title: Association of 25-Hydroxyvitamin D status and genetic variation in the vitamin D metabolic pathway with FEV1 in the Framingham Heart Study.
abstract: BACKGROUND
  Vitamin D is associated with lung function in cross-sectional studies, and vitamin D inadequacy is hypothesized to play a role in the pathogenesis of chronic obstructive pulmonary disease. Further data are needed to clarify the relation between vitamin D status, genetic variation in vitamin D metabolic genes, and cross-sectional and longitudinal changes in lung function in healthy adults.
  
  
  METHODS
  We estimated the association between serum 25-hydroxyvitamin D [25(OH)D] and cross-sectional forced expiratory volume in the first second (FEV1) in Framingham Heart Study (FHS) Offspring and Third Generation participants and the association between serum 25(OH)D and longitudinal change in FEV1 in Third Generation participants using linear mixed-effects models. Using a gene-based approach, we investigated the association between 241 SNPs in 6 select vitamin D metabolic genes in relation to longitudinal change in FEV1 in Offspring participants and pursued replication of these findings in a meta-analyzed set of 4 independent cohorts.
  
  
  RESULTS
  We found a positive cross-sectional association between 25(OH)D and FEV1 in FHS Offspring and Third Generation participants (P=0.004). There was little or no association between 25(OH)D and longitudinal change in FEV1 in Third Generation participants (P=0.97). In Offspring participants, the CYP2R1 gene, hypothesized to influence usual serum 25(OH)D status, was associated with longitudinal change in FEV1 (gene-based P<0.05). The most significantly associated SNP from CYP2R1 had a consistent direction of association with FEV1 in the meta-analyzed set of replication cohorts, but the association did not reach statistical significance thresholds (P=0.09).
  
  
  CONCLUSIONS
  Serum 25(OH)D status was associated with cross-sectional FEV1, but not longitudinal change in FEV1. The inconsistent associations may be driven by differences in the groups studied. CYP2R1 demonstrated a gene-based association with longitudinal change in FEV1 and is a promising candidate gene for further studies.
authors.affiliation: Division of Nutritional Sciences, Cornell University, 209 Savage Hall, Ithaca, NY, 14853, USA. jg553@cornell.edu.
authors.forename: J G
authors.initials: JG
authors.lastname: Hansen
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA. gaowei@bu.edu.
authors.forename: W
authors.initials: W
authors.lastname: Gao
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA. dupuis@bu.edu.|The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA. dupuis@bu.edu.
authors.forename: J
authors.initials: J
authors.lastname: Dupuis
authors.affiliation: The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA. goconnor@bu.edu.|Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA, USA. goconnor@bu.edu.
authors.forename: G T
authors.initials: GT
authors.lastname: O'Connor
authors.affiliation: Division of Nutritional Sciences, Cornell University, 209 Savage Hall, Ithaca, NY, 14853, USA. wt227@cornell.edu.
authors.forename: W
authors.initials: W
authors.lastname: Tang
authors.affiliation: Ontario Institute for Cancer Research, Toronto, ON, Canada. mkowgier@uhnresearch.ca.|Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada. mkowgier@uhnresearch.ca.
authors.forename: M
authors.initials: M
authors.lastname: Kowgier
authors.affiliation: University of New Mexico, Albuquerque, NM, USA. ASood@salud.unm.edu.
authors.forename: A
authors.initials: A
authors.lastname: Sood
authors.affiliation: Computational Medicine Core, Center for Lung Biology, Division of Pulmonary & Critical Care Medicine, Department of Medicine, University of Washington, Seattle, WA, USA. sagharib@u.washington.edu.
authors.forename: S A
authors.initials: SA
authors.lastname: Gharib
authors.affiliation: School of Public Health, University of Adelaide, Adelaide, Australia. lyle.palmer@adelaide.edu.au.
authors.forename: L J
authors.initials: LJ
authors.lastname: Palmer
authors.affiliation: Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA. Myriam.Fornage@uth.tmc.edu.|Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA. Myriam.Fornage@uth.tmc.edu.
authors.forename: M
authors.initials: M
authors.lastname: Fornage
authors.affiliation: Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA. heckbert@u.washington.edu.|Department of Epidemiology, University of Washington, Seattle, WA, USA. heckbert@u.washington.edu.|Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA. heckbert@u.washington.edu.
authors.forename: S R
authors.initials: SR
authors.lastname: Heckbert
authors.affiliation: Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA. psaty@u.washington.edu.|Department of Epidemiology, University of Washington, Seattle, WA, USA. psaty@u.washington.edu.|Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA. psaty@u.washington.edu.|Department of Medicine, University of Washington, Seattle, WA, USA. psaty@u.washington.edu.
authors.forename: B M
authors.initials: BM
authors.lastname: Psaty
authors.affiliation: Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA. sarah.booth@tufts.edu.
authors.forename: S L
authors.initials: SL
authors.lastname: Booth
authors.affiliation: Division of Nutritional Sciences, Cornell University, 209 Savage Hall, Ithaca, NY, 14853, USA. pac6@cornell.edu.|Division of Biostatistics and Epidemiology, Department of Healthcare Policy and Research, Weill Cornell Medical College, New York, NY, USA. pac6@cornell.edu.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Cassano
mesh_terms: D000328:Adult; D000368:Aged; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D004268:DNA-Binding Proteins / Q000097:blood* / Q000235:genetics*; D005260:Female; D014644:Genetic Variation / Q000502:physiology*; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008404:Massachusetts; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D008875:Middle Aged; D009687:Nuclear Proteins / Q000097:blood* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014157:Transcription Factors; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000097:blood / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C474280:FEV protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; D014807:Vitamin D; C104450:25-hydroxyvitamin D