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

May E. Montasser, Ayelet Ziv-Gal, Jessica P. Brown, Jodi A. Flaws, Istvan Merchenthaler

Research output: Contribution to journalArticlepeer-review


Objective: An increase in the use of selective serotonin reuptake inhibitors (SSRIs) and/or serotonin-norepinephrine reuptake inhibitors (SNRIs) to relieve menopausal hot flashes (HFs) has been observed recently. However, response to them has been heterogeneous. We hypothesized that this heterogeneity might be partially attributed to genetic variations in genes encoding the serotonin and/or norepinephrine transporters (SLC6A4 and SLC6A2). As a first step in testing the role of genetics in response to SSRIs/SNRIs, we examined the association between HFs and genetic variants within these two genes.

Methods: We tested 29 haplotype-tagging single nucleotide polymorphisms within SLC6A4 and SLC6A2 for their association with HFs separately for European-American (396 cases and 392 controls) and African-American (125 cases and 81 controls) premenopausal and perimenopausal women.

Results: We found that the minor allele of SLC6A4-rs11080121 was associated with protection against HFs (odds ratio, 0.75; 95% CI, 0.60-0.94) only in European-American women. Bioinformatics analyses indicated that rs11080121 is fully correlated with rs1042173 in the 3′ untranslated region of SLC6A4. The minor allele of rs1042173 seems to disrupt a conserved binding site for hsa-miR-590-3p microRNA.

Conclusions: Disruption of a microRNA binding site leads to higher expression of SLC6A4, higher expression of SLC6A4 leads to depletion of serotonin in synaptic clefts, and depletion of serotonin triggers the presynaptic autoreceptor feedback mechanism to produce more serotonin, which is protective against HFs. This is the first study to test the association between HFs in both European-American and African-American premenopausal and perimenopausal women and genetic variants in two neurotransmitter transporter genes, SLC6A2 and SLC6A4. This information can be used in tailoring the pharmaceutical use of SSRIs/SNRIs for HF relief.

Original languageEnglish (US)
Pages (from-to)108-113
Number of pages6
Issue number1
StatePublished - Jan 3 2015
Externally publishedYes


  • Hot flashes
  • Menopause
  • Selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors
  • SLC6A2
  • SLC6A4

ASJC Scopus subject areas

  • Obstetrics and Gynecology


Dive into the research topics of 'A potentially functional variant in the serotonin transporter gene is associated with premenopausal and perimenopausal hot flashes'. Together they form a unique fingerprint.

Cite this