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Causal Relationship between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts

Title: Causal Relationship between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts
Authors: Vimaleswaran, KS
Berry, DJ
Lu, C
Tikkanen, E
Pilz, S
Hiraki, LT
Cooper, JD
Dastani, Z
Li, R
Houston, DK
Wood, AR
Michaelsson, K
Vandenput, L
Zgaga, L
Yerges-Armstrong, LM
McCarthy, MI
Dupuis, J
Kaakinen, M
Kleber, ME
Jameson, K
Arden, N
Raitakari, O
Viikari, J
Lohman, KK
Ferrucci, L
Melhus, H
Ingelsson, E
Byberg, L
Lind, L
Lorentzon, M
Salomaa, V
Campbell, H
Dunlop, M
Mitchell, BD
Herzig, K-H
Pouta, A
Hartikainen, A-L
Streeten, EA
Theodoratou, E
Jula, A
Wareham, NJ
Ohlsson, C
Frayling, TM
Kritchevsky, SB
Spector, TD
Richards, JB
Lehtimaki, T
Ouwehand, WH
Kraft, P
Cooper, C
Maerz, W
Power, C
Loos, RJF
Wang, TJ
Jaervelin, M-R
Whittaker, JC
Hingorani, AD
Hyppoenen, E
Item Type: Journal Article
Abstract: 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.
Issue Date: 5-Feb-2013
Date of Acceptance: 24-Dec-2012
URI: http://hdl.handle.net/10044/1/48650
DOI: https://dx.doi.org/10.1371/journal.pmed.1001383
ISSN: 1549-1277
Publisher: Public Library of Science
Journal / Book Title: PLOS Medicine
Volume: 10
Issue: 2
Copyright Statement: © 2013 Vimaleswaran et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Sponsor/Funder: Medical Research Council (MRC)
National Institute for Health Research
Medical Research Council (MRC)
Funder's Grant Number: G0801056B
NF-SI-0611-10136
G0801056/1
Keywords: Science & Technology
Life Sciences & Biomedicine
Medicine, General & Internal
General & Internal Medicine
MEDICINE, GENERAL & INTERNAL
BODY-MASS INDEX
CARDIOVASCULAR-DISEASE RISK
GENOME-WIDE ASSOCIATION
GENETIC-VARIANTS
INSTRUMENTAL VARIABLES
D DEFICIENCY
25-HYDROXYVITAMIN D
D INSUFFICIENCY
COMMON OBESITY
PREVALENCE
Adult
Aged
Aged, 80 and over
Biomarkers
Body Mass Index
Europe
European Continental Ancestry Group
Evidence-Based Medicine
Female
Genetic Predisposition to Disease
Humans
Linear Models
Male
Mendelian Randomization Analysis
Middle Aged
Multivariate Analysis
North America
Obesity
Phenotype
Polymorphism, Single Nucleotide
Risk Assessment
Risk Factors
Vitamin D
Vitamin D Deficiency
Genetic Investigation of Anthropometric Traits-GIANT Consortium
11 Medical And Health Sciences
Publication Status: Published
Article Number: ARTN e1001383
Appears in Collections:Department of Medicine
Faculty of Medicine
Epidemiology, Public Health and Primary Care



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