Causal Relationship between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts
Year: 2013
Type: article
Study design: Observational Study
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/m(2) 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.
Source: PLoS Medicine
Authors: Karani S. Vimaleswaran, Diane J. Berry, Chen Lu, Emmi Tikkanen, Stefan Pilz, Linda T. Hiraki, Jason D. Cooper, Zari Dastani, Rui Li, Denise K. Houston, Andrew R. Wood, Karl Michaëlsson, Liesbeth Vandenput, Lina Zgaga, Laura M. Yerges-Armstrong, Mark I. McCarthy, Josée Dupuis, Marika Kaakinen, Marcus E. Kleber, Karen Jameson, Nigel Arden, Olli Raitakari, Jorma Viikari, Kurt K. Lohman, Luigi Ferrucci, Håkan Melhus, Erik Ingelsson, Liisa Byberg, Lars Lind, Mattias Lorentzon, Veikko Salomaa, Harry Campbell, Malcolm Dunlop, Braxton D. Mitchell, Karl-Heinz Herzig, Anneli Pouta, Anna-Liisa Hartikainen, Elizabeth A. Streeten, Evropi Theodoratou, Antti Jula, Nicholas J. Wareham, Claes Ohlsson, Timothy M. Frayling, Stephen B. Kritchevsky, Timothy D. Spector, J. Brent Richards, Terho Lehtimäki, Willem H. Ouwehand, Peter Kraft, Cyrus Cooper, Winfried März, Chris Power, Ruth J. F. Loos, Thomas J. Wang, Marjo-Riitta Järvelin, John C. Whittaker, Aroon D. Hingorani, Elina Hyppönen
Institutions: University College London, Boston University, University of Helsinki, Finnish Institute for Health and Welfare, Institute for Molecular Medicine Finland, Medical University of Graz, Amsterdam Public Health, Amsterdam UMC Location Vrije Universiteit Amsterdam, Harvard University, University of Cambridge, Wellcome Trust, Jewish General Hospital, Lady Davis Institute for Medical Research, McGill University, Wake Forest University Health Sciences, Wake Forest University, University of Exeter, Peninsula College of Medicine and Dentistry, Uppsala University, University of Gothenburg, University of Zagreb, Andrija Stampar Teaching Institute of Public Health, University of Edinburgh, University of Maryland, Baltimore, Centre for Human Genetics, Churchill Hospital, University of Oxford, NIHR Oxford Biomedical Research Centre, Oxford Centre for Diabetes, Endocrinology and Metabolism, Framingham Heart Study, University of Oulu, Heidelberg University, Medizinische Fakultät Mannheim, MRC Lifecourse Epidemiology Unit, University of Southampton, University of Turku, Turku University Hospital, MedStar Harbor Hospital, Karolinska Institutet, Western General Hospital, Institute of Genetics and Cancer, MRC Human Genetics Unit, Kuopio University Hospital, Addenbrooke's Hospital, MRC Epidemiology Unit, King's College London, Tampere University Hospital, Fimlab (Finland), University of Tampere, NHS Blood and Transplant, Wellcome Sanger Institute, Synlab (Germany), Massachusetts General Hospital, Imperial College London, GlaxoSmithKline (United Kingdom), London School of Hygiene & Tropical Medicine
Language: English
Topic: Vitamin D Research Studies
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,460
Funders: Amgen, Eli Lilly and Company, GlaxoSmithKline, London School of Hygiene and Tropical Medicine, Wellcome Trust, Cancer Research UK, National Institute for Health and Care Research, British Heart Foundation, University College London, Great Ormond Street Hospital for Children, Novo Nordisk Fonden, Servier, Versus Arthritis, Canadian Institutes of Health Research, Medical Research Council, National Institute on Alcohol Abuse and Alcoholism, National Institute on Aging
Awards: Aetiology of type 2 diabetes and related metabolic disorders, GENE-ENVIRONMENT INTERPLAY IN ALCOHOLISM, G3511822935, G3559258740, G3665250518, G3682927731, G3688637288, G4157653541, NIHR Senior Investigator Award, G4411580604, G4896492730, NIHR Senior Investigator Award, Vitamin D and the risk of cardiovascular disease and related traits: a large-scale genetic association study, G5440576569, NIHR Senior Investigator Award, G5897142711, NIHR Senior Investigator Award, G6313944714, NIHR Senior Investigator Award, G6428189107, Lifecourse Determinants of Bone and Joint Disease, Understanding the genetic basis of common human diseases: core funding for the Wellcome Trust Centre for Human Genetics., G731175165, G7719503476, G7964317829, Vitamin D status, related gene polymorphisms, and physical function in elders, G8396204260, G8598900290, Genetics and Genomics and Respiratory Disease., Wake Forest Claude D. Pepper OAIC - Renewal
OpenAlex ID: W2117706634