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Catechol-O-Methyltransferase Polymorphism Is Associated With Increased Uterine Leiomyoma Risk in Different Ethnic Groups

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Abstract

Objectives

Uterine leiomyomas (ULMs) are estrogen-dependent tumors that are more common in African American women. The etiology for such ethnic disparity is currently unknown. Catechol-O-methyltransferase (COMT) is an essential enzyme in estrogen metabolism. In the current study, we investigated the association of the functional COMT Val158 Met polymorphism with ULM in different ethnic groups. We also studied the biologic role of COMT in tumor formation in human and rat leiomyoma cell lines and the potential therapeutic utility of COMT inhibitors.

Methods

The genotype frequencies of the functional COMT Val158 Met polymorphism among participants with (186 women) or without (142 women) ULMs were compared, as was the differential ethnic distribution of that polymorphism using polymerase chain reaction (PCR) and restriction fragment linkage polymorphism. Proliferation, Western blot, and reporter trans activation analyses were applied to myometrial and leiomyoma cells representative of different COMT genotypes.

Results

Women with the high-activity COMT Val/Val genotype are 2.5 times more likely to develop ULMs than women with other genotypes (confidence interval, 1.017 to 6.151; P <.001). The prevalence of this genotype was significantly higher in African American women (47%) compared with white (19%) or Hispanic (30%) women (P =.003). Myometrial cell lines expressing the Val/Val genotype exhibited significantly enhanced responses to estrogen in proliferation and in estrogen-responsive element reporter assays. COMT-specific inhibitors reversed such a response and induced apoptosis. Myometrial specimens from Val/Val women demonstrated distinct estrogen-regulated gene expression that was consistent with enhanced proliferation and decreased apoptosis.

Conclusions

The high-activity COMT Val/Val genotype is associated with increased risk of ULM. Our results provide a possible explanation for the higher prevalence of ULMs among African American women and offer a potential new target for nonsurgical treatment using COMT inhibitors. (J Soc Gynecol Investig 2006;13:136-44) Copyright © 2006 by the Society for Gynecologic Investigation.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, University of Texas Medical Branch, 301 University Blvd., Galveston, Texas, 77555, USA

    Ayman Al-Hendy MD, PhD, FRCSC, FACOG & Salama A. Salama PhD

Authors
  1. Ayman Al-Hendy MD, PhD, FRCSC, FACOG
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  2. Salama A. Salama PhD
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Corresponding author

Correspondence to Ayman Al-Hendy MD, PhD, FRCSC, FACOG.

Additional information

Supported by a National Institutes of Health grant to A.A-H. (R01 HD46228).

The authors would like to acknowledge J.L. Simpson for review of the manuscript and Ye Wang for excellent technical assistance.

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Al-Hendy, A., Salama, S.A. Catechol-O-Methyltransferase Polymorphism Is Associated With Increased Uterine Leiomyoma Risk in Different Ethnic Groups. Reprod. Sci. 13, 136–144 (2006). https://doi.org/10.1016/j.jsgi.2005.10.007

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