A potentially functional variant in the serotonin transporter gene is associated with premenopausal and perimenopausal hot flashes

Abstract

Objective There is a recent increase in using selective serotonin reuptake inhibitors and/or serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs) to relieve menopausal hot flashes (HF). However the response to them is heterogeneous. We hypothesized that this heterogeneity might be partially due to genetic variations in the genes encoding the serotonin and/or norepinephrine transporters (SLC6A4, SLC6A2). As a first step in testing the role of genetics in response to SSRIs/SNRIs, we examined the association between HF and genetic variants within these two genes. Methods We tested 29 haplotype tag SNPs within SLC6A4 and SLC6A2 for their association with HF separately in European American (EA; 396 cases, 392 controls) and African American (AA; 125 cases, 81 controls) pre/peri-menopausal women. Results We found that the minor allele of SLC6A4_rs11080121 was associated with protection against HF (OR=0.75, 95CI=0.60-0.94) only in EA. Bioinformatics analyses indicated that rs11080121 is fully correlated with rs1042173 in the 3’UTR of SLC6A4. The minor allele of rs1042173 seems to disrupt a conserved binding site for hsa-miR-590-3p microRNA. Conclusions Disrupting a microRNA binding site should lead to higher expression of SLC6A4, higher SLC6A4 will lead to depleted serotonin from the synaptic cleft, and that will trigger the presynaptic autoreceptor feedback mechanism to produce more serotonin, which is protective against HF. This is the first study to test the association between HF in both EA and AA pre/peri-menopausal women and genetic variants in two neurotransmitter transporter genes: SLC6A2 and SLC6A4. This information can be used in tailoring pharmaceutical use of SSRIs/SNRIs for HF relief.

Intermittent fasting protects against the deterioration of cognitive function, energy metabolism and dyslipidemia in Alzheimer’s disease-induced estrogen deficient rats

“…Neurotransmitters including serotonin and norepinephrine are also involved in these processes: estrogen deficiency increases norepinephrine levels and serotonin receptors in the hypothalamus. 39,40 The increased serotonin receptors result in lower circulating serotonin levels in the brain, which narrows the thermoneutral zone. 39 The known risk factors for hot flashes are obesity, nicotine, and negative moods.…”

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

“…Candidate gene studies suggest that genetic variants may be associated with VMS, including single-nucleotide polymorphisms (SNPs) in estrogen receptor genes and the estrogen metabolism pathway ( cytochrome P450 [CYP] CYP1A1, CYP1A2, CYP1B1 , and CYP19A1, catechol-O-methyltransferase [COMT], 17-beta-hydroxysteroid dehydrogenase [17HSD], and sulfotransferase A1 [SULT1A1] genes ) 8-16 . Other candidate gene studies have suggested associations of drug metabolism-related SNPs 17, 18 and serotonin transporter SNPs 19 with VMS. Another candidate gene study suggested associations between genes that control angiogenesis ( endothelial nitric oxide synthase [eNOS] and hypoxia inducible factor-1 alpha [HIF1α] ) and VMS 20 .…”

The Midlife Women’s Health Study – a study protocol of a longitudinal prospective study on predictors of menopausal hot flashes

“…The MWHS was conducted between 2006 and 2015 as a prospective longitudinal population-based study of generally healthy midlife women recruited during their menopausal transition. The overall goal of the study was to expand findings from a previous cross-sectional study that was conducted by the same team [8–23], while focusing on the mechanisms by which obesity is associated with an increased risk of hot flashes. Specifically, the MWHS was developed to test the hypothesis that obesity is associated with an increased risk of hot flashes through mechanisms that involve ovarian failure, altered sex steroid hormone levels, and selected genetic polymorphisms.…”