Vitamin D and Estrogen Receptor Allelic Variants in Italian Postmenopausal Women: Evidence of Multiple Gene Contribution to Bone Mineral Density

Abstract

Bone mass and bone turnover are under genetic control. Restriction fragment length polymorphisms (RFLPs) at the vitamin D receptor (VDR) gene locus have been recently correlated to bone mineral density (BMD) and rate of bone loss. However, agreement on this relationship is not universal. The existence of ethnical and environmental differences between populations, a health-based selection bias in several previous studies, and the involvement of other genes could explain these discordant findings. In this study, we examined the relationship of VDR and estrogen receptor (ER) gene RFLPs with lumbar spine and upper femur BMD in 426 Italian postmenopausal women, 57.7 +/- 0.4 yr old (144 normal, 106 osteopenic, and 176 osteoporotic). VDR gene RFLPs for ApaI, Bsm I, and TaqI restriction endonucleases and ER RFLPs for PvuII and XbaI restriction endonucleases were assessed by Southern blotting analysis and were indicated, respectively, as A-a, B-b, T-t, P-p, and X-x (uppercase letters signifying the absence and lowercase letters the presence of the restriction site). After correcting for potential confounding factors (age, height, weight, age since menopause, osteophytosis, and facet joint osteoarthritis), a statistically significant VDR genotype effect on lumbar BMD (P = 0.01, analysis of covariance), but not on femoral BMD, was detected, with subjects in AABBtt genotype showing a 13% lower BMD than those with aabbTT genotype (P < 0.05, Tukey's test). Moreover, a statistically significant prevalence of AABBtt genotype in osteoporotics, and of AabbTT and aabbTT genotypes in nonosteoporotics, were detected. Conversely, there was no significant relationship of ER genotype to either lumbar or femoral BMD, even though a trend for higher BMD values in women with the ER PP genotype (with respect to those with ER pp genotype) was detected. When mean lumbar BMD was calculated for women grouped by ER and VDR genotype, we observed a significant difference between those within the 2 opposite associations AABBtt-PPXX and aabbTT-ppxx (0.71 +/- 0.05 vs. 0.97 +/- 0.03 g/cm2, P < 0.05 Tukey's test). These results are consistent with a segregation of the VDR AABBtt genotype with a higher risk of developing osteoporosis, in the Italian female population. The introduction of another variable, the ER genotype, in the analysis of VDR genetic determination of BMD, may represent a useful model in the identification of patients at risk of developing a multigenic disorder like osteoporosis.

The anti-proliferative effects of 1α,25(OH)2D3 on breast and prostate cancer cells are associated with induction of BRCA1 gene expression

“…For example, the VDR knockout mouse displays critical growth defects in the female reproductive organs, speci®cally hypoplasia of the uterus, partly attributable to a lack of estrogen production, thus further supporting a role for VDR in the regulation of estrogenic events (Yoshizawa et al, 1997). Similarly, speci®c VDR and ER polymorphisms are linked to bone mineral density in postmenopausal women (Gennari et al, 1998;Deng et al, 1998) and to the regulation of infant growth (Suarez et al, 1998). Also, VDR polymorphisms are associated with increased risk for prostate cancer and the progression of breast cancer, possible as a result of altered transcriptional activity (Ingles et al, 1997;Lundin et al, 1999;Jurutka et al, 2000).…”

Association of estrogen receptor α polymorphisms with breast cancer risk in older Caucasian women

“…These same 2 SNP have also been associated with other estrogen-linked conditions, 22,23 as well as factors associated with increased breast cancer risk, such as age at menopause 24 and age at menarche. 25 In addition, increased bone mineral density, a potential surrogate marker of cumulative estrogen exposure and a predictor of breast cancer risk, 26 has also been associated with these SNP, 27,28 although not consistently. 29 These data suggest that the ESR1 2401 T/C and 2354 A/G polymorphisms may act as susceptibility or risk-modifying alleles for breast cancer.…”

Oestrogen receptor α gene polymorphism associates with occurrence of graft-versus-host disease and reduced survival in HLA-matched sib-allo BMT

“…Restriction fragment length polymorphisms (RFLPs) for a PvuII and a XbaI restriction site in intron 1 have also been associated with alterations in BMD. Different populations of European origin 11,12 show very similar allele frequencies at these loci, in contrast to oriental and Japanese populations, 13 which show markedly different allele fre-quencies. Consequently, although studies on both groups have shown gene associations with BMD, direct comparisons are difficult to make, and it has been suggested that some of these genetic associations may be population specific.…”

“…7 The oestrogen receptors are also involved in a wide range of biological responses, including repression of the inflammatory response. 8 Gene polymorphisms have been reported for both ERa and ERb genes, and associations have been reported between specific ER alleles and a number of biological characteristics, including variation in bone mineral density (BMD) [9][10][11][12][13][14][15] in normal subjects, risk of developing Alzheimer's disease (AD), 16,17 and risk of developing endometrial cancer. 18 In the ERa gene (located at 6q24), variation in size of a (AT) microsatellite in the gene promoter region has been associated with variation in BMD, with alleles possessing a greater number of repeat elements being associated with increased BMD in both European 9 and Japanese 10 subjects.…”