title: A Reverse J-Shaped Association Between Serum 25-Hydroxyvitamin D and Cardiovascular Disease Mortality: The CopD Study.
abstract: BACKGROUND
  Cardiovascular disease is the major cause of death in the Western world, but the association between 25-hydroxyvitamin D [25(OH)D] levels and the risk of cardiovascular disease mortality remains unclear.
  
  
  OBJECTIVE
  The objective of the study was to determine the association between cardiovascular, stroke, and acute myocardial infarct mortality and serum levels of 25(OH)D.
  
  
  METHODS
  This was an observational cohort study, the Copenhagen vitamin D study, data from a single laboratory center in Copenhagen, Denmark. Follow-up was from 2004 to 2011.
  
  
  METHODS
  Serum 25(OH)D was analyzed from 247 574 subjects from the Copenhagen general practice sector.
  
  
  METHODS
  Examination of the association 25(OH)D levels and mortality from cardiovascular disease, stroke, and acute myocardial infarct was performed among 161 428 women and 86 146 men.
  
  
  METHODS
  A multivariate Cox regression analysis was used to compute hazard ratios for cardiovascular, stroke, and acute myocardial infarct mortality.
  
  
  RESULTS
  Of 247 574 subjects, a total of 16 645 subjects died in the ensuing 0-7 years. A total of 5454 died from cardiovascular disease including 1574 from stroke and 702 from acute myocardial infarct. The 25(OH)D level of 70 nmol/L was associated with the lowest cardiovascular disease mortality risk. Compared with that level, the hazard ratio for cardiovascular disease mortality was 2.0 [95% confidence interval (CI) 1.8-2.1] at the lower extreme (∼ 12.5 nmol/L) with a higher risk for men [2.5 (95% CI 2.2-2.9)] than for women [1.7 (95% CI 1.5-1.9)]. At the higher extreme (∼ 125 nmol/L), the hazard ratio of cardiovascular disease mortality was 1.3 (95% CI 1.2-1.4), with a similar risk among men and women. Results were similar for stroke and acute myocardial subgroups.
  
  
  CONCLUSIONS
  In this large observational study, low and high levels of 25(OH)D were associated with cardiovascular disease, stroke, and acute myocardial mortality in a nonlinear, reverse J-shaped manner, with the highest risk at lower levels. Whether this was a causal or associational finding cannot be determined from our data. There is a need for randomized clinical trials that include information on the effects of 25(OH)D levels greater than 100 nmol/L.
authors.affiliation: Department of Drug Design and Pharmacology (D.D.M., A.-M.H.), and Faculty of Health and Medical Sciences (P.S.), University of Copenhagen, 2650 Glostrup, Denmark; Department of Clinical Biochemistry (H.L.J.), Copenhagen University Hospital Bispebjerg, 2400 Copenhagen, Denmark; Danish Cancer Society Research Center (J.C., A.T., A.O., J.H.), 2100 Copenhagen, Denmark; and The Elective Laboratory of the Capital Region (B.L.) and the Research Centre of Ageing and Osteoporosis (P.S.), Department of Medicine M, Copenhagen University Hospital Glostrup, 2600 Glostrup, Denmark.
authors.forename: Darshana
authors.initials: D
authors.lastname: Durup
authors.affiliation: Department of Drug Design and Pharmacology (D.D.M., A.-M.H.), and Faculty of Health and Medical Sciences (P.S.), University of Copenhagen, 2650 Glostrup, Denmark; Department of Clinical Biochemistry (H.L.J.), Copenhagen University Hospital Bispebjerg, 2400 Copenhagen, Denmark; Danish Cancer Society Research Center (J.C., A.T., A.O., J.H.), 2100 Copenhagen, Denmark; and The Elective Laboratory of the Capital Region (B.L.) and the Research Centre of Ageing and Osteoporosis (P.S.), Department of Medicine M, Copenhagen University Hospital Glostrup, 2600 Glostrup, Denmark.
authors.forename: Henrik Løvendahl
authors.initials: HL
authors.lastname: Jørgensen
authors.affiliation: Department of Drug Design and Pharmacology (D.D.M., A.-M.H.), and Faculty of Health and Medical Sciences (P.S.), University of Copenhagen, 2650 Glostrup, Denmark; Department of Clinical Biochemistry (H.L.J.), Copenhagen University Hospital Bispebjerg, 2400 Copenhagen, Denmark; Danish Cancer Society Research Center (J.C., A.T., A.O., J.H.), 2100 Copenhagen, Denmark; and The Elective Laboratory of the Capital Region (B.L.) and the Research Centre of Ageing and Osteoporosis (P.S.), Department of Medicine M, Copenhagen University Hospital Glostrup, 2600 Glostrup, Denmark.
authors.forename: Jane
authors.initials: J
authors.lastname: Christensen
authors.affiliation: Department of Drug Design and Pharmacology (D.D.M., A.-M.H.), and Faculty of Health and Medical Sciences (P.S.), University of Copenhagen, 2650 Glostrup, Denmark; Department of Clinical Biochemistry (H.L.J.), Copenhagen University Hospital Bispebjerg, 2400 Copenhagen, Denmark; Danish Cancer Society Research Center (J.C., A.T., A.O., J.H.), 2100 Copenhagen, Denmark; and The Elective Laboratory of the Capital Region (B.L.) and the Research Centre of Ageing and Osteoporosis (P.S.), Department of Medicine M, Copenhagen University Hospital Glostrup, 2600 Glostrup, Denmark.
authors.forename: Anne
authors.initials: A
authors.lastname: Tjønneland
authors.affiliation: Department of Drug Design and Pharmacology (D.D.M., A.-M.H.), and Faculty of Health and Medical Sciences (P.S.), University of Copenhagen, 2650 Glostrup, Denmark; Department of Clinical Biochemistry (H.L.J.), Copenhagen University Hospital Bispebjerg, 2400 Copenhagen, Denmark; Danish Cancer Society Research Center (J.C., A.T., A.O., J.H.), 2100 Copenhagen, Denmark; and The Elective Laboratory of the Capital Region (B.L.) and the Research Centre of Ageing and Osteoporosis (P.S.), Department of Medicine M, Copenhagen University Hospital Glostrup, 2600 Glostrup, Denmark.
authors.forename: Anja
authors.initials: A
authors.lastname: Olsen
authors.affiliation: Department of Drug Design and Pharmacology (D.D.M., A.-M.H.), and Faculty of Health and Medical Sciences (P.S.), University of Copenhagen, 2650 Glostrup, Denmark; Department of Clinical Biochemistry (H.L.J.), Copenhagen University Hospital Bispebjerg, 2400 Copenhagen, Denmark; Danish Cancer Society Research Center (J.C., A.T., A.O., J.H.), 2100 Copenhagen, Denmark; and The Elective Laboratory of the Capital Region (B.L.) and the Research Centre of Ageing and Osteoporosis (P.S.), Department of Medicine M, Copenhagen University Hospital Glostrup, 2600 Glostrup, Denmark.
authors.forename: Jytte
authors.initials: J
authors.lastname: Halkjær
authors.affiliation: Department of Drug Design and Pharmacology (D.D.M., A.-M.H.), and Faculty of Health and Medical Sciences (P.S.), University of Copenhagen, 2650 Glostrup, Denmark; Department of Clinical Biochemistry (H.L.J.), Copenhagen University Hospital Bispebjerg, 2400 Copenhagen, Denmark; Danish Cancer Society Research Center (J.C., A.T., A.O., J.H.), 2100 Copenhagen, Denmark; and The Elective Laboratory of the Capital Region (B.L.) and the Research Centre of Ageing and Osteoporosis (P.S.), Department of Medicine M, Copenhagen University Hospital Glostrup, 2600 Glostrup, Denmark.
authors.forename: Bent
authors.initials: B
authors.lastname: Lind
authors.affiliation: Department of Drug Design and Pharmacology (D.D.M., A.-M.H.), and Faculty of Health and Medical Sciences (P.S.), University of Copenhagen, 2650 Glostrup, Denmark; Department of Clinical Biochemistry (H.L.J.), Copenhagen University Hospital Bispebjerg, 2400 Copenhagen, Denmark; Danish Cancer Society Research Center (J.C., A.T., A.O., J.H.), 2100 Copenhagen, Denmark; and The Elective Laboratory of the Capital Region (B.L.) and the Research Centre of Ageing and Osteoporosis (P.S.), Department of Medicine M, Copenhagen University Hospital Glostrup, 2600 Glostrup, Denmark.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Heegaard
authors.affiliation: Department of Drug Design and Pharmacology (D.D.M., A.-M.H.), and Faculty of Health and Medical Sciences (P.S.), University of Copenhagen, 2650 Glostrup, Denmark; Department of Clinical Biochemistry (H.L.J.), Copenhagen University Hospital Bispebjerg, 2400 Copenhagen, Denmark; Danish Cancer Society Research Center (J.C., A.T., A.O., J.H.), 2100 Copenhagen, Denmark; and The Elective Laboratory of the Capital Region (B.L.) and the Research Centre of Ageing and Osteoporosis (P.S.), Department of Medicine M, Copenhagen University Hospital Glostrup, 2600 Glostrup, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Schwarz
mesh_terms: D000328:Adult; D000368:Aged; D002318:Cardiovascular Diseases / Q000401:mortality*; D002423:Cause of Death; D003718:Denmark / Q000453:epidemiology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood / Q000401:mortality; D020521:Stroke / Q000097:blood / Q000401:mortality; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000097:blood; D014808:Vitamin D Deficiency / Q000097:blood* / Q000453:epidemiology*
chemical_list: D014807:Vitamin D; C104450:25-hydroxyvitamin D