title: Association of the VDR translation start site polymorphism and fracture risk in older women.
abstract: We evaluated the association between the VDR translation start site polymorphism and osteoporotic phenotypes among 6698 older white women. Women with the C/C genotype had lower wrist BMD and an increased risk of wrist and all non-spine/low-trauma fractures. The high frequency of this variant confers a population attributable risk that is similar to several established risk factors for fracture.
  
  
  BACKGROUND
  The vitamin D receptor (VDR) is a nuclear receptor that regulates bone formation, bone resorption, and calcium homeostasis. A common C to T polymorphism in exon 2 of the VDR gene introduces a new translation start site and a protein that differs in length by three amino acids (T = 427aa, C = 424aa; rs10735810).
  
  
  METHODS
  We conducted genetic association analyses of this polymorphism, BMD, and fracture outcomes in a prospective cohort of 6698 white American women >or=65 years of age. Incident fractures were confirmed by physician adjudication of radiology reports. There were 2532 incident nontraumatic/nonvertebral fractures during 13.6 yr of follow-up including 509 wrist and 703 hip fractures.
  
  
  RESULTS
  Women with the C/C genotype had somewhat lower distal radius BMD compared with those with the T/T genotype (CC=0.358 g/cm(2), CT=0.361 g/cm(2), TT=0.369 g/cm(2), p=0.003). The C/C genotype was also associated with increased risk of non-spine, low traumatic fractures (HR: 1.18; 95% CI: 1.04, 1.33) and wrist fractures (HR: 1.33; 95% CI: 1.01, 1.75) compared with the T/T genotype in age-adjusted models. Further adjustments for distal radius BMD only slightly attenuated these associations. The VDR polymorphism was not associated with hip fracture. The population attributable risk (PAR) of the C/C genotype for incident fractures was 6.1%. The PAR for established risk factors for fracture were: low femoral neck BMD (PAR=16.3%), maternal history of fracture (PAR=5.1%), low body weight (PAR=5.3%), corticosteroid use (PAR=1.3%), and smoking (PAR=1.6%). Similar PAR results were observed for wrist fractures.
  
  
  CONCLUSIONS
  The common and potentially functional VDR translation start site polymorphism confers a modestly increased relative risk of fracture among older white women. However, the high frequency of this variant confers a population attributable risk that is similar to or greater than several established risk factors for fracture.
authors.affiliation: Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA. susan.moffett@hgen.pitt.edu
authors.forename: Susan P
authors.initials: SP
authors.lastname: Moffett
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Zmuda
authors.forename: Jane A
authors.initials: JA
authors.lastname: Cauley
authors.forename: Kristine E
authors.initials: KE
authors.lastname: Ensrud
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Hillier
authors.forename: Marc C
authors.initials: MC
authors.lastname: Hochberg
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Shelia
authors.initials: S
authors.lastname: Cayabyab
authors.forename: Jocelyn M
authors.initials: JM
authors.lastname: Lee
authors.forename: Gary
authors.initials: G
authors.lastname: Peltz
authors.forename: Steven R
authors.initials: SR
authors.lastname: Cummings
mesh_terms: D000367:Age Factors; D000368:Aged; D000595:Amino Acid Sequence / Q000235:genetics; D015519:Bone Density / Q000235:genetics*; D018387:Codon, Initiator / Q000235:genetics*; D005260:Female; D050723:Fractures, Bone / Q000235:genetics*; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D018167:Receptors, Calcitriol / Q000235:genetics*; D012307:Risk Factors; D044465:White People
chemical_list: D018387:Codon, Initiator; D018167:Receptors, Calcitriol