title: Joint effects of smoking and gene variants involved in sex steroid metabolism on hot flashes in late reproductive-age women.
abstract: BACKGROUND
  Although smoking has a known association with hot flashes, the factors distinguishing smokers at greatest risk for menopausal symptoms have not been well delineated. Recent evidence supports a relationship between menopausal symptoms and variants in several genes encoding enzymes that metabolize substrates such as sex steriods, xenobiotics, and catechols. It is currently not known whether the impact of smoking on hot flashes is modified by the presence of such variants.
  
  
  OBJECTIVE
  The objective of the study was to investigate the relationship between smoking and hot flash occurrence as a function of genetic variation in sex steroid-metabolizing enzymes.
  
  
  METHODS
  A cross-sectional analysis of data from the Penn Ovarian Aging study, an ongoing population-based cohort of late reproductive-aged women, was performed. Smoking behavior was characterized. Single-nucleotide polymorphisms in five genes were investigated: COMT Val158Met (rs4680), CYP1A2*1F (rs762551), CYP1B1*4 (Asn452Ser, rs1800440), CYP1B1*3 (Leu432Val, rs1056836), and CYP3A4*1B (rs2740574).
  
  
  RESULTS
  Compared with nonsmokers, European-American COMT Val158Met double-variant carriers who smoked had increased odds of hot flashes [adjusted odds ratio (AOR) 6.15, 95% confidence interval (CI) 1.32-28.78)]; European-American COMT Val158Met double-variant carriers who smoked heavily had more frequent moderate or severe hot flashes than nonsmokers (AOR 13.7, 95% CI 1.2-154.9). European-American CYP 1B1*3 double-variant carriers who smoked described more frequent moderate or severe hot flashes than nonsmoking (AOR 20.6, 95% CI 1.64-257.93) and never-smoking (AOR 20.59, 95% CI 1.39-304.68) carriers, respectively. African-American single-variant CYP 1A2 carriers who smoked were more likely to report hot flashes than the nonsmoking carriers (AOR 6.16, 95% CI 1.11-33.91).
  
  
  CONCLUSIONS
  This is the first report demonstrating the effects of smoking within the strata of gene variants involved in sex steroid metabolism on hot flashes in late reproductive-age women. The identification of individuals with a genetic susceptibility to smoking-related menopausal symptoms could contribute to interventions targeted at reducing reproductive morbidity both in the menopause and across the reproductive life course.
authors.affiliation: Division of Infertility and Reproductive Endocrinology, Perelman School of Medicine, University of Pennsylvania, 3701 Market Street, Suite 800, Philadelphia, Pennsylvania 19104, USA. sbutts@obgyn.upenn.edu
authors.forename: Samantha F
authors.initials: SF
authors.lastname: Butts
authors.forename: Ellen W
authors.initials: EW
authors.lastname: Freeman
authors.forename: Mary D
authors.initials: MD
authors.lastname: Sammel
authors.forename: Kaila
authors.initials: K
authors.lastname: Queen
authors.forename: Hui
authors.initials: H
authors.lastname: Lin
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Rebbeck
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D044383:Black People / Q000235:genetics / Q000706:statistics & numerical data; D002394:Catechol O-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics* / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D005260:Female; D014644:Genetic Variation; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D019584:Hot Flashes / Q000453:epidemiology* / Q000235:genetics; D006801:Humans; D008593:Menopause / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009017:Morbidity; D017698:Postmenopause / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D012907:Smoking / Q000453:epidemiology*; D044465:White People / Q000235:genetics / Q000706:statistics & numerical data; D001741:Black or African American
chemical_list: D012739:Gonadal Steroid Hormones; D001189:Aryl Hydrocarbon Hydroxylases; C504573:CYP1A2 protein, human; C585496:CYP1B1 protein, human; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D002394:Catechol O-Methyltransferase