Association of the VDR translation start site polymorphism and fracture risk in older women.
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.
Moffett
Susan P
SP
Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA. susan.moffett@hgen.pitt.edu
Zmuda
Joseph M
JM
Cauley
Jane A
JA
Ensrud
Kristine E
KE
Hillier
Teresa A
TA
Hochberg
Marc C
MC
Li
Jia
J
Cayabyab
Shelia
S
Lee
Jocelyn M
JM
Peltz
Gary
G
Cummings
Steven R
SR
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
D018387:Codon, Initiator; D018167:Receptors, Calcitriol