Pharmacogenomics of estrogens on changes in carotid artery intima-medial thickness and coronary arterial calcification: Kronos Early Estrogen Prevention Study.
Prior to the initiation of menopausal hormone treatment (MHT), genetic variations in the innate immunity pathway were found to be associated with carotid artery intima-medial thickness (CIMT) and coronary arterial calcification (CAC) in women (n = 606) enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). Whether MHT might affect these associations is unknown. The association of treatment outcomes with variation in the same 764 candidate genes was evaluated in the same KEEPS participants 4 yr after randomization to either oral conjugated equine estrogens (0.45 mg/day), transdermal 17β-estradiol (50 μg/day), each with progesterone (200 mg/day) for 12 days each month, or placebo pills and patch. Twenty SNPs within the innate immunity pathway most related with CIMT after 4 yr were not among those associated with CIMT prior to MHT. In 403 women who completed the study in their assigned treatment group, single nucleotide polymorphisms (SNPs) within the innate immunity pathway were found to alter the treatment effect on 4 yr change in CIMT (i.e., significant interaction between treatment and genetic variation in the innate immunity pathway; P < 0.001). No SNPs by treatment effects were observed with changes of CAC >5 Agatston units after 4 yr. Results of this study suggest that hormonal status may interact with genetic variants to influence cardiovascular phenotypes, specifically, the pharmacogenomic effects within the innate immunity pathway for CIMT.
Department of Surgery, Mayo Clinic, Rochester, Minnesota; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; miller.virginia@mayo.edu.
Virginia M
VM
Miller
Department of Health Sciences Research (Divisions of Biomedical Statistics and Informatics and Epidemiology), Mayo Clinic, Rochester, Minnesota;
Gregory D
GD
Jenkins
Department of Health Sciences Research (Divisions of Biomedical Statistics and Informatics and Epidemiology), Mayo Clinic, Rochester, Minnesota;
Joanna M
JM
Biernacka
Department of Internal Medicine (Division of Cardiovascular Diseases), Mayo Clinic, Rochester, Minnesota;
John A
JA
Heit
MCRI Center for Translational Genomics, Molecular Cardiology Research Institute, Tufts, Medical Center, Boston, Massachusetts;
Gordon S
GS
Huggins
Atherosclerosis Research Unit, Departments of Medicine and Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California;
Howard N
HN
Hodis
Los Angeles Biomedical Research Institute, Torrance, California;
Matthew J
MJ
Budoff
Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, New York, New York;
Rogerio A
RA
Lobo
Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut;
Hugh S
HS
Taylor
Department of Preventive Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts;
JoAnn E
JE
Manson
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California;
Dennis M
DM
Black
Reproductive Biology Research, New York University School of Medicine, New York, New York; and.
Frederick
F
Naftolin
Kronos Longevity Research Institute and Phoenix VA Health Care System, Phoenix, Arizona.
S Mitchell
SM
Harman
Department of Health Sciences Research (Divisions of Biomedical Statistics and Informatics and Epidemiology), Mayo Clinic, Rochester, Minnesota;
Mariza
M
de Andrade
D000818:Animals; D002114:Calcinosis / Q000235:genetics*; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology*; D059168:Carotid Intima-Media Thickness; D016001:Confidence Intervals; D003331:Coronary Vessels / Q000187:drug effects / Q000473:pathology*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D056726:Genetic Association Studies; D006736:Horses; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D010597:Pharmacogenetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013997:Time Factors
D004967:Estrogens
atherosclerosis; candidate genes; estrogen; innate immunity; thrombosis