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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

Directed acyclic graph (DAG) showing the instrumental variable assumptions underpinning our Mendelian randomisation study (note the instrument is not allowed to have a direct effect on the outcome, hence this line is dashed).Instrumental variable models use associations C and A to estimate the causal effect of a risk factor on an outcome (B).
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pone-0037662-g002: Directed acyclic graph (DAG) showing the instrumental variable assumptions underpinning our Mendelian randomisation study (note the instrument is not allowed to have a direct effect on the outcome, hence this line is dashed).Instrumental variable models use associations C and A to estimate the causal effect of a risk factor on an outcome (B).

Mentions: Establishing causal relationships between environmental exposures and common diseases using conventional methods of observational studies is problematic due to unresolved confounding, reverse causation and selection bias [16]. The theory underpinning the Mendelian randomization (MR) approach is based on the random assortment of alleles at the time of gamete formation, which is equivalent to a randomized controlled trial in which people are randomly allocated to therapeutic interventions. The main concept of a MR study is based on three relationships: genotype–intermediate phenotype; intermediate phenotype–disease; genotype–disease [17], [18] and it can be used to identify causal environmental risk factors without the several potential problems of observational epidemiology [19]. The MR approach can also strengthen causal conclusions by limiting reverse causation problems (biological, through exposure assignment, due to reporting bias), selection bias and regression dilution bias [19]. Figure 2 illustrates how this concept is applied to inform causal inference.


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)

Directed acyclic graph (DAG) showing the instrumental variable assumptions underpinning our Mendelian randomisation study (note the instrument is not allowed to have a direct effect on the outcome, hence this line is dashed).Instrumental variable models use associations C and A to estimate the causal effect of a risk factor on an outcome (B).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0037662-g002: Directed acyclic graph (DAG) showing the instrumental variable assumptions underpinning our Mendelian randomisation study (note the instrument is not allowed to have a direct effect on the outcome, hence this line is dashed).Instrumental variable models use associations C and A to estimate the causal effect of a risk factor on an outcome (B).
Mentions: Establishing causal relationships between environmental exposures and common diseases using conventional methods of observational studies is problematic due to unresolved confounding, reverse causation and selection bias [16]. The theory underpinning the Mendelian randomization (MR) approach is based on the random assortment of alleles at the time of gamete formation, which is equivalent to a randomized controlled trial in which people are randomly allocated to therapeutic interventions. The main concept of a MR study is based on three relationships: genotype–intermediate phenotype; intermediate phenotype–disease; genotype–disease [17], [18] and it can be used to identify causal environmental risk factors without the several potential problems of observational epidemiology [19]. The MR approach can also strengthen causal conclusions by limiting reverse causation problems (biological, through exposure assignment, due to reporting bias), selection bias and regression dilution bias [19]. Figure 2 illustrates how this concept is applied to inform causal inference.

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