Instrumental variable estimation of the causal effect of plasma 25-hydroxy-vitamin D on colorectal cancer risk: a mendelian randomization analysis.
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 (<0.35). The prevalence and degree of vitamin D deficiency amongst individuals living in northerly latitudes is of considerable importance because of its relationship to disease. To elucidate the effect of vitamin D on CRC cancer risk, additional large studies of vitamin D and CRC risk are required and/or the application of alternative methods that are less sensitive to weak instrument restrictions.
Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom. E.Theodoratou@ed.ac.uk
Evropi
E
Theodoratou
Tom
T
Palmer
Lina
L
Zgaga
Susan M
SM
Farrington
Paul
P
McKeigue
Farhat V N
FV
Din
Albert
A
Tenesa
George
G
Davey-Smith
Malcolm G
MG
Dunlop
Harry
H
Campbell
D015652:25-Hydroxyvitamin D 2 / Q000097:blood / Q000235:genetics; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002853:Chromatography, Liquid; D015179:Colorectal Neoplasms / Q000097:blood* / Q000209:etiology*; D005260:Female; D005838:Genotype; D006801:Humans; D016013:Likelihood Functions; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D012606:Scotland / Q000453:epidemiology; D053719:Tandem Mass Spectrometry; D014808:Vitamin D Deficiency / Q000150:complications* / Q000453:epidemiology*
D015652:25-Hydroxyvitamin D 2