Effect of CYP1A1 gene polymorphisms on estrogen metabolism and bone density.
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.
Napoli
Nicola
N
Division of Bone and Mineral Diseases, Washington University School of Medicine, St Louis, MO 63110, USA.
Villareal
Dennis T
DT
Mumm
Steven
S
Halstead
Linda
L
Sheikh
Sharmin
S
Cagaanan
Manuel
M
Rini
Giovam Battista
GB
Armamento-Villareal
Reina
R
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
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