin D and colorectal cancer (CRC). Using a case-control study design, we tested the association between plasma 25-hydroxy-vitamin D (25-OHD) and CRC (2,001 cases, 2,237 controls). To determine whether plasma 25-OHD levels are causally linked to CRC risk, we applied the control function instrumental variable (IV) method of the Mendelian randomization (MR) approach using four single nucleotide polymorphisms (rs2282679, rs12785878, rs10741657, rs6013897) previously shown to be associated with plasma 25-OHD. Low plasma 25-OHD levels were associated with CRC risk in the crude model (odds ratio (OR): 0.76, 95% Confidence Interval (CI): 0.71, 0.81, p: 1.4×10−14) and after adjusting for age, sex and other confounding factors. Using an allele score that combined all four SNPs as the IV, the estimated causal effect was OR 1.16 (95% CI 0.60, 2.23), whilst it was 0.94 (95% CI 0.46, 1.91) and 0.93 (0.53, 1.63) when using an upstream (rs12785878, rs10741657) and a downstream allele score (rs2282679, rs6013897), respectively. 25-OHD levels were inversely associated with CRC risk, in agreement with recent meta-analyses. The fact that this finding was not replicated when the MR approach was employed might be due to weak instruments, giving low power to demonstrate an effect (

Suggested Citation

  • Evropi Theodoratou & Tom Palmer & Lina Zgaga & Susan M Farrington & Paul McKeigue & Farhat V N Din & Albert Tenesa & George Davey-Smith & Malcolm G Dunlop & Harry Campbell, 2012. "Instrumental Variable Estimation of the Causal Effect of Plasma 25-Hydroxy-Vitamin D on Colorectal Cancer Risk: A Mendelian Randomization Analysis," PLOS ONE, Public Library of Science, vol. 7(6), pages 1-10, June.
    • Handle: RePEc:plo:pone00:0037662
    DOI: 10.1371/journal.pone.0037662
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    Cited by:

    1. Rajeev K Mehlotra & Noemi B Hall & Barne Willie & Catherine M Stein & Aaron Weinberg & Peter A Zimmerman & Lance T Vernon, 2016. "Associations of Toll-Like Receptor and β-Defensin Polymorphisms with Measures of Periodontal Disease (PD) in HIV+ North American Adults: An Exploratory Study," PLOS ONE, Public Library of Science, vol. 11(10), pages 1-15, October.
    2. Lu Deng & Han Zhang & Lei Song & Kai Yu, 2020. "Approximation of bias and mean‐squared error in two‐sample Mendelian randomization analyses," Biometrics, The International Biometric Society, vol. 76(2), pages 369-379, June.
    3. Lina Zgaga & Felix Agakov & Evropi Theodoratou & Susan M Farrington & Albert Tenesa & Malcolm G Dunlop & Paul McKeigue & Harry Campbell, 2013. "Model Selection Approach Suggests Causal Association between 25-Hydroxyvitamin D and Colorectal Cancer," PLOS ONE, Public Library of Science, vol. 8(5), pages 1-11, May.

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