Effect of CYP1A1 gene polymorphisms on estrogen metabolism and bone density

Nicola Napoli, Dennis T. Villareal, Steven Mumm, Linda Halstead, Sharmin Sheikh, Manuel Cagaanan, Giovam Battista Rini, Reina C. Armamento-Villareal

Research output: Contribution to journalArticle

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Abstract

In this study, we evaluated the effect of polymorphisms of the CYP1A1 gene, linked to hormone-related cancers, on estrogen metabolism and BMD. We found that variants carrying the A allele (CA and AA) for the C4887A polymorphism have a significantly higher degree of estrogen catabolism and lower femoral BMD. Introduction: Polymorphisms of the CYP1A1 gene, one of the key enzymes that metabolize estrogen, have been linked with hormone-related cancers. We investigated the impact of these polymorphisms on estrogen metabolism and BMD, which is another hormone-dependent health issue. Materials and Methods: One hundred seventy postmenopausal women (mean age, 63.5 ± 0.6 years) participated in the study, but analysis was limited to 156 white women. Genotyping was performed by restriction fragment length polymorphism analysis, urinary estrogen metabolites by enzyme immunoassay, serum estradiol by ultrasensitive radioimmunoassay, serum sex hormone-binding globulin by immunoradiometric assay, and BMD by DXA. Differences in the levels of urinary metabolites and BMD among the different variants were analyzed by analysis of covariance, whereas differences in free estradiol index, urinary N-telopeptide of type 1 collagen (NTx), and bone size were compared by one-way ANOVA. Results: We found that subjects carrying the A allele (CA or AA) for the C4887A polymorphism of the CYP1A1 gene have significantly lower free estradiol index (0.323 ± 0.08 versus 0.506 ± 0.04; p = 0.04; pmol/nmol) and higher levels of total urinary estrogen metabolites (ng/mg Cr) than CC subjects (27.92 ± 2.03 versus 21.15 ± 1.04; p = 0.03), suggestive of an accelerated estrogen catabolism in these (CA + AA) individuals. They also had significantly lower BMD (g/cm2) in all regions of the femur than subjects with the CC genotype, (total hip: 0.809 ± 0.02 versus 0.865 ± 0.01; neck: 0.671 ± 0.02 versus 0.722 ± 0.01; trochanter: 0.614 ± 0.02 versus 0.656 ± 0.01; and intertrochanter: 0.969 ± 0.03 versus 1.039 ± 0.01; all p <0.05). No significant effect of this gene polymorphism was detected on lumbar spine BMD. Urinary NTx, a marker for bone resorption, was also significantly higher in the CA + AA compared with the CC variants (186.09 ± 16.15 versus 124.00 ± 11.87 nmol of bone collagen equivalent/mmol of creatinine; p = 0.003). Genotype frequencies for this polymorphism showed CC as the most common genotype (127/156), followed by CA (28/156), whereas AA was rare (1/156). Conclusion: Women with the A allele seem to have increased estrogen catabolism, as indicated by higher urinary estrogen metabolites and lower free estradiol index. This is associated with increased bone resorption and lower femoral BMD in those with the A allele. Our data, therefore, suggest that, through its effect on the rate of estrogen catabolism, the C4887A polymorphism of the CYP1A1 gene may represent a possible genetic risk factor for osteoporosis.

Original languageEnglish
Pages (from-to)232-239
Number of pages8
JournalJournal of Bone and Mineral Research
Volume20
Issue number2
DOIs
Publication statusPublished - Feb 2005

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Cytochrome P-450 CYP1A1
Bone Density
Estrogens
Genes
Estradiol
Alleles
Genotype
Hormones
Bone Resorption
Thigh
Femur
Immunoradiometric Assay
Bone and Bones
Serum Globulins
Sex Hormone-Binding Globulin
Collagen Type I
Immunoenzyme Techniques
Restriction Fragment Length Polymorphisms
Osteoporosis
Radioimmunoassay

Keywords

  • Epidemiology
  • Genetic research
  • Hormones and receptors
  • Menopause
  • Osteoporosis

ASJC Scopus subject areas

  • Surgery

Cite this

Napoli, N., Villareal, D. T., Mumm, S., Halstead, L., Sheikh, S., Cagaanan, M., ... Armamento-Villareal, R. C. (2005). Effect of CYP1A1 gene polymorphisms on estrogen metabolism and bone density. Journal of Bone and Mineral Research, 20(2), 232-239. https://doi.org/10.1359/JBMR.041110

Effect of CYP1A1 gene polymorphisms on estrogen metabolism and bone density. / Napoli, Nicola; Villareal, Dennis T.; Mumm, Steven; Halstead, Linda; Sheikh, Sharmin; Cagaanan, Manuel; Rini, Giovam Battista; Armamento-Villareal, Reina C.

In: Journal of Bone and Mineral Research, Vol. 20, No. 2, 02.2005, p. 232-239.

Research output: Contribution to journalArticle

Napoli, N, Villareal, DT, Mumm, S, Halstead, L, Sheikh, S, Cagaanan, M, Rini, GB & Armamento-Villareal, RC 2005, 'Effect of CYP1A1 gene polymorphisms on estrogen metabolism and bone density', Journal of Bone and Mineral Research, vol. 20, no. 2, pp. 232-239. https://doi.org/10.1359/JBMR.041110
Napoli N, Villareal DT, Mumm S, Halstead L, Sheikh S, Cagaanan M et al. Effect of CYP1A1 gene polymorphisms on estrogen metabolism and bone density. Journal of Bone and Mineral Research. 2005 Feb;20(2):232-239. https://doi.org/10.1359/JBMR.041110
Napoli, Nicola ; Villareal, Dennis T. ; Mumm, Steven ; Halstead, Linda ; Sheikh, Sharmin ; Cagaanan, Manuel ; Rini, Giovam Battista ; Armamento-Villareal, Reina C. / Effect of CYP1A1 gene polymorphisms on estrogen metabolism and bone density. In: Journal of Bone and Mineral Research. 2005 ; Vol. 20, No. 2. pp. 232-239.
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T1 - Effect of CYP1A1 gene polymorphisms on estrogen metabolism and bone density

AU - Napoli, Nicola

AU - Villareal, Dennis T.

AU - Mumm, Steven

AU - Halstead, Linda

AU - Sheikh, Sharmin

AU - Cagaanan, Manuel

AU - Rini, Giovam Battista

AU - Armamento-Villareal, Reina C.

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N2 - In this study, we evaluated the effect of polymorphisms of the CYP1A1 gene, linked to hormone-related cancers, on estrogen metabolism and BMD. We found that variants carrying the A allele (CA and AA) for the C4887A polymorphism have a significantly higher degree of estrogen catabolism and lower femoral BMD. Introduction: Polymorphisms of the CYP1A1 gene, one of the key enzymes that metabolize estrogen, have been linked with hormone-related cancers. We investigated the impact of these polymorphisms on estrogen metabolism and BMD, which is another hormone-dependent health issue. Materials and Methods: One hundred seventy postmenopausal women (mean age, 63.5 ± 0.6 years) participated in the study, but analysis was limited to 156 white women. Genotyping was performed by restriction fragment length polymorphism analysis, urinary estrogen metabolites by enzyme immunoassay, serum estradiol by ultrasensitive radioimmunoassay, serum sex hormone-binding globulin by immunoradiometric assay, and BMD by DXA. Differences in the levels of urinary metabolites and BMD among the different variants were analyzed by analysis of covariance, whereas differences in free estradiol index, urinary N-telopeptide of type 1 collagen (NTx), and bone size were compared by one-way ANOVA. Results: We found that subjects carrying the A allele (CA or AA) for the C4887A polymorphism of the CYP1A1 gene have significantly lower free estradiol index (0.323 ± 0.08 versus 0.506 ± 0.04; p = 0.04; pmol/nmol) and higher levels of total urinary estrogen metabolites (ng/mg Cr) than CC subjects (27.92 ± 2.03 versus 21.15 ± 1.04; p = 0.03), suggestive of an accelerated estrogen catabolism in these (CA + AA) individuals. They also had significantly lower BMD (g/cm2) in all regions of the femur than subjects with the CC genotype, (total hip: 0.809 ± 0.02 versus 0.865 ± 0.01; neck: 0.671 ± 0.02 versus 0.722 ± 0.01; trochanter: 0.614 ± 0.02 versus 0.656 ± 0.01; and intertrochanter: 0.969 ± 0.03 versus 1.039 ± 0.01; all p <0.05). No significant effect of this gene polymorphism was detected on lumbar spine BMD. Urinary NTx, a marker for bone resorption, was also significantly higher in the CA + AA compared with the CC variants (186.09 ± 16.15 versus 124.00 ± 11.87 nmol of bone collagen equivalent/mmol of creatinine; p = 0.003). Genotype frequencies for this polymorphism showed CC as the most common genotype (127/156), followed by CA (28/156), whereas AA was rare (1/156). Conclusion: Women with the A allele seem to have increased estrogen catabolism, as indicated by higher urinary estrogen metabolites and lower free estradiol index. This is associated with increased bone resorption and lower femoral BMD in those with the A allele. Our data, therefore, suggest that, through its effect on the rate of estrogen catabolism, the C4887A polymorphism of the CYP1A1 gene may represent a possible genetic risk factor for osteoporosis.

AB - In this study, we evaluated the effect of polymorphisms of the CYP1A1 gene, linked to hormone-related cancers, on estrogen metabolism and BMD. We found that variants carrying the A allele (CA and AA) for the C4887A polymorphism have a significantly higher degree of estrogen catabolism and lower femoral BMD. Introduction: Polymorphisms of the CYP1A1 gene, one of the key enzymes that metabolize estrogen, have been linked with hormone-related cancers. We investigated the impact of these polymorphisms on estrogen metabolism and BMD, which is another hormone-dependent health issue. Materials and Methods: One hundred seventy postmenopausal women (mean age, 63.5 ± 0.6 years) participated in the study, but analysis was limited to 156 white women. Genotyping was performed by restriction fragment length polymorphism analysis, urinary estrogen metabolites by enzyme immunoassay, serum estradiol by ultrasensitive radioimmunoassay, serum sex hormone-binding globulin by immunoradiometric assay, and BMD by DXA. Differences in the levels of urinary metabolites and BMD among the different variants were analyzed by analysis of covariance, whereas differences in free estradiol index, urinary N-telopeptide of type 1 collagen (NTx), and bone size were compared by one-way ANOVA. Results: We found that subjects carrying the A allele (CA or AA) for the C4887A polymorphism of the CYP1A1 gene have significantly lower free estradiol index (0.323 ± 0.08 versus 0.506 ± 0.04; p = 0.04; pmol/nmol) and higher levels of total urinary estrogen metabolites (ng/mg Cr) than CC subjects (27.92 ± 2.03 versus 21.15 ± 1.04; p = 0.03), suggestive of an accelerated estrogen catabolism in these (CA + AA) individuals. They also had significantly lower BMD (g/cm2) in all regions of the femur than subjects with the CC genotype, (total hip: 0.809 ± 0.02 versus 0.865 ± 0.01; neck: 0.671 ± 0.02 versus 0.722 ± 0.01; trochanter: 0.614 ± 0.02 versus 0.656 ± 0.01; and intertrochanter: 0.969 ± 0.03 versus 1.039 ± 0.01; all p <0.05). No significant effect of this gene polymorphism was detected on lumbar spine BMD. Urinary NTx, a marker for bone resorption, was also significantly higher in the CA + AA compared with the CC variants (186.09 ± 16.15 versus 124.00 ± 11.87 nmol of bone collagen equivalent/mmol of creatinine; p = 0.003). Genotype frequencies for this polymorphism showed CC as the most common genotype (127/156), followed by CA (28/156), whereas AA was rare (1/156). Conclusion: Women with the A allele seem to have increased estrogen catabolism, as indicated by higher urinary estrogen metabolites and lower free estradiol index. This is associated with increased bone resorption and lower femoral BMD in those with the A allele. Our data, therefore, suggest that, through its effect on the rate of estrogen catabolism, the C4887A polymorphism of the CYP1A1 gene may represent a possible genetic risk factor for osteoporosis.

KW - Epidemiology

KW - Genetic research

KW - Hormones and receptors

KW - Menopause

KW - Osteoporosis

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