TY - JOUR
T1 - Causal Relationship between Obesity and Vitamin D Status
T2 - Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts
AU - Genetic Investigation of Anthropometric Traits-GIANT Consortium
AU - Vimaleswaran, Karani S.
AU - Berry, Diane J.
AU - Lu, Chen
AU - Tikkanen, Emmi
AU - Pilz, Stefan
AU - Hiraki, Linda T.
AU - Cooper, Jason D.
AU - Dastani, Zari
AU - Li, Rui
AU - Houston, Denise K.
AU - Wood, Andrew R.
AU - Michaëlsson, Karl
AU - Vandenput, Liesbeth
AU - Zgaga, Lina
AU - Yerges-Armstrong, Laura M.
AU - McCarthy, Mark I.
AU - Dupuis, Josée
AU - Kaakinen, Marika
AU - Kleber, Marcus E.
AU - Jameson, Karen
AU - Arden, Nigel
AU - Raitakari, Olli
AU - Viikari, Jorma
AU - Lohman, Kurt K.
AU - Ferrucci, Luigi
AU - Melhus, Håkan
AU - Ingelsson, Erik
AU - Byberg, Liisa
AU - Lind, Lars
AU - Lorentzon, Mattias
AU - Salomaa, Veikko
AU - Campbell, Harry
AU - Dunlop, Malcolm
AU - Mitchell, Braxton D.
AU - Herzig, Karl Heinz
AU - Pouta, Anneli
AU - Hartikainen, Anna Liisa
AU - Streeten, Elizabeth A.
AU - Theodoratou, Evropi
AU - Jula, Antti
AU - Wareham, Nicholas J.
AU - Ohlsson, Claes
AU - Frayling, Timothy M.
AU - Kritchevsky, Stephen B.
AU - Spector, Timothy D.
AU - Richards, J. Brent
AU - Lehtimäki, Terho
AU - Ouwehand, Willem H.
AU - Kraft, Peter
AU - Hottenga, J. J.
PY - 2013/2/5
Y1 - 2013/2/5
N2 - Background: Obesity 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 Findings: We 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/m2 higher BMI was associated with 1.15% lower 25(OH)D (p = 6.52×10-27). The BMI allele score was associated both with BMI (p = 6.30×10-62) 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≤8.07×10-57 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). Conclusions: On 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. Please see later in the article for the Editors' Summary.
AB - Background: Obesity 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 Findings: We 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/m2 higher BMI was associated with 1.15% lower 25(OH)D (p = 6.52×10-27). The BMI allele score was associated both with BMI (p = 6.30×10-62) 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≤8.07×10-57 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). Conclusions: On 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. Please see later in the article for the Editors' Summary.
UR - https://www.scopus.com/pages/publications/84874505939
U2 - 10.1371/journal.pmed.1001383
DO - 10.1371/journal.pmed.1001383
M3 - Article
C2 - 23393431
AN - SCOPUS:84874505939
SN - 1549-1277
VL - 10
JO - PLoS Medicine
JF - PLoS Medicine
IS - 2
M1 - e1001383
ER -