A CAG repeat polymorphism in the androgen receptor gene is associated with reduced bone mass and increased risk of osteoporotic fractures.

Osteoporosis is a common disease with a strong genetic component. Hypogonadism results in low bone mass and it increases significantly the risk of osteoporosis in both sexes. The estrogen and androgen receptor genes are therefore strong candidates for mediating the genetic influence on bone mass and risk of osteoporosis. A CAG repeat in the first exon of the androgen receptor (AR) is associated with reduced transcriptional activity of the AR. We therefore examined whether this CAG repeat polymorphism is associated with changes in bone mass and risk of osteoporotic fractures in 284 osteoporotic patients with vertebral fractures and 327 normal individuals. The number of CAG repeats varied between 13 and 30 in men and between 7 and 34 in women. The short and long alleles comprised 19.2 +/- 2.5 and 19.0 +/- 2.3 repeats (ns) and 22.7 +/- 2.4 and 21.9 +/- 2.4 (P < 0.01) in women with vertebral fractures and normal women, respectively. This difference was also reflected in the average number of CAG repeats: 21.0 +/- 2.0 in osteoporotic women vs. 20.5 +/- 2.0 in normal women (P < 0.05). 54.8% of women with osteoporotic fractures vs. 45.9% of normal women had average number of CAG repeats of 21 and more (chi2 = 3.11, P = 0.08). Logistic regression analyses revealed that both the average number of CAG repeats and the length of the long allele were significant predictors of osteoporotic fractures in women (P < 0.05 and P < 0.01, respectively). Men with vertebral fractures had 20.0 +/- 2.8 CAG repeats compared with 20.7 +/- 2.5 CAG repeats in normal men (ns). Linear regression analysis revealed that the length of the long allele was negatively correlated with BMD of the lumbar spine (P < 0.05) and femoral neck (P < 0.05) in women. In men, linear regression analyses demonstrated that BMD of the lumbar spine (P < 0.05), femoral neck (P < 0.05) and total hip (P < 0.05) was positively correlated with length of the CAG repeat polymorphism. In conclusion, we have demonstrated that the CAG repeat polymorphism in the first exon of the AR gene is associated with reduced bone mass and increased risk of osteoporotic fractures in women.