TY - JOUR
T1 - SLCO1B1 genetic variation and hormone therapy in menopausal women
AU - Moyer, Ann M.
AU - de Andrade, Mariza
AU - Faubion, Stephanie S.
AU - Kapoor, Ekta
AU - Dudenkov, Tanda
AU - Weinshilboum, Richard M.
AU - Miller, Virginia M.
N1 - Funding Information:
Received January 12, 2018; revised and accepted February 15, 2018. From the 1Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN; 2Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN; 3Women’s Health Clinic, Division of General Internal Medicine, Mayo Clinic, Rochester, MN; 4Division of Endocrinology, Metabolism, & Nutrition, Mayo Clinic, Rochester, MN; 5Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN; and 6Departments of Surgery and Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN. Funding/support: This work was supported by grants from the Aurora Foundation to the Kronos Longevity Research Institute, U19 GM61388 (The Pharmacogenomics Research Network), NIH P50 AG044170, RO1 GM28157, UL1TR00013 (from the National Center for Research Resources (NCRR), a component of the National Institutes of Health [NIH], and the NIH Roadmap for Medical Research. Contents of this paper are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. Information on NCRR is available at http://www.ncrr.nih.gov/. Information on Reengineering the Clinical Research enterprise can be obtained from http://nihroadmap.nih.gov), American Heart Association-Scientist Development Grant, AHA 08-30503Z, American Heart Association, Grant-in-Aid, 12GRNT12050147, and the Mayo Foundation. Financial disclosure/conflicts of interest: None declared. Address correspondence to: Virginia M. Miller, PhD, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail: Miller.Virginia@Mayo.edu This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
Publisher Copyright:
© 2018 The Author(s). Published by Wolters Kluwer Health, Inc., on behalf of The North American Menopause Society.
PY - 2018/8/1
Y1 - 2018/8/1
N2 - Objective: Response to menopausal hormone therapy (MHT) shows individual variation. SLCO1B1 encodes the OATP1B1 transporter expressed in the liver that transports many endogenous substances, including estrone sulfate, from the blood into hepatocytes. This study evaluated the relationship between genetic variation in SLCO1B1 and response to MHT in women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS) at Mayo Clinic, Rochester, MN. Methods: KEEPS participants were randomized to oral conjugated equine estrogen (n = 33, oCEE), transdermal 17b-estradiol (n = 33, tE2), or placebo (n = 34) for 48 months. Menopausal symptoms (hot flashes, night sweats, insomnia, palpitations) were self-reported before treatment and at 48 months. Estrone (E1), E2, and sulfated conjugates (E1S, E2S) were measured using high-performance liquid chromatography-tandem mass spectrometry. SLCO1B1 rs4149056 (c.521T>C, p.Val174Ala) was genotyped using a TaqMan assay. Results: After adjusting for treatment, there was a significant association between the SLCO1B1 rs4149056 TT genotype (encoding normal function transporter) and lower E1S, E1S/E1, and E2S (P = 0.032, 0.010, and 0.008, respectively) compared with women who were heterozygous (TC) or homozygous (CC) for the reduced function allele. The interactions between genotype, treatment, and E2S concentration were stronger in women assigned to tE2 (P = 0.013) than the women taking oCEE (P = 0.056). Among women assigned to active treatment, women with the CT genotype showed a significantly greater decrease in night sweats (P = 0.041) than those with the TT genotype. Conclusions: Individual variation in sulfated estrogens is explained, in part, by genetic variation in SLCO1B1. Bioavailability of sulfated estrogens may contribute to relief of night sweats.
AB - Objective: Response to menopausal hormone therapy (MHT) shows individual variation. SLCO1B1 encodes the OATP1B1 transporter expressed in the liver that transports many endogenous substances, including estrone sulfate, from the blood into hepatocytes. This study evaluated the relationship between genetic variation in SLCO1B1 and response to MHT in women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS) at Mayo Clinic, Rochester, MN. Methods: KEEPS participants were randomized to oral conjugated equine estrogen (n = 33, oCEE), transdermal 17b-estradiol (n = 33, tE2), or placebo (n = 34) for 48 months. Menopausal symptoms (hot flashes, night sweats, insomnia, palpitations) were self-reported before treatment and at 48 months. Estrone (E1), E2, and sulfated conjugates (E1S, E2S) were measured using high-performance liquid chromatography-tandem mass spectrometry. SLCO1B1 rs4149056 (c.521T>C, p.Val174Ala) was genotyped using a TaqMan assay. Results: After adjusting for treatment, there was a significant association between the SLCO1B1 rs4149056 TT genotype (encoding normal function transporter) and lower E1S, E1S/E1, and E2S (P = 0.032, 0.010, and 0.008, respectively) compared with women who were heterozygous (TC) or homozygous (CC) for the reduced function allele. The interactions between genotype, treatment, and E2S concentration were stronger in women assigned to tE2 (P = 0.013) than the women taking oCEE (P = 0.056). Among women assigned to active treatment, women with the CT genotype showed a significantly greater decrease in night sweats (P = 0.041) than those with the TT genotype. Conclusions: Individual variation in sulfated estrogens is explained, in part, by genetic variation in SLCO1B1. Bioavailability of sulfated estrogens may contribute to relief of night sweats.
KW - 17b-estradiol
KW - Conjugated equine estrogens
KW - Kronos Early Estrogen Prevention Study
KW - OATP1B1
KW - Personalized therapy
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U2 - 10.1097/GME.0000000000001109
DO - 10.1097/GME.0000000000001109
M3 - Article
C2 - 29738412
AN - SCOPUS:85056281855
VL - 25
SP - 877
EP - 882
JO - Menopause
JF - Menopause
SN - 1072-3714
IS - 8
ER -