Catechol-O-methyltransferase polymorphism is associated with increased uterine leiomyoma risk in different ethnic groups

Ayman Al-Hendy, Salama A. Salama

Research output: Contribution to journalArticle

78 Citations (Scopus)

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 Val158Met 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 Val158Met 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 transactivation 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.

Original languageEnglish (US)
Pages (from-to)136-144
Number of pages9
JournalJournal of the Society for Gynecologic Investigation
Volume13
Issue number2
DOIs
StatePublished - Feb 1 2006

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Catechol O-Methyltransferase
Leiomyoma
Ethnic Groups
Genotype
Estrogens
African Americans
Apoptosis
Cell Line
Hispanic Americans
Transcriptional Activation
Neoplasms
Western Blotting
Confidence Intervals
Gene Expression
Polymerase Chain Reaction

Keywords

  • COMT
  • Estrogen
  • Ethnicity
  • Uterine leiomyoma

ASJC Scopus subject areas

  • Obstetrics and Gynecology

Cite this

Catechol-O-methyltransferase polymorphism is associated with increased uterine leiomyoma risk in different ethnic groups. / Al-Hendy, Ayman; Salama, Salama A.

In: Journal of the Society for Gynecologic Investigation, Vol. 13, No. 2, 01.02.2006, p. 136-144.

Research output: Contribution to journalArticle

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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 Val158Met 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 Val158Met 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 transactivation 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.",
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