Gene-Hormone Therapy Interaction and Fracture Risk in Postmenopausal Women.
Evidence supports a protective effect of menopausal hormone therapy (HT) on bone. However, whether genetic susceptibility modifies the association of HT and fracture risk is not sufficiently explored.



The objective was to test an interaction between genetic susceptibility and HT on fracture risk.



We constructed two weighted genetic risk scores (GRSs) based on 16 fracture-associated variants (Fx-GRSs) and 50 bone mineral density variants (BMD-GRSs). We used Cox regression to estimate the main effects of GRSs and their interactions with HT on fracture risk. We estimated the relative excess risk due to interaction (RERI) as a measure of additive interaction. We also used the case-only approach to test for a multiplicative interaction.



Forty US clinical centers.



A total of 9922 genotyped white postmenopausal women (age, 50 to 79) from the Women's Health Initiative HT randomized trials.



Adjudicated fracture incidence.



Both GRSs were associated with fracture risk per 1-unit increment in GRS (hazard ratio, 1.04 [95% confidence interval, 1.02 to 1.06] for Fx-GRS and hazard ratio, 1.03 [95% confidence interval,1.02-1.04] for BMD-GRS). We found no evidence for multiplicative interaction for either of the GRS. However, we observed a substantial additive interaction, where the highest quartile of both GRSs and randomization to placebo have excess fracture risk: Fx-GRS P for RERI = 0.047, BMD-GRS P for RERI = 0.046.



These results suggest that HT reduces fracture risk in postmenopausal women, especially in those at highest genetic risk of fracture and low BMD.
Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, The State University of New York, Buffalo, New York 14214.
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, New York 14214.
Jean
J
Wactawski-Wende
College of Pharmacy, The Ohio State University, Columbus, Ohio 43210.|Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio 43210.
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, New York 14214.
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, New York 14214.
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, New York 14214.
Jing
J
Nie
Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, Columbus, Ohio 43210.
Rebecca D
RD
Jackson
Center for Pharmacogenomics, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio 43210.
Samuel K
SK
Handelman
Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, California 95616.
Rami
R
Nassir
Division of General Internal Medicine and Health Sciences Research, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095.
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, New York 14214.
Heather M
HM
Ochs-Balcom
D000368:Aged; D015519:Bone Density / Q000235:genetics*; D003271:Contraceptive Agents, Female; D015914:Estrogen Replacement Therapy / Q000706:statistics & numerical data*; D004967:Estrogens / Q000627:therapeutic use; D004966:Estrogens, Conjugated (USP) / Q000627:therapeutic use; D005260:Female; D050723:Fractures, Bone / Q000453:epidemiology / Q000235:genetics*; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015994:Incidence; D017258:Medroxyprogesterone Acetate / Q000627:therapeutic use; D008875:Middle Aged; D016016:Proportional Hazards Models; D014481:United States; D044465:White People / Q000235:genetics
D003271:Contraceptive Agents, Female; D004967:Estrogens; D004966:Estrogens, Conjugated (USP); D017258:Medroxyprogesterone Acetate