The associations of 25-hydroxyvitamin D levels, vitamin D binding protein gene polymorphisms, and race with risk of incident fracture-related hospitalization: Twenty-year follow-up in a bi-ethnic cohort (the ARIC Study).
BACKGROUND
Deficient levels of 25-hydroxyvitamin D [25(OH)D] have been associated with increased fracture risk. Racial differences in fracture risk may be related to differences in bioavailable vitamin D due to single nucleotide polymorphism (SNP) variations in the vitamin D binding protein (DBP).


METHODS
We measured 25(OH)D levels in 12,781 middle-aged White and Black participants [mean age 57 years (SD 5.7), 25% Black] in the ARIC Study who attended the second examination from 1990-1992. Participants were genotyped for two DBP SNPs (rs4588 and rs7041). Incident hospitalized fractures were measured by abstracting hospital records for ICD-9 codes. We used Cox proportional hazards models to evaluate the association between 25(OH)D levels and risk of fracture with adjustment for possible confounders. Interactions were tested by race and DBP genotype.


RESULTS
There were 1122 incident fracture-related hospitalizations including 267 hip fractures over a median of 19.6 years of follow-up. Participants with deficient 25(OH)D (<20 ng/mL) had a higher risk of any fracture hospitalization [HR=1.21 (95% CI 1.05-1.39)] and hospitalization for hip fracture [HR=1.35 (1.02-1.79)]. No significant racial interaction was noted (p-interaction=0.20 for any fracture; 0.74 for hip fracture). There was no independent association of rs4588 and rs7041 with fracture. However, there was a marginal interaction for 25(OH)D deficiency with rs7041 among Whites (p-interaction=0.065). Whites with both 25(OH)D deficiency and the GG genotype [i.e., with predicted higher levels of DBP and lower bioavailable vitamin D] were at the greatest risk for any fracture [HR=1.48 (1.10-2.00)] compared to Whites with the TT genotype and replete 25(OH)D (reference group).


CONCLUSIONS
Deficient 25(OH)D levels are associated with higher incidence of hospitalized fractures. Marginal effects were seen in Whites for the DBP genotype associated with lower bioavailable vitamin D, but result inconclusive. Further investigation is needed to more directly evaluate the association between bioavailable vitamin D and fracture risk.
Northeast Ohio Medical University, Akron, OH, USA.
Radhika
R
Takiar
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MD, USA.
Pamela L
PL
Lutsey
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
Di
D
Zhao
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
Eliseo
E
Guallar
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Medicine, Division of General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Andrea L C
AL
Schneider
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Medicine, Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Morgan E
ME
Grams
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Medicine, Division of General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Lawrence J
LJ
Appel
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
Elizabeth
E
Selvin
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: edonnell@jhmi.edu.
Erin D
ED
Michos
D000368:Aged; D000483:Alleles; D044383:Black People; D005006:Ethnicity; D005260:Female; D005500:Follow-Up Studies; D017102:Fracture Healing; D014644:Genetic Variation; D005838:Genotype; D006620:Hip Fractures / Q000097:blood / Q000208:ethnology* / Q000235:genetics*; D006760:Hospitalization; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000097:blood; D014809:Vitamin D-Binding Protein / Q000235:genetics*; D044465:White People
D014809:Vitamin D-Binding Protein; D014807:Vitamin D; C104450:25-hydroxyvitamin D
Epidemiology; Fracture; Race; Vitamin D; Vitamin D binding protein polymorphisms