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Int J Mol Epidemiol Genet 2011;2(4):316-327

Original Article
The causal roles of vitamin B12 and transcobalamin in prostate cancer: can
Mendelian randomization analysis provide definitive answers?

Simon M Collin, Chris Metcalfe, Tom M Palmer, Helga Refsum, Sarah J Lewis, George Davey Smith, Angela Cox, Michael
Davis, Gemma Marsden, Carole Johnston, J Athene Lane, Jenny L Donovan, David E Neal, Freddie C Hamdy, A David Smith,
Richard M Martin

School of Social and Community Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol, BS8 2PS, UK; MRC
Centre for Causal Analysis in Translational Epidemiology (CAiTE), School of Social and Community Medicine, University of
Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK; Department of Pharmacology, University of Oxford, Le Gros Clark
Building, South Parks Road, Oxford, OX1 3QX, UK; Department of Nutrition, Institute of Basic Medical Sciences, Faculty of
Medicine, University of Oslo, Oslo, Norway; Institute for Cancer Studies, University of Sheffield, G Floor Medical School, Beech
Hill Road, Sheffield, S10 2RX, UK; Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital,
Headley Way, Headington, Oxford, OX3 9DU, UK; Department of Oncology, University of Cambridge, Box 279 (S4),
Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK

Received July 23, 2011; accepted August 23, 2011; Epub November 15, 2011; published December 15, 2011

Abstract: Circulating vitamin B12 (cobalamin/B12) 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 B12-related genes (MTR, MTRR,
FUT2, TCN2, TCN1, CUBN, and MUT) with plasma concentrations of B12, 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 B12 and tTC on prostate cancer. We observed that B12 was lower in men with FUT2 204G>A
(rs492602), CUBN 758C>T (rs1801222) and MUT 1595G>A (rs1141321) alleles (Ptrend<0.001); tTC was lower in men with the
TCN2 776C>G (rs1801198) allele (Ptrend<0.001). FUT2 204G>A and CUBN 758C>T were selected as instruments for B12;
TCN2 776C>G for tTC. Conventional and IV estimates for the association of loge (B12) 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. (IJMEG1107004).

Key words: Vitamin B12/cobalamin, transcobalamin, prostate cancer, Mendelian Randomization

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Address all correspondence to:
Dr. Simon M Collin
School of Social and Community Medicine
University of Bristol, Canynge Hall
39 Whatley Road, Bristol, BS8 2PS, UK.
Tel: 0117 3313323; Fax: 0117 3314088
E-mail: simon.collin@bristol.ac.uk