Genetic determinants of serum vitamin B12 and their relation to body mass index

Kristine H Allin; Nele Friedrich; Maik Pietzner; Niels Grarup; Betina H Thuesen; Allan Linneberg; Charlotta Pisinger; Torben Hansen; Oluf Pedersen; Camilla H Sandholt

doi:10.1007/s10654-016-0215-x

Genetic determinants of serum vitamin B12 and their relation to body mass index

Kristine H Allin, Nele Friedrich, Maik Pietzner, Niels Grarup, Betina H Thuesen, Allan Linneberg, Charlotta Pisinger, Torben Hansen, Oluf Pedersen, Camilla H Sandholt

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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 (n_total = 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 (n_total = 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.

Original language	English
Journal	European Journal of Epidemiology
Volume	32
Issue number	2
Pages (from-to)	125–134
ISSN	0393-2990
DOIs	https://doi.org/10.1007/s10654-016-0215-x
Publication status	Published - 1 Feb 2017

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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.",

author = "Allin, {Kristine H} and Nele Friedrich and Maik Pietzner and Niels Grarup and Thuesen, {Betina H} and Allan Linneberg and Charlotta Pisinger and Torben Hansen and Oluf Pedersen and Sandholt, {Camilla H}",

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doi = "10.1007/s10654-016-0215-x",

language = "English",

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T1 - Genetic determinants of serum vitamin B12 and their relation to body mass index

AU - Allin, Kristine H

AU - Friedrich, Nele

AU - Pietzner, Maik

AU - Grarup, Niels

AU - Thuesen, Betina H

AU - Linneberg, Allan

AU - Pisinger, Charlotta

AU - Hansen, Torben

AU - Pedersen, Oluf

AU - Sandholt, Camilla H

PY - 2017/2/1

Y1 - 2017/2/1

N2 - 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.

AB - 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.

U2 - 10.1007/s10654-016-0215-x

DO - 10.1007/s10654-016-0215-x

M3 - Journal article

C2 - 27995393

SN - 0393-2990

VL - 32

SP - 125

EP - 134

JO - European Journal of Epidemiology

JF - European Journal of Epidemiology

IS - 2

ER -

Genetic determinants of serum vitamin B12 and their relation to body mass index

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