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Physiol Genomics. 2016 Jan;48(1):33-41. doi: 10.1152/physiolgenomics.00029.2015. Epub 2015 Oct 27.

Pharmacogenomics of estrogens on changes in carotid artery intima-medial thickness and coronary arterial calcification: Kronos Early Estrogen Prevention Study.

Author information

  • 1Department of Surgery, Mayo Clinic, Rochester, Minnesota; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota;
  • 2Department of Health Sciences Research (Divisions of Biomedical Statistics and Informatics and Epidemiology), Mayo Clinic, Rochester, Minnesota;
  • 3Department of Internal Medicine (Division of Cardiovascular Diseases), Mayo Clinic, Rochester, Minnesota;
  • 4MCRI Center for Translational Genomics, Molecular Cardiology Research Institute, Tufts, Medical Center, Boston, Massachusetts;
  • 5Atherosclerosis Research Unit, Departments of Medicine and Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California;
  • 6Los Angeles Biomedical Research Institute, Torrance, California;
  • 7Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, New York, New York;
  • 8Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut;
  • 9Department of Preventive Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts;
  • 10Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California;
  • 11Reproductive Biology Research, New York University School of Medicine, New York, New York; and.
  • 12Kronos Longevity Research Institute and Phoenix VA Health Care System, Phoenix, Arizona.


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.


atherosclerosis; candidate genes; estrogen; innate immunity; thrombosis

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