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Association of genetic variation in the tachykinin receptor 3 locus with hot flashes and night sweats in the Women's Health Initiative Study

Crandall, Carolyn J. MD, MS; Manson, JoAnn E. MD, DrPH; Hohensee, Chancellor MS; Horvath, Steve PhD, ScD; Wactawski-Wende, Jean PhD; LeBlanc, Erin S. MD, MPH; Vitolins, Mara Z. DrPH; Nassir, Rami PhD; Sinsheimer, Janet S. PhD

doi: 10.1097/GME.0000000000000763
Original Articles

Objective: Vasomotor symptoms (VMS, ie, hot flashes or night sweats) are reported by many, but not all, women. The extent to which VMS are genetically determined is unknown. We evaluated the relationship of genetic variation and VMS.

Methods: In this observational study, we accessed data from three genome-wide association studies (GWAS) (SNP Health Association Resource cohort [SHARe], WHI Memory Study cohort [WHIMS+], and Genome-Wide Association Studies of Treatment Response in Randomized Clinical Trials [GARNET] studies, total n = 17,695) of European American, African American, and Hispanic American postmenopausal women aged 50 to 79 years at baseline in the Women's Health Initiative Study. We examined genetic variation in relation to VMS (yes/no) in each study and using trans-ethnic inverse variance fixed-effects meta-analysis. A total of 11,078,977 single-nucleotide polymorphisms (SNPs) met the quality criteria.

Results: After adjustment for covariates and population structure, three SNPs (on chromosomes 3 and 11) were associated with VMS at the genome-wide threshold of 5 × 10−8 in the African American SHARe GWAS, but were not associated in the other cohorts. In the meta-analysis, 14 SNPs, all located on chromosome 4 in the tachykinin receptor 3 (TACR3) locus, however, had P < 5 × 10−8. These SNPs’ effect sizes were similar across studies/participants’ ancestry (odds ratio ∼1.5).

Conclusions: Genetic variation in TACR3 may contribute to the risk of VMS. To our knowledge, this is the first GWAS to examine SNPs associated with VMS. These results support the biological hypothesis of a role for TACR3 in VMS, which was previously hypothesized from animal and human studies. Further study of these variants may lead to new insights into the biological pathways involved in VMS, which are poorly understood.

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1Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA

2Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA

3Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA

4Department of Human Genetics and Biostatistics, David Geffen School of Medicine at UCLA, Los Angeles, CA

5Department of Epidemiology and Environmental Health, University at Buffalo, The State University of New York, Buffalo, NY

6Center for Health Research NW, Kaiser Permanente, Portland, OR

7Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, NC

8Department of Biochemistry and Molecular Medicine, University of California-Davis, Davis, CA

9Department of Human Genetics and Biomathematics, David Geffen School of Medicine at UCLA, Los Angeles, CA.

Address correspondence to: Carolyn J. Crandall, MD, MS, Professor of Medicine, David Geffen School of Medicine at UCLA, UCLA Medicine/GIM, 911 Broxton Avenue, 1st Floor, Los Angeles, CA 90024. E-mail:

Received 6 July, 2016

Revised 17 August, 2016

Accepted 17 August, 2016

C.H. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of data analysis; study concept and design: C.J.C., J.S.S.; acquisition of data: J.E.M., J.W.-W.; analysis and interpretation of data: all authors; drafting of the manuscript: C.J.C.; critical revision of the manuscript for important intellectual content: all authors; statistical analysis: C.H.; obtained funding: J.E.M., J.W.-W.

Representatives of the National Heart, Lung, and Blood Institute participated in Women's Health Initiative committees that had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparations, review, or approval of the manuscript.

Funding/support: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. J.S.S. is partially funded by NIH grant GM053275 and NSF grant DMS 1264153.

Financial disclosure/conflicts of interest: The following authors have no relevant conflicts of interest to disclose: C.J.C., S.H., J.S.S., M.Z.V., C.H., R.N., J.W.-W., and J.E.M. E.S.L.'s institution has received funding from Amgen Inc, Astrazeneca, Bristol-Meyers-Squibb, and Merck for research projects unrelated to the current manuscript.

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© 2017 by The North American Menopause Society.