Genetics of bone density and bone loss in men: Role of androgen and estrogen receptor gene variation.

摘要

Male osteoporosis is an increasingly important health problem, for which there are few well-established risk factors. The importance of sex steroid hormones and genetic factors in the regulation of bone mineral density (BMD) in men prompted us to study the effects of androgen (AR) and estrogen (ESRA) receptor gene polymorphisms on BMD and bone loss in a cohort of older men. All 541 men aged 50--88 years enrolled in the Study of Osteoporotic Risk in Men were invited to participate in a second examination between 1997--1999, after an average of 7 years. Hip BMD was remeasured in 327 men (74% of survivors) who completed the clinic examination. Men were genotyped for a CAG repeat polymorphism within the first exon of the AR gene and XbaI and PvuII restriction fragment length polymorphisms located 350 base pairs upstream from exon 2 in the ESRA gene.;None of the individual loci were significantly related to BMD. When AR and ESRA polymorphisms were considered together, however, there was a significant gene-gene interaction effect. Men with the XbaI -/- genotype and longer AR alleles had nearly one standard deviation greater femoral neck BMD compared to men with the shorter alleles, an effect that was not present among other XbaI genotypes and independent of potential confounders (P = 0.008 for interaction).;Men with longer AIR alleles also experienced significantly greater weight loss between the baseline and follow-up examinations than men with shorter alleles (-0.88 kg vs 0.93 kg, respectively; P 0.01). Men with longer AR alleles also experienced significantly greater bone loss at the hip than men with shorter alleles (-0.24 %/yr vs -0.03 %/yr respectively; P = 0.02), although this association was no longer statistically significant after adjusting for the greater weight loss among men with longer AR alleles.;These results suggest that expansion of the CAG repeat polymorphism in the AR gene is associated with greater weight loss in aging men, and that this effect may contribute to more rapid bone loss. Our results also suggest that the joint effect of the AR and ESRA genes may influence BMD and osteoporotic risk in older men.