title: Effect of CYP1A1 gene polymorphisms on estrogen metabolism and bone density.
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.
  
  
  BACKGROUND
  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.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Bone and Mineral Diseases, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Napoli
authors.forename: Dennis T
authors.initials: DT
authors.lastname: Villareal
authors.forename: Steven
authors.initials: S
authors.lastname: Mumm
authors.forename: Linda
authors.initials: L
authors.lastname: Halstead
authors.forename: Sharmin
authors.initials: S
authors.lastname: Sheikh
authors.forename: Manuel
authors.initials: M
authors.lastname: Cagaanan
authors.forename: Giovam Battista
authors.initials: GB
authors.lastname: Rini
authors.forename: Reina
authors.initials: R
authors.lastname: Armamento-Villareal
mesh_terms: D015502:Absorptiometry, Photon; D000368:Aged; D000483:Alleles; D015519:Bone Density; D001862:Bone Resorption; D003094:Collagen / Q000652:urine; D024042:Collagen Type I / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D004958:Estradiol / Q000097:blood / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005269:Femur / Q000378:metabolism*; D005838:Genotype; D006801:Humans; D007124:Immunoenzyme Techniques; D008593:Menopause; D008875:Middle Aged; D010455:Peptides / Q000652:urine; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D017698:Postmenopause; D011863:Radioimmunoassay; D012307:Risk Factors; D013997:Time Factors
chemical_list: D024042:Collagen Type I; D004967:Estrogens; D010455:Peptides; C052929:collagen type I trimeric cross-linked peptide; D004958:Estradiol; D003094:Collagen; D019363:Cytochrome P-450 CYP1A1