title: The causal effect of vitamin D binding protein (DBP) levels on calcemic and cardiometabolic diseases: a Mendelian randomization study.
abstract: BACKGROUND
  Observational studies have shown that vitamin D binding protein (DBP) levels, a key determinant of 25-hydroxy-vitamin D (25OHD) levels, and 25OHD levels themselves both associate with risk of disease. If 25OHD levels have a causal influence on disease, and DBP lies in this causal pathway, then DBP levels should likewise be causally associated with disease. We undertook a Mendelian randomization study to determine whether DBP levels have causal effects on common calcemic and cardiometabolic disease.
  
  
  RESULTS
  We measured DBP and 25OHD levels in 2,254 individuals, followed for up to 10 y, in the Canadian Multicentre Osteoporosis Study (CaMos). Using the single nucleotide polymorphism rs2282679 as an instrumental variable, we applied Mendelian randomization methods to determine the causal effect of DBP on calcemic (osteoporosis and hyperparathyroidism) and cardiometabolic diseases (hypertension, type 2 diabetes, coronary artery disease, and stroke) and related traits, first in CaMos and then in large-scale genome-wide association study consortia. The effect allele was associated with an age- and sex-adjusted decrease in DBP level of 27.4 mg/l (95% CI 24.7, 30.0; n = 2,254). DBP had a strong observational and causal association with 25OHD levels (p = 3.2 × 10(-19)). While DBP levels were observationally associated with calcium and body mass index (BMI), these associations were not supported by causal analyses. Despite well-powered sample sizes from consortia, there were no associations of rs2282679 with any other traits and diseases: fasting glucose (0.00 mmol/l [95% CI -0.01, 0.01]; p = 1.00; n = 46,186); fasting insulin (0.01 pmol/l [95% CI -0.00, 0.01,]; p = 0.22; n = 46,186); BMI (0.00 kg/m(2) [95% CI -0.01, 0.01]; p = 0.80; n = 127,587); bone mineral density (0.01 g/cm(2) [95% CI -0.01, 0.03]; p = 0.36; n = 32,961); mean arterial pressure (-0.06 mm Hg [95% CI -0.19, 0.07]); p = 0.36; n = 28,775); ischemic stroke (odds ratio [OR]  = 1.00 [95% CI 0.97, 1.04]; p = 0.92; n = 12,389/62,004 cases/controls); coronary artery disease (OR = 1.02 [95% CI 0.99, 1.05]; p = 0.31; n = 22,233/64,762); or type 2 diabetes (OR = 1.01 [95% CI 0.97, 1.05]; p = 0.76; n = 9,580/53,810).
  
  
  CONCLUSIONS
  DBP has no demonstrable causal effect on any of the diseases or traits investigated here, except 25OHD levels. It remains to be determined whether 25OHD has a causal effect on these outcomes independent of DBP. Please see later in the article for the Editors' Summary.
authors.affiliation: Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada; Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Aaron
authors.initials: A
authors.lastname: Leong
authors.affiliation: Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada; Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Waheed
authors.initials: W
authors.lastname: Rehman
authors.affiliation: Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Zari
authors.initials: Z
authors.lastname: Dastani
authors.affiliation: Segal Cancer Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada; Department of Oncology, McGill University, Montreal, Quebec, Canada; Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada; Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Celia
authors.initials: C
authors.lastname: Greenwood
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Timpson
authors.affiliation: CaMos Coordinating Centre, McGill University, Montreal, Quebec, Canada.
authors.forename: Lisa
authors.initials: L
authors.lastname: Langsetmo
authors.affiliation: CaMos Coordinating Centre, McGill University, Montreal, Quebec, Canada.
authors.forename: Claudie
authors.initials: C
authors.lastname: Berger
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Department of Clinical Pathology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
authors.forename: Lei
authors.initials: L
authors.lastname: Fu
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Department of Clinical Pathology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
authors.forename: Betty Y L
authors.initials: BY
authors.lastname: Wong
authors.affiliation: Office of Biotechnology, Genomics and Population Health, Public Health Agency of Canada, Toronto, Ontario, Canada.
authors.forename: Suneil
authors.initials: S
authors.lastname: Malik
authors.affiliation: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Malik
authors.affiliation: Division of Endocrinology and Medicine, Department of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: David A
authors.initials: DA
authors.lastname: Hanley
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Department of Clinical Pathology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
authors.forename: David E C
authors.initials: DE
authors.lastname: Cole
authors.affiliation: Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Goltzman
authors.affiliation: Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada; Department of Medicine, McGill University, Montreal, Quebec, Canada; Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
authors.forename: J Brent
authors.initials: JB
authors.lastname: Richards
mesh_terms: D003327:Coronary Disease / Q000097:blood / Q000453:epidemiology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000453:epidemiology; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D020521:Stroke / Q000097:blood / Q000453:epidemiology; D014807:Vitamin D / Q000031:analogs & derivatives / Q000097:blood; D014809:Vitamin D-Binding Protein / Q000097:blood*
chemical_list: D014809:Vitamin D-Binding Protein; D014807:Vitamin D; C104450:25-hydroxyvitamin D