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Cigarettes, genetic background, and menopausal timing: the presence of single nucleotide polymorphisms in cytochrome P450 genes is associated with increased risk of natural menopause in European-American smokers

Butts, Samantha F. MD, MSCE1,2; Sammel, Mary D. ScD2; Greer, Christine BS3; Rebbeck, Timothy R. PhD2,4; Boorman, David W. MS5; Freeman, Ellen W. PhD1

doi: 10.1097/GME.0000000000000140
Original Articles

Objective This study aims to evaluate associations between variations in genes involved in the metabolism of environmental chemicals and steroid hormones and risk of menopause in smokers.

Methods Survival analysis was performed on 410 eligible participants from the Penn Ovarian Aging study (ongoing for 14 years), a cohort study of late-reproductive-age women. Single nucleotide polymorphisms at the following loci were studied: COMT Val158Met, CYP1B1*4 Asn452Ser, CYP1B1*3 Leu432Val, and CYP3A4*1B.

Results Significant interactions between smoking and single nucleotide polymorphisms were observed in European-American carriers of CYP3A4*1B and CYP1B1*3, supporting a greater risk of menopause entry compared with those not carrying these alleles. Among CYP1B1*3 carriers, smokers had a greater risk of menopause entry than nonsmokers (adjusted hazard ratio [HR], 2.26; 95% CI, 1.4-3.67; median time to menopause, 10.42 and 11.07 y, respectively). No association between smoking and menopause was identified in CYP1B1 wild types. Among CYP3A4*1B carriers, smokers were at greater risk for menopause entry than nonsmokers (adjusted HR, 15.1; 95% CI, 3.31-69.2; median time to menopause, 11.36 and 13.91 y, respectively). Risk of menopause entry in CYP3A4 wild types who smoked was far lower (adjusted HR, 1.59; 95% CI, 1.03-2.44). Heavily smoking CYP1B1*3 carriers (adjusted HR, 3.0; 95% CI, 1.54-5.84; median time to menopause, 10.41 y) and heavily smoking CYP3A4*1B carriers (adjusted HR, 17.79; 95% CI, 3.21-98.65; median time to menopause, 5.09 y) had the greatest risk of menopause entry.

Conclusions Our finding that the risk of menopause entry in European-American smokers varies depending on genetic background represents a novel gene-environment interaction in reproductive aging.

Supplemental Digital Content is available in the text.

From the 1Department of Obstetrics and Gynecology, and 2Center for Clinical Epidemiology and Biostatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; 3University of Miami School of Medicine, Miami, FL; 4Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; and 5Drexel University School of Medicine, Philadelphia, PA.

Received July 25, 2013; revised and accepted September 26, 2013.

This paper was presented as an oral presentation at the 60th Annual Scientific. Meeting of the Society for Gynecologic Investigation, Orlando, FL, March 20 to 23, 2013.

Funding/support: This study was supported by National Institutes of Health grant R01-AG-12745 to E.W.F., National Institute of Environmental Health Sciences grant 5P30ES013508-07 to S.F.B., Perelman School of Medicine Center of Excellence for Diversity grant to S.F.B., and Perelman School of Medicine Translational and Clinical Research Center grant RR024134 to E.W.F.

Financial disclosure/conflicts of interest: M.D.S. serves as a paid consultant for Swiss Precision Diagnostics. E.W.F. has previously received grant support from Forest and Xenodyne Pharmaceuticals. S.F.B., T.R.R., C.G., and D.W.B. declare no conflicts of interest.

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Address correspondence to: Samantha F. Butts, MD, MSCE, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Suite 800, 3701 Market Street, Philadelphia, PA 19104. E-mail:

© 2014 by The North American Menopause Society.