title: Genetic determinants of serum vitamin B12 and their relation to body mass index.
abstract: Lower serum vitamin B12 levels have been related to adverse metabolic health profiles, including adiposity. We used a Mendelian randomization design to test whether this relation might be causal. We included two Danish population-based studies (ntotal= 9311). Linear regression was used to test for associations between (1) serum vitamin B12 levels and body mass index (BMI), (2) genetic variants and serum vitamin B12 levels, and (3) genetic variants and BMI. The effect of a genetically determined decrease in serum vitamin B12 on BMI was estimated by instrumental variable regression. Decreased serum vitamin B12 associated with increased BMI (P < 1 × 10-4). A genetic risk score based on eight vitamin B12 associated variants associated strongly with serum vitamin B12 (P < 2 × 10-43), but not with BMI (P = 0.91). Instrumental variable regression showed that a 20% decrease in serum vitamin B12 was associated with a 0.09 kg/m2(95% CI 0.05; 0.13) increase in BMI (P = 3 × 10-5), whereas a genetically induced 20% decrease in serum vitamin B12 had no effect on BMI [-0.03 (95% CI -0.22; 0.16) kg/m2] (P = 0.74). Nevertheless, the strongest serum vitamin B12 variant, FUT2 rs602662, which was excluded from the B12 genetic risk score due to potential pleiotropic effects, showed a per allele effect of 0.15 kg/m2(95% CI 0.01; 0.32) on BMI (P = 0.03). This association was accentuated including two German cohorts (ntotal= 5050), with a combined effect of 0.19 kg/m2(95% CI 0.08; 0.30) (P = 4 × 10-4). We found no support for a causal role of decreased serum vitamin B12 levels in obesity. However, our study suggests that FUT2, through its regulation of the cross-talk between gut microbes and the human host, might explain a part of the observational association between serum vitamin B12 and BMI.
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 1, 2100, Copenhagen, Denmark. kristine.allin@sund.ku.dk.
authors.forename: Kristine H
authors.initials: KH
authors.lastname: Allin
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.|Research Centre for Prevention and Health, The Capital Region of Denmark, Copenhagen, Denmark.
authors.forename: Nele
authors.initials: N
authors.lastname: Friedrich
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Maik
authors.initials: M
authors.lastname: Pietzner
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 1, 2100, Copenhagen, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Grarup
authors.affiliation: Research Centre for Prevention and Health, The Capital Region of Denmark, Copenhagen, Denmark.
authors.forename: Betina H
authors.initials: BH
authors.lastname: Thuesen
authors.affiliation: Research Centre for Prevention and Health, The Capital Region of Denmark, Copenhagen, Denmark.|Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Denmark.
authors.forename: Allan
authors.initials: A
authors.lastname: Linneberg
authors.affiliation: Research Centre for Prevention and Health, The Capital Region of Denmark, Copenhagen, Denmark.
authors.forename: Charlotta
authors.initials: C
authors.lastname: Pisinger
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 1, 2100, Copenhagen, Denmark.|Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 1, 2100, Copenhagen, Denmark.|Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark.
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 1, 2100, Copenhagen, Denmark.
authors.forename: Camilla H
authors.initials: CH
authors.lastname: Sandholt
mesh_terms: D000328:Adult; D000367:Age Factors; D015992:Body Mass Index; D003718:Denmark; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D014805:Vitamin B 12 / Q000097:blood*
chemical_list: D014805:Vitamin B 12
keywords: BMI; Cobalamin; FUT2; Mendelian randomization; Secretor/nonsecretor; Vitamin B12