title: A serum 25-hydroxyvitamin D concentration-associated genetic variant in DHCR7 interacts with type 2 diabetes status to influence subclinical atherosclerosis (measured by carotid intima-media thickness).
abstract: OBJECTIVE
  The findings of studies investigating whether or not low serum 25-hydroxyvitamin D [25(OH)D] concentration promotes development of atherosclerosis have been contradictory. The present study employed a Mendelian randomisation approach and carotid artery intima-media thickness (cIMT), a surrogate marker of coronary artery disease, to address this question.
  
  
  METHODS
  The multicentre, longitudinal Carotid Intima-Media Thickness and IMT-Progression as Predictors of Vascular Events in a High-Risk European Population (IMPROVE) cohort study, which enrolled individuals with at least three cardiovascular risk factors and no history or symptoms of cardiovascular disease, was used for the present investigation. Participants underwent carotid ultrasound examination at baseline and at months 15 and 30. Six single nucleotide polymorphisms (SNPs) associated with serum 25(OH)D concentration in genome-wide association studies were identified and genotyped in 3,418 individuals, of whom 929 had type 2 diabetes.
  
  
  RESULTS
  SNPs in the genes encoding vitamin D binding protein (GC; rs2282679 and rs7041) and 7-dehydrocholesterol reductase/NAD synthetase-1 (DHCR7; rs12785878 and rs3829251) were negatively associated with 25(OH)D levels. Effect sizes and significance of associations between SNPs and 25(OH)D levels differed between individuals with and without type 2 diabetes, although no significant interactions were observed. A SNP in DHCR7 interacted with type 2 diabetes to significantly influence progression of cIMT measures independent of 25(OH)D levels and established risk factors. Expression analysis demonstrated that this SNP modulates DHCR7 mRNA levels in aortic adventitia.
  
  
  CONCLUSIONS
  SNPs in GC and DHCR7 were associated with serum levels of 25(OH)D, but only rs3829251 (DHCR7) influenced progression of subclinical atherosclerosis, as measured by cIMT, in a manner dependent on type 2 diabetes status but independent of 25(OH)D levels.
authors.affiliation: Atherosclerosis Research Unit, Centre for Molecular Medicine, Building L8:03, Karolinska University Hospital Solna, 17176, Stockholm, Sweden, Rona.Strawbridge@ki.se.
authors.forename: Rona J
authors.initials: RJ
authors.lastname: Strawbridge
authors.forename: Anna
authors.initials: A
authors.lastname: Deleskog
authors.forename: Olga
authors.initials: O
authors.lastname: McLeod
authors.forename: Lasse
authors.initials: L
authors.lastname: Folkersen
authors.forename: Maryam
authors.initials: M
authors.lastname: Kavousi
authors.forename: Karl
authors.initials: K
authors.lastname: Gertow
authors.forename: Damiano
authors.initials: D
authors.lastname: Baldassarre
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Veglia
authors.forename: Karin
authors.initials: K
authors.lastname: Leander
authors.forename: Bruna
authors.initials: B
authors.lastname: Gigante
authors.forename: Jussi
authors.initials: J
authors.lastname: Kauhanen
authors.forename: Rainer
authors.initials: R
authors.lastname: Rauramaa
authors.forename: Andries J
authors.initials: AJ
authors.lastname: Smit
authors.forename: Elmo
authors.initials: E
authors.lastname: Mannarino
authors.forename: Philippe
authors.initials: P
authors.lastname: Giral
authors.forename: Abbas
authors.initials: A
authors.lastname: Dehghan
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Oscar H
authors.initials: OH
authors.lastname: Franco
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
authors.forename: Elena
authors.initials: E
authors.lastname: Tremoli
authors.forename: Ulf
authors.initials: U
authors.lastname: de Faire
authors.forename: Sven
authors.initials: S
authors.lastname: Gustafsson
authors.forename: Claes-Göran
authors.initials: CG
authors.lastname: Östensson
authors.forename: Per
authors.initials: P
authors.lastname: Eriksson
authors.forename: John
authors.initials: J
authors.lastname: Öhrvik
authors.forename: Anders
authors.initials: A
authors.lastname: Hamsten
mesh_terms: D000368:Aged; D059168:Carotid Intima-Media Thickness; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000097:blood
chemical_list: D014807:Vitamin D; C104450:25-hydroxyvitamin D; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase