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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.

Theodoratou E, Palmer T, Zgaga L, Farrington SM, McKeigue P, Din FV, Tenesa A, Davey-Smith G, Dunlop MG, Campbell H - PLoS ONE (2012)

Bottom Line: 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).

View Article: PubMed Central - PubMed

Affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom. E.Theodoratou@ed.ac.uk

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.

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Related in: MedlinePlus

Vitamin D metabolic pathway.
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pone-0037662-g001: Vitamin D metabolic pathway.

Mentions: Vitamin D can be ingested or synthesized in the skin from inactive precursors through the action of UV sunlight. Its active form, 1,25(OH)2D (1,25(OH)2D2 and/or 1,25(OH)2D3) is produced after two hydroxylation steps in the liver and kidneys (Figure 1) [1]. 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]. In a recent study of over 2000 healthy individuals living in Scotland, we found that 77.5% of the individuals were vitamin D deficient [3]. Although the Reference Nutrient Intake (RNI) of vitamin D by the Scientific Advisory Committee on Nutrition in Scotland for people over 65 years old is 10 ug per day [4], there is a great variation of the recommended daily allowances (RDA) by different research groups and institutions [5]–[8].


Instrumental variable estimation of the causal effect of plasma 25-hydroxy-vitamin D on colorectal cancer risk: a mendelian randomization analysis.

Theodoratou E, Palmer T, Zgaga L, Farrington SM, McKeigue P, Din FV, Tenesa A, Davey-Smith G, Dunlop MG, Campbell H - PLoS ONE (2012)

Vitamin D metabolic pathway.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3368918&req=5

pone-0037662-g001: Vitamin D metabolic pathway.
Mentions: Vitamin D can be ingested or synthesized in the skin from inactive precursors through the action of UV sunlight. Its active form, 1,25(OH)2D (1,25(OH)2D2 and/or 1,25(OH)2D3) is produced after two hydroxylation steps in the liver and kidneys (Figure 1) [1]. 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]. In a recent study of over 2000 healthy individuals living in Scotland, we found that 77.5% of the individuals were vitamin D deficient [3]. Although the Reference Nutrient Intake (RNI) of vitamin D by the Scientific Advisory Committee on Nutrition in Scotland for people over 65 years old is 10 ug per day [4], there is a great variation of the recommended daily allowances (RDA) by different research groups and institutions [5]–[8].

Bottom Line: 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).

View Article: PubMed Central - PubMed

Affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom. E.Theodoratou@ed.ac.uk

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.

Show MeSH
Related in: MedlinePlus