Kate Johnson

October 13, 2015

LAS VEGAS — Postmenopausal women who have variations in the gene that codes for tachykinin receptor 3 are more likely to experience vasomotor symptoms than women without those gene variations, according to a genome-wide association study.

"Although these results are not conclusive, because we still don't clearly understand the biology that is responsible for vasomotor symptoms, these results open new pathways for investigating the biological mechanisms underlying symptoms," said lead investigator Carolyn Crandall, MD, from the University of California, Los Angeles.

"If other studies confirm a role for the tachykinin receptor 3, these results could lead to new drug targets to help manage severe vasomotor symptoms, she added.

The results of the study were reported here at the North American Menopause Society 2015 Annual Meeting.

In a genome-wide association study, markers in the complete sets of DNA, or genomes, of many people are quickly scanned to look for genetic variations associated with a particular disease, Dr Crandall explained.

"To our knowledge, this is the first genome-wide study that has investigated genetic variation in relation to vasomotor symptoms in a large cohort of postmenopausal women in the United States," she told Medscape Medical News.

The study involved baseline genotype samples from 17,695 women enrolled in three Women's Health Initiative genetic studies. The GARNET and WHIMS+ studies involved women of European descent, and the SHARE study involved women of black and Hispanic descent.

The investigators evaluated more than 19 million single-nucleotide polymorphisms (SNPs) for the presence or absence of vasomotor symptoms.

Table. Characteristics of the Women Analyzed

Variable Black Women Hispanic Women White Women in GARNET White Women in WHIMS+
Mean age, years 61.3 60.2 65.7 68.2
Vasomotor symptoms, % 77.3 67.5 65.1 62.3


Overall, 39.3% of the women reported using hormone therapy at some time, and 19.0% reported undergoing bilateral oophorectomy. Current smoking was unusual, at 9.6%, as was the consumption of more than one alcoholic drink per day, at 8.7%. And 33.3% of the women had at least a college education.

"The models were adjusted for the usual suspects — covariates that were strongly associated with vasomotor symptoms in previous studies," said Dr Crandall. This included bilateral oophorectomy, age, smoking, alcohol intake, physical activity, population structure, body mass index, education, income, and menopausal estrogen therapy.

A number of SNPs on chromosome 4 were found to be associated with vasomotor symptoms. In fact, the odds of vasomotor symptoms was increased 1.4 to 1.6 times for each of these SNPs, Dr Crandall reported.

"All of these SNPs were on the tachykinin receptor 3 gene, which is implicated in the secretion of gonadotropin-releasing hormone [GNRH] and found in the arcuate nucleus, where it feeds back to the GNRH pulse generation," she explained.

It's very exciting to finally see the first genome-wide association study for such an important and understudied trait.

"Mutations in this tachykinin receptor 3 gene cause understimulation of GNRH, leading to hypogonadism in animal studies, so it seems to make biological sense," said Dr Crandall. "However, this is the first genome-wide association study, so we have to be cautious in our interpretation."

"It's very exciting to finally see the first genome-wide association study for such an important and understudied trait," said May Montasser, PhD, from the University of Maryland School of Medicine in Baltimore, who was involved in a recent study on a potentially functional variant in the serotonin transporter gene associated with vasomotor symptoms (Menopause. 2015;22:108-113).

"However, the study identified only one signal. A whole-genome sequencing analysis is warranted to identify all common and rare genetic determinants of hot flashes," she told Medscape Medical News. "This information will be very valuable in understanding the underlying biological mechanism and pointing to new therapeutic targets."

Dr Crandall and Dr Montasser have disclosed no relevant financial relationships.

North American Menopause Society (NAMS) 2015 Annual Meeting: Abstract S-11. Presented October 2, 2015.


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