The influence of genetic susceptibility and calcium plus vitamin D supplementation on fracture risk

Am J Clin Nutr. 2017 Apr;105(4):970-979. doi: 10.3945/ajcn.116.144550. Epub 2017 Feb 1.

Abstract

Background: Fracture is a complex trait, affected by both genetic and environmental factors. A meta-analysis of genome-wide association studies (GWASs) identified multiple bone mineral density (BMD) and fracture-associated loci.Objective: We conducted a study to evaluate whether fracture genetic risk score (Fx-GRS) and bone mineral density genetic risk score (BMD-GRS) modify the association between the intake of calcium with vitamin D (CaD) and fracture risk.Design: Data from 5823 white postmenopausal women from the Women's Health Initiative CaD randomized trial were included. Participants received 1000 mg elemental Ca with 400 IU vitamin D3/d or placebo (median follow-up: 6.5 y). Total fracture was defined as first fracture of any type. We computed the Fx-GRS with 16 fracture- and BMD-associated variants, and the BMD-GRS with 50 BMD-associated variants. We used Cox regression and a case-only approach to test for multiplicative interaction. Additive interaction was assessed with the relative excess risk due to interaction (RERI). We analyzed genetic risk score as a continuous variable and a categorical variable based on quartile (quartile 1, quartiles 2-3, and quartile 4).Results: We observed no interaction between the Fx-GRS and CaD on fracture risk; however, we observed a significant multiplicative interaction between the BMD-GRS and CaD assignment (P-interaction = 0.01). In addition, there was a significant negative additive interaction between placebo assignment and higher BMD-GRS: quartiles 2-3, PRERI = 0.03; quartile 4, PRERI = 0.03. In a stratified analysis, the protective effect of CaD on fracture risk was observed in women in the lowest BMD-GRS quartile (HR: 0.60, 95% CI: 0.44, 0.81) but not in women with a higher BMD-GRS.Conclusions: We observed significant effects of CaD intake on fracture risk only in women with the lowest genetic predisposition to low BMD. Future large-scale studies with functional characterization of GWAS findings are warranted to assess the utility of genetic risk score in analysis of risks and benefits of CaD for bone.

Keywords: bone mineral density; calcium; fracture; genetic risk score; postmenopausal women; vitamin D.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Bone Density*
  • Bone and Bones
  • Calcium / therapeutic use*
  • Calcium, Dietary / therapeutic use
  • Cholecalciferol / therapeutic use*
  • Dietary Supplements*
  • Female
  • Fractures, Bone / genetics
  • Fractures, Bone / prevention & control*
  • Gene-Environment Interaction*
  • Genetic Predisposition to Disease
  • Genotype*
  • Humans
  • Middle Aged
  • Postmenopause
  • Proportional Hazards Models
  • Risk Factors

Substances

  • Calcium, Dietary
  • Cholecalciferol
  • Calcium