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

Abstract

Objective Vasomotor symptoms (VMS, i.e. 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)(SHARe, WHIMS+, GARNET studies, total n= 17,695) of European American (EA), African American (AA), and Hispanic American (HA) postmenopausal women aged 50-79 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.11,078,977 single-nucleotide polymorphisms (SNPs) met the quality criteria. Results After adjustment for covariates and population structure 3 SNPs (on chromosomes 3 and 11) were associated with VMS at the genome-wide threshold of 5 × 10-8 in the AA SHARE GWAS but were not associated in the other cohorts. However, in the meta-analysis, 14 SNPs, all located on chromosome 4 in the tachykinin receptor 3 (TACR3) locus, had p-values of <5×10-8. These SNPs’ effect sizes were similar across studies/participants’ ancestry (OR~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.

Neurokinin 3 Receptor Antagonism Reveals Roles for Neurokinin B in the Regulation of Gonadotropin Secretion and Hot Flashes in Postmenopausal Women

“…In premenopausal women, NKB itself administered as an intravenous infusion over 30 min induced the sensation of heat, which was accompanied by an increased heart rate and skin conductance, resembling events associated with menopausal hot flashes [23]. Moreover, a recent genome-wide association study has localised single nucleotide polymorphisms associated with vasomotor symptoms to the NK3R locus (TAC3R) [35]. Reduced cutaneous vasodilation in rodents with ablation of NKBexpressing neurones [36] and a lowered body core temperature in NK3R antagonist-treated sheep [19] lend further support to the involvement of NKB signalling in hot flashes.…”

Genetic variants in sex hormone pathways and the risk of type 2 diabetes among African American, Hispanic American, and European American postmenopausal women in the US

“…The WHI-SHARe included 8236 AA women (6263 controls, 1973 diabetes cases) and 3497 HA women (2881 controls, 615 diabetes cases) from the WHI CT or OS, who provided consent for DNA analysis. [14][15][16] The WHI-GARNET included 3147 EA women (2127 controls, 1020 diabetes cases) who had been enrolled in the WHI Hormone Therapy trial and who provided consent for DNA analysis (Table 1). Of the approximately 27 000 women who participated in the WHI Hormone Therapy trial, incident diabetes cases and matched controls of EA women who were free of prevalent or incident diabetes, coronary heart disease, stroke, and venous thrombosis were included.…”

Flushing in (neuro)endocrinology

“…More than two thirds of perimenopausal women experience hot flashes which may represent a marker of underlying cardiovascular disease (61); a recent study examined the role of genetic variation in the tachykinin receptor 3 ( TACR3 ) as a contributor to hot flashes (62). Treatment should be individually tailored and includes use of systemic hormone therapy (estrogen +/− progestogen), selective serotonin reuptake inhibitors, gabapentin, clonidine, and other modalities (63,64).…”