The role of estrogen receptor-alpha gene TA polymorphism and aromatase gene TTTA polymorphism on peak bone mass attainment in males: is there an additive negative effect of certain allele combinations?

Idiopathic osteoporosis in males is influenced predominantly by low peak bone mass as a feature under a strong genetic control. Among a number of candidate genes, alpha-estrogen receptor (ERalpha) and CYP19 genes are of particular interest due to important role of estrogen in pathophysiology of osteoporosis. In the present study we examined the association of certain allelic combinations of ERalpha gene thymine-adenine (TA) polymorphism and aromatase gene TTTA polymorphism on bone mineral density (BMD) in young men. The study sample consisted of 92 unrelated healthy male volunteers, aged 21-35. In each subject, lumbar spine and proximal femur BMD, parameters of bone turnover and 25-OHD level were measured. Two ERalpha (TA)( n ) alleles, allele 19 and allele 21, were found to be associated with lower BMD. The presence of allele 19 was associated with significantly lower lumbar spine (P = 0.006) and trochanter (P = 0.02) BMD while the subjects positive for allele 21 had significantly lower lumbar spine (P = 0.04), trochanter (P = 0.02) and total hip (P = 0.03) BMD. Men with CYP19 (TTTA)(7-3)/ERalpha (TA)(19) allele combination had significantly lower lumbar spine BMD (P = 0.02) and those with CYP19 (TTTA)(7-3)/ERalpha (TA)(21) allele combination had significantly lower BMD for all three measurements, i.e. lumbar spine (P = 0.02), femoral neck (P = 0.02) and total hip (P = 0.008). These particular combinations of high-risk alleles were associated with lower median lumbar spine, femoral neck and total hip BMD than either of the allele alone suggesting that negative effect of two risk alleles on peak bone mass add up.