The Val432Leu polymorphism of the CYP1B1 gene is associated with differences in estrogen metabolism and bone density

Nicola Napoli, Giovam Battista Rini, Daniel Serber, Tusar Giri, Jayasree Yarramaneni, Salvatore Bucchieri, Lawrence Camarda, Gaetana Di Fede, Marcello Rosolino Camarda, Sudahansu Jain, Steven Mumm, Reina Armamento-Villareal

Research output: Contribution to journalArticle

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Abstract

Polymorphisms of the CYP450 genes that encode for the enzymes that metabolize estrogen are linked to hormone-related cancers. We investigated the impact of two polymorphisms of the CYP1B1 gene previously reported to be associated with hormone-related disorders on estrogen metabolism and bone mineral density (BMD), another hormone-dependent condition, in women from different ethnic backgrounds. Four hundred sixty-eight postmenopausal Caucasian women, 220 from St. Louis, MO, USA (mean age = 63.5 ± 0.53 years) and 248 from Palermo, Italy (mean age = 72.9 ± 0.44 years) participated in the study. Measurements of urinary estrogen metabolites by enzyme-linked immunoassay, serum estradiol by ultrasensitive radioimmnunoassay, and serum sex hormone-binding globulin by immunoradiometric assay were performed only in the American women, while BMD by dual energy X-ray absorptiometry and genotyping by pyrosequencing were performed in both American and Italian women. Differences in the levels of metabolites, free estradiol index and BMD were analyzed by analysis of covariance. Analysis among the American participants for the Valine432Leucine polymorphism showed that, compared to women with the Val/Val genotype, women with the Leu allele (Val/Leu and Leu/Leu) had significantly higher log-transformed values of total urinary estrogen metabolite (ng/mg-creatinine) levels (1.23 ± 0.04, 1.35 ± 0.02, and 1.34 ± 0.03; p = 0.03), and significantly lower BMD (gm/cm2) in the lumbar spine (1.009 ± 0.02, 0.955 ± 0.01 and 0.931 ± 0.02; p = 0.03) and the femoral neck (0.748 ± 0.02, 0.717 ± 0.01 and 0.693 ± 001, p = 0.03) for the Val/Val, Val/Leu and Leu/Leu genotypes respectively. There were no significant differences in the urinary metabolites and BMD in the different genotypes for the Alanine119Serine polymorphism among the American women. Meanwhile, a separate analysis among the Italian women revealed no significant differences in BMD among the different genotypes for the two polymorphisms investigated. In conclusion, women with the Leu allele for the CYP1B1 Val432polymorphism have increased estrogen catabolism, as indicated by higher urinary estrogen metabolites, compared to those with Val/Val genotype. This may lead to relative hypoestrogenism and lower BMD in the lumbar spine and femoral neck in these women. Our data suggest that through its effect on the rate of estrogen catabolism, the Val432Leu polymorphism of the CYP1B1 gene may represent as a possible genetic risk factor for osteoporosis in American women.

Original languageEnglish
Pages (from-to)442-448
Number of pages7
JournalBone
Volume44
Issue number3
DOIs
Publication statusPublished - Mar 2009

Fingerprint

Bone Density
Estrogens
Genes
Genotype
Femur Neck
Hormones
Estradiol
Spine
Alleles
Immunoradiometric Assay
Serum Globulins
Sex Hormone-Binding Globulin
Photon Absorptiometry
Immunoenzyme Techniques
Italy
Osteoporosis
Creatinine
Enzymes

Keywords

  • Epidemiology
  • Genetic research
  • Hormone
  • Menopause
  • Osteoporosis
  • Receptors

ASJC Scopus subject areas

  • Physiology
  • Endocrinology, Diabetes and Metabolism
  • Histology

Cite this

Napoli, N., Rini, G. B., Serber, D., Giri, T., Yarramaneni, J., Bucchieri, S., ... Armamento-Villareal, R. (2009). The Val432Leu polymorphism of the CYP1B1 gene is associated with differences in estrogen metabolism and bone density. Bone, 44(3), 442-448. https://doi.org/10.1016/j.bone.2008.09.018

The Val432Leu polymorphism of the CYP1B1 gene is associated with differences in estrogen metabolism and bone density. / Napoli, Nicola; Rini, Giovam Battista; Serber, Daniel; Giri, Tusar; Yarramaneni, Jayasree; Bucchieri, Salvatore; Camarda, Lawrence; Di Fede, Gaetana; Camarda, Marcello Rosolino; Jain, Sudahansu; Mumm, Steven; Armamento-Villareal, Reina.

In: Bone, Vol. 44, No. 3, 03.2009, p. 442-448.

Research output: Contribution to journalArticle

Napoli, N, Rini, GB, Serber, D, Giri, T, Yarramaneni, J, Bucchieri, S, Camarda, L, Di Fede, G, Camarda, MR, Jain, S, Mumm, S & Armamento-Villareal, R 2009, 'The Val432Leu polymorphism of the CYP1B1 gene is associated with differences in estrogen metabolism and bone density', Bone, vol. 44, no. 3, pp. 442-448. https://doi.org/10.1016/j.bone.2008.09.018
Napoli, Nicola ; Rini, Giovam Battista ; Serber, Daniel ; Giri, Tusar ; Yarramaneni, Jayasree ; Bucchieri, Salvatore ; Camarda, Lawrence ; Di Fede, Gaetana ; Camarda, Marcello Rosolino ; Jain, Sudahansu ; Mumm, Steven ; Armamento-Villareal, Reina. / The Val432Leu polymorphism of the CYP1B1 gene is associated with differences in estrogen metabolism and bone density. In: Bone. 2009 ; Vol. 44, No. 3. pp. 442-448.
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T1 - The Val432Leu polymorphism of the CYP1B1 gene is associated with differences in estrogen metabolism and bone density

AU - Napoli, Nicola

AU - Rini, Giovam Battista

AU - Serber, Daniel

AU - Giri, Tusar

AU - Yarramaneni, Jayasree

AU - Bucchieri, Salvatore

AU - Camarda, Lawrence

AU - Di Fede, Gaetana

AU - Camarda, Marcello Rosolino

AU - Jain, Sudahansu

AU - Mumm, Steven

AU - Armamento-Villareal, Reina

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N2 - Polymorphisms of the CYP450 genes that encode for the enzymes that metabolize estrogen are linked to hormone-related cancers. We investigated the impact of two polymorphisms of the CYP1B1 gene previously reported to be associated with hormone-related disorders on estrogen metabolism and bone mineral density (BMD), another hormone-dependent condition, in women from different ethnic backgrounds. Four hundred sixty-eight postmenopausal Caucasian women, 220 from St. Louis, MO, USA (mean age = 63.5 ± 0.53 years) and 248 from Palermo, Italy (mean age = 72.9 ± 0.44 years) participated in the study. Measurements of urinary estrogen metabolites by enzyme-linked immunoassay, serum estradiol by ultrasensitive radioimmnunoassay, and serum sex hormone-binding globulin by immunoradiometric assay were performed only in the American women, while BMD by dual energy X-ray absorptiometry and genotyping by pyrosequencing were performed in both American and Italian women. Differences in the levels of metabolites, free estradiol index and BMD were analyzed by analysis of covariance. Analysis among the American participants for the Valine432Leucine polymorphism showed that, compared to women with the Val/Val genotype, women with the Leu allele (Val/Leu and Leu/Leu) had significantly higher log-transformed values of total urinary estrogen metabolite (ng/mg-creatinine) levels (1.23 ± 0.04, 1.35 ± 0.02, and 1.34 ± 0.03; p = 0.03), and significantly lower BMD (gm/cm2) in the lumbar spine (1.009 ± 0.02, 0.955 ± 0.01 and 0.931 ± 0.02; p = 0.03) and the femoral neck (0.748 ± 0.02, 0.717 ± 0.01 and 0.693 ± 001, p = 0.03) for the Val/Val, Val/Leu and Leu/Leu genotypes respectively. There were no significant differences in the urinary metabolites and BMD in the different genotypes for the Alanine119Serine polymorphism among the American women. Meanwhile, a separate analysis among the Italian women revealed no significant differences in BMD among the different genotypes for the two polymorphisms investigated. In conclusion, women with the Leu allele for the CYP1B1 Val432polymorphism have increased estrogen catabolism, as indicated by higher urinary estrogen metabolites, compared to those with Val/Val genotype. This may lead to relative hypoestrogenism and lower BMD in the lumbar spine and femoral neck in these women. Our data suggest that through its effect on the rate of estrogen catabolism, the Val432Leu polymorphism of the CYP1B1 gene may represent as a possible genetic risk factor for osteoporosis in American women.

AB - Polymorphisms of the CYP450 genes that encode for the enzymes that metabolize estrogen are linked to hormone-related cancers. We investigated the impact of two polymorphisms of the CYP1B1 gene previously reported to be associated with hormone-related disorders on estrogen metabolism and bone mineral density (BMD), another hormone-dependent condition, in women from different ethnic backgrounds. Four hundred sixty-eight postmenopausal Caucasian women, 220 from St. Louis, MO, USA (mean age = 63.5 ± 0.53 years) and 248 from Palermo, Italy (mean age = 72.9 ± 0.44 years) participated in the study. Measurements of urinary estrogen metabolites by enzyme-linked immunoassay, serum estradiol by ultrasensitive radioimmnunoassay, and serum sex hormone-binding globulin by immunoradiometric assay were performed only in the American women, while BMD by dual energy X-ray absorptiometry and genotyping by pyrosequencing were performed in both American and Italian women. Differences in the levels of metabolites, free estradiol index and BMD were analyzed by analysis of covariance. Analysis among the American participants for the Valine432Leucine polymorphism showed that, compared to women with the Val/Val genotype, women with the Leu allele (Val/Leu and Leu/Leu) had significantly higher log-transformed values of total urinary estrogen metabolite (ng/mg-creatinine) levels (1.23 ± 0.04, 1.35 ± 0.02, and 1.34 ± 0.03; p = 0.03), and significantly lower BMD (gm/cm2) in the lumbar spine (1.009 ± 0.02, 0.955 ± 0.01 and 0.931 ± 0.02; p = 0.03) and the femoral neck (0.748 ± 0.02, 0.717 ± 0.01 and 0.693 ± 001, p = 0.03) for the Val/Val, Val/Leu and Leu/Leu genotypes respectively. There were no significant differences in the urinary metabolites and BMD in the different genotypes for the Alanine119Serine polymorphism among the American women. Meanwhile, a separate analysis among the Italian women revealed no significant differences in BMD among the different genotypes for the two polymorphisms investigated. In conclusion, women with the Leu allele for the CYP1B1 Val432polymorphism have increased estrogen catabolism, as indicated by higher urinary estrogen metabolites, compared to those with Val/Val genotype. This may lead to relative hypoestrogenism and lower BMD in the lumbar spine and femoral neck in these women. Our data suggest that through its effect on the rate of estrogen catabolism, the Val432Leu polymorphism of the CYP1B1 gene may represent as a possible genetic risk factor for osteoporosis in American women.

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KW - Genetic research

KW - Hormone

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KW - Osteoporosis

KW - Receptors

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