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)

- Deficient levels of 25(OH)D (< 20 ng/ml) was associated with an increased incidence of hospitalized fracture over 20 years of follow-up.
- There was no independent association of key vitamin D binding protein SNPs (rs4588 and rs7041) with fracture risk.
- Genetic variation in the rs7041 SNP may modify fracture risk in Whites with deficient vitamin D, but result not conclusive.
- Further investigation is needed to determine whether treatment strategies for low 25(OH)D should vary by bioavailable vitamin D status.

BackgroundDeficient 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).MethodsWe 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.ResultsThere 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).ConclusionsDeficient 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.