title: A potentially functional variant in the serotonin transporter gene is associated with premenopausal and perimenopausal hot flashes.
abstract: 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.
authors.affiliation: From the 1Department of Medicine, School of Medicine, University of Maryland, Baltimore, MD; 2Department of Comparative Biosciences, University of Illinois, Urbana, IL; and Departments of 3Epidemiology and Public Health and 4Anatomy and Neurobiology, School of Medicine, University of Maryland, Baltimore, MD.
authors.forename: May E
authors.initials: ME
authors.lastname: Montasser
authors.forename: Ayelet
authors.initials: A
authors.lastname: Ziv-Gal
authors.forename: Jessica P
authors.initials: JP
authors.lastname: Brown
authors.forename: Jodi A
authors.initials: JA
authors.lastname: Flaws
authors.forename: Istvan
authors.initials: I
authors.lastname: Merchenthaler
mesh_terms: D001741:Black or African American / Q000235:genetics; D000483:Alleles; D001665:Binding Sites / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D006239:Haplotypes; D019584:Hot Flashes / Q000235:genetics*; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism; D008875:Middle Aged; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000235:genetics; D047648:Perimenopause / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017697:Premenopause / Q000502:physiology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: C568221:MIRN590 microRNA, human; D035683:MicroRNAs; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493227:SLC6A2 protein, human; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins