The influence of genetic susceptibility and calcium plus vitamin D supplementation on fracture risk.
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.
Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, The State University of New York, Buffalo, NY.
Youjin
Y
Wang
Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, The State University of New York, Buffalo, NY.
Jean
J
Wactawski-Wende
College of Pharmacy.|Department of Veterinary Biosciences, College of Veterinary Medicine.
Lara E
LE
Sucheston-Campbell
Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, The State University of New York, Buffalo, NY.|Department of Cancer Prevention and Control, Division of Cancer Prevention and Population Sciences, Roswell Park Cancer Institute, Buffalo, NY.
Leah
L
Preus
Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, The State University of New York, Buffalo, NY.
Kathleen M
KM
Hovey
Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, The State University of New York, Buffalo, NY.
Jing
J
Nie
Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, and.
Rebecca D
RD
Jackson
Center for Pharmacogenomics, Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH.
Samuel K
SK
Handelman
Department of Biochemistry and Molecular Medicine, University of California, Davis, Davis, CA; and.
Rami
R
Nassir
Division of General Internal Medicine and Health Sciences Research, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
Carolyn J
CJ
Crandall
Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, The State University of New York, Buffalo, NY; hmochs2@buffalo.edu.
Heather M
HM
Ochs-Balcom
D000368:Aged; D015519:Bone Density; D001842:Bone and Bones; D002118:Calcium / Q000627:therapeutic use*; D002136:Calcium, Dietary / Q000627:therapeutic use; D002762:Cholecalciferol / Q000627:therapeutic use*; D019587:Dietary Supplements; D005260:Female; D050723:Fractures, Bone / Q000235:genetics / Q000517:prevention & control*; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D017698:Postmenopause; D016016:Proportional Hazards Models; D012307:Risk Factors
D002136:Calcium, Dietary; D002762:Cholecalciferol; D002118:Calcium
bone mineral density; calcium; fracture; genetic risk score; postmenopausal women; vitamin D