Estrogen receptor alpha gene polymorphisms and bone mineral density: Haplotype analysis in women from the United Kingdom

Genetic factors are important in the pathogenesis of osteoporosis and the e strogen receptor has been suggested as a possible candidate gene for regula tion of bone mineral density (BMD). We investigated the relationship betwee n PvuII, XbaI, and dinucleotide (TA)(n) repeat polymorphisms of the estroge n receptor alpha (ER-alpha) gene and BMD in a study of women from northeast Scotland in the United Kingdom. No significant association was observed be tween BMD values at the lumbar spine (LS) and femoral neck (FN) in relation to PvuII and XbaI polymorphisms individually, but haplotype analysis showe d that BMD values (Z score) were significantly lower in those who carried t he Px haplotype (n = 36) compared with those who did not (n = 170) at both the LS (mean +/- SEM; -0.775 +/- 0.125 vs. -0.285 +/- 0.082; p = 0.002) and the FN (-0.888 +/- 0.130 vs. -0.335 +/- 0.083; p = 0.0006). In keeping wit h this, the Pr haplotype also was found to be an independent predictor of L S BMD (p = 0.019) and FN BMD (p = 0.005) in a multiple regression analysis model that included other possible predictors of BMD including age, years s ince menopause (YSM), hormone-replacement therapy (HRT) use, weight, and he ight. This model explained 15.7% and 23.4% of the total observed variance i n LS and FN BMD, respectively, with the Pr haplotype accounting for similar to3% of the variance at both sites. Although the TA repeat polymorphism wa s in strong linkage disequilibrium (LD) with the PvuII (chi (2) = 109.8; p < 0.0001) and XbaI (<chi>(2) = 97.2; p < 0.0001) polymorphisms, there was n o overall association between TA repeat number and BMD. We conclude that po lymorphisms of the ER-<alpha> gene are significantly related to BMD) in our population and that this association is dependent on the Pr haplotype, sug gesting that it is the Pr haplotype, or a linked polymorphism, that confers risk.