Genetic effects of estrogen receptor α and collagen IA1 genes on the relationships of parathyroid hormone and 25 hydroxyvitamin D with bone mineral density in caucasian women

There is a growing body of evidence that estrogen receptor α (ERα) and collagen IA1 (COLIA1) genes may affect bone mineral density (BMD) levels in postmenopausal women. In a recent study we found that the Px haplotype of the ERα gene (resulting from combined Pvull and Xbal restriction fragment-length polymorphisms [RFLPs] in intron 1) was associated with low radiographic phalangeal hand BMD in elderly women (62.7 ± 6.5 years of age), of European origin. The combination of the Px haplotype and "s" allele of the COLIA1 gene (Msd RFLP in Spl locus) decreased BMD in these women. The major aim of the present study was to investigate whether the genetic effects of these genotypes on cancellous and cortical hand BMD, in the same elderly women (N = 122), are possibly mediated through circulating levels of parathyroid hormone (PTH) and/or 25 hydroxyvitamin D [25(OH)D], and may be related to biochemical markers of bone turnover (propeptide of type I procollagen [PICP] and osteocalcin). Multiple regression analyses of age-adjusted cancellous BMD revealed that ERα polymorphism and circulating levels of PTH were independent predictors of about 12.9% of its variation. Some 17.9% of cortical BMD variations were attributable to the combined effects of ERα polymorphism and plasma concentrations of 25(OH)D, estradiol, and PTH. The significant inverse association between PTH and BMD of both types was further confirmed by association analysis according to categorical subgroups of BMD values, as well by haplotype status. The mean difference in PTH concentrations between subjects carrying the Px haplotype (higher mean) and those lacking it (lower mean) reached 0.59 SD (P = .01). The difference in PTH levels further increased when explored in the 4 subgroups formed by combinations of polymorphic ERα and COLIA1 genotypes. Mean PTH of subjects carrying both the Px haplotype and "s" allele was higher by 1.52 SD (P = .001) than in subjects lacking both the Px haplotype and "s" allele. Those carrying both Px haplotype and "s" allele were also characterized by highest mean value of PICP and lowest means of 25(OH)D and BMD (both tissue types). We conclude that in the studied elderly women, the Px haplotype may be involved in causing the phenotypic expression of higher circulating levels of PTH and higher bone turnover, which, in turn, may lead to bone loss.