Association of estrogen receptor α gene microsatellite polymorphism with annual changes in bone mineral density in Korean women with hormone replacement therapy

Abstract

Variation in drug response to hormone replacement therapy (HRT) may reflect genetic heterogeneity in the estrogen-related genes, possibly including estrogen receptor alpha (ERalpha) gene. However, only a few association studies of the drug response to HRT have been reported, focusing mainly on the intronic polymorphisms of the ERalpha gene. We therefore examined 284 postmenopausal women (mean age, 52.2 +/- 5.0 years) for the microsatellite thymine-adenine (TA) repeat polymorphism in the promoter of the ERalpha gene and its relationship to drug response by measuring changes in bone mineral density (BMD) after 1 year of HRT. In our study population, the most common number of TA repeats was 14, with a range of values between 11 and 27. At baseline, the number of TA repeats was neither associated with measured lumbar spine or femoral neck BMD nor with bone markers. When we categorized the subjects by the TA repeat numbers into an L group (n = 142), with a low mean number of repeats (TA < 16), and an H group (n = 142), with a high mean number of repeats (TA > or = 16), no significant genotypic differences were noted in spinal or femoral neck BMD or in bone markers. However, the drug response on lumbar spine BMD after 1 year of HRT correlated with the mean number of TA repeats (r = -0.131, P = 0.035) after adjustment for confounding factors such as body mass index and years since menopause. This correlation was also seen with the number of TA repeats on the shorter allele (r = -0.159, P = 0.012), which was defined as the allele with the lower number of TA repeats. However, this genotypic association was not found in the femoral neck BMD (r = 0.053, P = 0.396). When we defined the nonresponder group as women who had lost BMD even with HRT, 15.9% of the subjects were included, and this group was significantly younger and had higher initial BMD than the responder group. After further adjustment for age and initial BMD, the number of TA repeats on the shorter allele remained significantly associated with drug responsiveness (P = 0.005). These data indicate significant effects of the ERalpha TA repeat polymorphism on the estrogen responsiveness of lumbar spine BMD after 1 year of HRT in Korean women.

Association between Wnt signaling pathway gene polymorphisms and bone response to hormone therapy in postmenopausal Korean women

“…The GT haplotype allele did not show an increased risk of nonresponse at the femoral neck. The present findings were similar to the results of Yim et al, 20 showing that the ER-> (thymine adenine) repeat polymorphism was associated with nonresponsiveness to HT at the lumbar spine and that this association was not found for BMD at the femoral neck. These findings suggest that the bone effects of HT may be heterogeneous in different sites of the skeleton, probably because of different proportions of both cortical and cancellous bone, as well as polymorphisms of the candidate gene.…”

“…These discrepancies may be due to ethnicity, type of HT, and the influence of confounding factors, such as initial baseline BMD before HT. In Korean postmenopausal women, calcitonin cytosine adenine 17 and ER-> thymine adenine 20 Many studies have been performed to elucidate the relationship between the LRP5 gene polymorphism and BMD. However, the results differed according to the nationality studied, even in the same ethnicity.…”

Postmenopausal Hormone Therapy: An Endocrine Society Scientific Statement

“…ER polymorphisms have been associated with annual changes in BMD and estrogen responsiveness (497) and with the cardiovascular effects of MHT (498,499). It may thus be possible to select for or against treatment in patients particularly likely to achieve benefit or to experience risks greater than the norm.…”

A gene-to-gene interaction between aromatase and estrogen receptors influences bone mineral density

“…Nevertheless, the hypothesis is consistent with a number of investigations showing that the ERa genotype influences the response to exogenous estrogenic compounds. It has been reported that the TA microsatellite, and several SNPs in intron 1 and other regions of the ER, modulate the skeletal response to hormone replacement therapy both in Asian and European women (30)(31)(32)(33). The AG SNP in intron 1 has also been reported to modulate the BMD response to raloxifene in women on chronic hemodialysis (34).…”