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 (<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.
Highlights
Vitamin D can be ingested or synthesized in the skin from inactive precursors through the action of UV sunlight
The 25-OHD colorectal cancer (CRC) association was stronger for men than women (Table S2)
The 25-OHD CRC association was similar for early versus late American Joint Committee on Cancer (AJCC) stage
Summary
Vitamin D can be ingested or synthesized in the skin from inactive precursors through the action of UV sunlight. The prevalence of vitamin D deficiency in Scotland is high due to high northern latitude, often cloudy weather (lack of sunlight impairs vitamin D synthesis during winter months), indoors oriented lifestyle and poor diet, and so routine vitamin D and calcium supplementation for the housebound (.65 years old) is recommended [2]. Vitamin D has been considered relevant to skeletal disease and calcium metabolism, but there is growing evidence that vitamin D deficiency might be a risk factor for cancer, cardiovascular, metabolic, infectious and autoimmune diseases [3]. Vitamin D may affect colorectal cancer (CRC) risk via its binding to the vitamin D receptor (VDR) [9] influencing cell proliferation, differentiation, apoptosis and angiogenesis [10,11] or affecting insulin resistance [12]. Results from case-control and cohort studies are inconclusive, but results from cohort studies measuring 25-hydroxy-vitamin D (25-OHD) in the blood or the serum are more consistent indicating an inverse association with CRC [13,14,15]
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