Effects of polymorphisms of the sex hormone-binding globulin (SHBG) gene on free estradiol and bone mineral density

Abstract

Background Polymorphisms of the sex hormone-binding globulin (SHBG) gene are associated with differences in SHBG levels, influencing the risk for breast cancer and polycystic ovarian syndrome, but no association has been reported for osteoporosis in postmenopausal women. Objective To determine the effect of G to A substitution in the 5′UTR (rs1799941) and the Asp356Asn (rs6259) polymorphisms of the SHBG gene on bone mineral density (BMD). Methods This is a cross-sectional study in a university-based research center from May, 2002 to December, 2007. A total of two hundred and thirteen healthy postmenopausal Caucasian women ≥ 1 year from last menstrual period participated to this study. Serum estradiol by ultrasensitive radioimmnunoassay, serum sex hormone-binding globulin by immunoradiometric assay, and urinary NTx by enzyme-linked immunoassay were measured. BMD measurements were performed by dual energy X-ray absorptiometry and genotyping by Pyrosequencing. Results There were no significant differences in SHBG levels associated with either rs1799941 or rs6259. Using a p value of < 0.00625 for significance, we found that subjects with the A allele (GA+AA) for the rs1799941, had a trend for lower free estradiol index (FEI) compared to the GG genotype ( p = 0.04). They also had significantly lower BMD at the intertrochanter ( p = 0.003) and trend for lower BMD at the total hip ( p = 0.02). There was no significant difference in FEI levels between the genotypes for the rs6259 polymorphism, but women with the Asn allele (Asp/Asn+Asn/Asn), had significantly lower BMD in the total femur ( p = 0.004) and intertrochanter (0.002) compared to those with the Asp/Asp genotype. Conclusions Our data suggest that polymorphisms of the SHBG gene are associated with significant differences in BMD at the proximal femur sites. Thus, genetic variations in the SHBG gene may influence BMD at the hip in postmenopausal women.