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.

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.

Conflict of interest statement

The authors have no conflict of interest.

Figures

FIG. 1.

CYP1A1 gene polymorphisms analyzed by RFLP. For each polymorphism, DNA samples were amplified by PCR, digested with restriction enzymes (as indicated below), and analyzed by agarose gel electrophoresis followed by ethidium bromide staining. For each gel, the first lane is a DNA size marker; the remaining lanes are analyses for individual DNA samples. (A) T6235C polymorphism in the 3’ UTR. PCR amplicons were digested with MspI, generating the following: for TT, one band (899 bp), for TC, three bands (899, 693, and 206 bp), and for CC, two bands (693 and 206 bp). For lanes 2, 3, and 6, the TC genotype was detected (three bands), whereas the remaining lanes show the TT genotype (one band). (B) A4889G polymorphism in exon 7. PCR amplicons were digested with BsrDI, generating the following: for AA, two bands (149 and 55 bp), for AG, three bands (204, 149, and 55 bp), and for GG, one band (204 bp). Lane 1 shows the AG genotype (three bands), whereas the remaining lanes show the AA genotype (two bands). (C) C4887A polymorphism in exon 7. PCR amplicons were digested with BsaI, generating the following: for CC, two bands (139 and 65 bp), for CA, three bands (204, 139, and 65 bp), and for AA, one band (204 bp). Lane 2 shows the CA genotype (three bands), whereas in lane 4, the AA genotype was detected (1 band); the remaining lanes show the CC genotype (two bands).