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The causal roles of vitamin B(12) and transcobalamin in prostate cancer: can Mendelian randomization analysis provide definitive answers?

ABSTRACT: Circulating vitamin B(12) (cobalamin/B(12)) and total transcobalamin (tTC) have been associated with increased and reduced risk, respectively, of prostate cancer. Mendelian randomization has the potential to determine whether these are causal associations. We estimated associations of single nucleotide polymorphisms in B(12)-related genes (MTR, MTRR, FUT2, TCN2, TCN1, CUBN, and MUT) with plasma concentrations of B(12), tTC, holo-transcobalamin, holo-haptocorrin, folate, and homocysteine and with prostate cancer risk in a case-control study (913 cases, 895 controls) nested within the UK-wide population-based ProtecT study of prostate cancer in men age 45-69 years. Instrumental variable (IV) analysis was used to estimate odds ratios for effects of B(12) and tTC on prostate cancer. We observed that B(12) was lower in men with FUT2 204G>A (rs492602), CUBN 758C>T (rs1801222) and MUT 1595G>A (rs1141321) alleles (P(trend)<0.001); tTC was lower in men with the TCN2 776C>G (rs1801198) allele (P(trend)<0.001). FUT2 204G>A and CUBN 758C>T were selected as instruments for B(12); TCN2 776C>G for tTC. Conventional and IV estimates for the association of log(e)(B(12)) with prostate cancer were: OR=1.17 (95% CI 0.90-1.51), P=0.2 and OR=0.60 (0.16-2.15), P=0.4, respectively. Conventional and IV estimates for the association of loge(tTC) with prostate cancer were: OR=0.81 (0.54-1.20), P=0.3 and OR=0.41 (0.13-1.32), P=0.1, respectively. Confidence intervals around the IV estimates in our study were too wide to allow robust inference. Sample size estimates based on our data indicated that Mendelian randomization in this context requires much larger studies or multiple genetic variants that explain all of the variance in the intermediate phenotype.

SUBMITTER: Collin SM

PROVIDER: S-EPMC3243448 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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The causal roles of vitamin B(12) and transcobalamin in prostate cancer: can Mendelian randomization analysis provide definitive answers?

Collin Simon M SM Metcalfe Chris C Palmer Tom M TM Refsum Helga H Lewis Sarah J SJ Smith George Davey GD Cox Angela A Davis Michael M Marsden Gemma G Johnston Carole C Lane J Athene JA Donovan Jenny L JL Neal David E DE Hamdy Freddie C FC Smith A David AD Martin Richard M RM

International journal of molecular epidemiology and genetics 20111128 4

Circulating vitamin B(12) (cobalamin/B(12)) and total transcobalamin (tTC) have been associated with increased and reduced risk, respectively, of prostate cancer. Mendelian randomization has the potential to determine whether these are causal associations. We estimated associations of single nucleotide polymorphisms in B(12)-related genes (MTR, MTRR, FUT2, TCN2, TCN1, CUBN, and MUT) with plasma concentrations of B(12), tTC, holo-transcobalamin, holo-haptocorrin, folate, and homocysteine and with ...[more]

PMID: 22199995

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Project description:BackgroundObesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis.Methods and findingsWe used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects. Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n?=?123,864). Each 1 kg/m(2) higher BMI was associated with 1.15% lower 25(OH)D (p?=?6.52×10?²?). The BMI allele score was associated both with BMI (p?=?6.30×10??²) and 25(OH)D (-0.06% [95% CI -0.10 to -0.02], p?=?0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p?8.07×10??? for both scores) but not with BMI (synthesis score, p?=?0.88; metabolism score, p?=?0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: -4.2 [95% CI -7.1 to -1.3], p?=?0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p?0.57 for both vitamin D scores).ConclusionsOn the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency.

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Dataset Information

The causal roles of vitamin B(12) and transcobalamin in prostate cancer: can Mendelian randomization analysis provide definitive answers?

Publications

The causal roles of vitamin B(12) and transcobalamin in prostate cancer: can Mendelian randomization analysis provide definitive answers?

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