title: Genetically high plasma vitamin C, intake of fruit and vegetables, and risk of ischemic heart disease and all-cause mortality: a Mendelian randomization study.
abstract: BACKGROUND
  High intake of fruit and vegetables as well as high plasma vitamin C concentrations have been associated with low risk of ischemic heart disease in prospective studies, but results from randomized clinical trials have been inconsistent.
  
  
  OBJECTIVE
  We tested the hypothesis that genetically high concentrations of plasma vitamin C, such as with high intake of fruit and vegetables, are associated with low risk of ischemic heart disease and all-cause mortality.
  
  
  METHODS
  We used a Mendelian randomization approach and genotyped for solute carrier family 23 member 1 (SLC23A1) rs33972313 in the sodium-dependent vitamin C transporter 1 in 97,203 white individuals of whom 10,123 subjects had ischemic heart disease, and 8477 subjects died. We measured plasma vitamin C in 3512 individuals and included dietary information on 83,256 individuals.
  
  
  RESULTS
  The SLC23A1 rs33972313 G allele was associated with 11% higher plasma vitamin C. The multivariable adjusted HRs for highest compared with lowest fruit and vegetable intakes were 0.87 (95% CI: 0.78, 0.97; P = 0.01) for ischemic heart disease and 0.80 (95% CI: 0.73, 0.88; P < 0.001) for all-cause mortality. Corresponding HRs for rs33972313 GG (93%) compared with AA plus AG (7%) genotypes were 0.95 (95% CI: 0.88, 1.02; P = 0.21) and 0.96 (0.88, 1.03; P = 0.29), respectively. In an instrumental variable analysis, the OR for genetically determined 25% higher plasma vitamin C concentrations was 0.90 (95% CI: 0.75, 1.08; P = 0.27) for ischemic heart disease and 0.88 (0.72, 1.08; P = 0.22) for all-cause mortality.
  
  
  CONCLUSIONS
  High intake of fruit and vegetables was associated with low risk of ischemic heart disease and all-cause mortality. Although the 95% CI for genetically high plasma vitamin C concentrations overlapped 1.0, which made certain statistical inferences difficult, effect sizes were comparable to those for fruit and vegetable intake. Thus, judging by the effect size, our data cannot exclude that a favorable effect of high intake of fruit and vegetables could in part be driven by high vitamin C concentrations.
authors.affiliation: From the Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark (CJK, SA, and BGN); the Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (CJK, SA, and BGN); the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom (GDS); and the Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Frederiksberg, Denmark (BGN).
authors.forename: Camilla J
authors.initials: CJ
authors.lastname: Kobylecki
authors.affiliation: From the Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark (CJK, SA, and BGN); the Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (CJK, SA, and BGN); the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom (GDS); and the Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Frederiksberg, Denmark (BGN).
authors.forename: Shoaib
authors.initials: S
authors.lastname: Afzal
authors.affiliation: From the Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark (CJK, SA, and BGN); the Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (CJK, SA, and BGN); the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom (GDS); and the Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Frederiksberg, Denmark (BGN).
authors.forename: George
authors.initials: G
authors.lastname: Davey Smith
authors.affiliation: From the Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark (CJK, SA, and BGN); the Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (CJK, SA, and BGN); the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom (GDS); and the Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Frederiksberg, Denmark (BGN). boerge.nordestgaard@regionh.dk.
authors.forename: Børge G
authors.initials: BG
authors.lastname: Nordestgaard
mesh_terms: D000368:Aged; D000483:Alleles; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000097:blood*; D015992:Body Mass Index; D002784:Cholesterol / Q000097:blood; D005260:Female; D005500:Follow-Up Studies; D005638:Fruit; D060005:Genotyping Techniques; D006801:Humans; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D009026:Mortality; D017202:Myocardial Ischemia / Q000453:epidemiology*; D016016:Proportional Hazards Models; D012307:Risk Factors; D012680:Sensitivity and Specificity; D060347:Sodium-Coupled Vitamin C Transporters / Q000235:genetics* / Q000378:metabolism; D011795:Surveys and Questionnaires; D014675:Vegetables
chemical_list: C555162:SLC23A1 protein, human; D060347:Sodium-Coupled Vitamin C Transporters; D002784:Cholesterol; D001205:Ascorbic Acid
keywords: Mendelian randomization; genetic variants; ischemic heart disease; mortality; vitamin C