title: No evidence that genetically reduced 25-hydroxyvitamin D is associated with increased risk of ischaemic heart disease or myocardial infarction: a Mendelian randomization study.
abstract: BACKGROUND
  Low plasma 25-hydroxyvitamin D [p-25(OH)D] is associated with increased risk of ischaemic heart disease and with the subgroup myocardial infarction. However, whether this association is causal or due to confounding or reverse causation is presently unknown. We tested the hypothesis that genetically reduced plasma 25(OH)D is associated with increased risk of ischaemic heart disease and myocardial infarction.
  
  
  METHODS
  We used a Mendelian randomization design in the Copenhagen City Heart Study, the Copenhagen General Population Study, and the Copenhagen Ischaemic Heart Disease Study. Two 25(OH)D reducing genetic variants in the DCHR7 gene (rs7944926 and rs11234027) and two in the CYP2R1 gene (rs10741657 and rs12794714) were genotyped in 92 416 participants of Danish descent, of whom 14 455 developed ischaemic heart disease (ICD-8:410-414; ICD-10:I20-I25) and 7061 myocardial infarction (ICD-8:410: ICD-10:I21-I22) from 1977 through 2011. P-25(OH)D was measured in 36,089 participants. APOE genotype was included as a positive control for risk of ischaemic heart disease.
  
  
  RESULTS
  The multivariable adjusted hazard ratios for lowest vs highest quartile of 25(OH)D were 1.82 [95% confidence interval (CI): 1.42-2.32] for ischaemic heart disease. Each allele increase in a combined allele score was associated with a 1.9-nmol/l decrease in p-25(OH)D (P = 7 × 10(-55); R(2) = 0.9%). The genetic variants were, however, not associated with increased risk of ischaemic heart disease. In instrumental variable analysis, the odds ratio for ischaemic heart disease for a genetically 25-nmol/l decrease in p-25(OH)D was 0.98 (95% CI: 0.76-1.26), with a corresponding observational hazard ratio by Cox regression of 1.07 (1.01-1.13). Similarly, with myocardial infarction as the outcome, observational analyses suggested an increased risk with lower 25(OH)D, whereas genetic analyses suggested no causal effect. For APOE genotype, the odds ratio for ischaemic heart disease for a 1-mmol/l genetic increase in plasma total cholesterol concentrations was 1.23 (1.08-1.41), with a corresponding observational hazard ratio of 1.08 (1.04-1.14).
  
  
  CONCLUSIONS
  We found no evidence to suggest that genetically reduced p-25(OH)D is associated with increased risk of ischaemic heart disease or myocardial infarction.
authors.affiliation: Department of Clinical Biochemistry, and Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark, Department of Clinical Biochemistry, Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark, Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Department of Clinical Biochemistry, and Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark, Department of Clinical Biochemistry, Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark, Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Department of Clinical Biochemistry, and Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark, Department of Clinical Biochemistry, Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark, Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Brøndum-Jacobsen
authors.affiliation: Department of Clinical Biochemistry, and Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark, Department of Clinical Biochemistry, Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark, Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Department of Clinical Biochemistry, and Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark, Department of Clinical Biochemistry, Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark, Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Department of Clinical Biochemistry, and Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark, Department of Clinical Biochemistry, Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark, Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Marianne
authors.initials: M
authors.lastname: Benn
authors.affiliation: Department of Clinical Biochemistry, and Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark, Department of Clinical Biochemistry, Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark, Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Department of Clinical Biochemistry, and Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark, Department of Clinical Biochemistry, Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark, Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Department of Clinical Biochemistry, and Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark, Department of Clinical Biochemistry, Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark, Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Shoaib
authors.initials: S
authors.lastname: Afzal
authors.affiliation: Department of Clinical Biochemistry, and Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark, Department of Clinical Biochemistry, Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark, Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Department of Clinical Biochemistry, and Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark, Department of Clinical Biochemistry, Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark, Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Department of Clinical Biochemistry, and Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark, Department of Clinical Biochemistry, Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark, Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Department of Clinical Biochemistry, and Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark, Department of Clinical Biochemistry, Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark, Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Boerge.Nordestgaard@regionh.dk.
authors.forename: Børge G
authors.initials: BG
authors.lastname: Nordestgaard
mesh_terms: D000328:Adult; D003718:Denmark / Q000453:epidemiology; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D009203:Myocardial Infarction / Q000453:epidemiology / Q000235:genetics; D017202:Myocardial Ischemia / Q000453:epidemiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011446:Prospective Studies; D012307:Risk Factors; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000235:genetics
chemical_list: D014807:Vitamin D; C104450:25-hydroxyvitamin D
keywords: 25-hydroxyvitamin D; Mendelian randomization; Vitamin D; cardiovascular disease; ischaemic heart disease; myocardial infarction