Association of the C-509→T polymorphism, alone or in combination with the T869→C polymorphism, of the transforming growth factor-β1 gene with bone mineral density and genetic susceptibility to osteoporosis in Japanese women

Transforming growth factor-beta (1) is an important local regulator of bone metabolism, acting downstream of estrogen and cooperatively with vitamin D. The possible association of a C-509-->T polymorphism in the promoter region of the transforming growth factor-beta (1) gene, alone or in combination with a T-869-->C (Leu(10)--> Pro) polymorphism, with bone mineral density and genetic susceptibility to osteoporosis was investigated in 625 postmenopausal Japanese women. The frequencies of the CC, CT, and TT genotypes of the C-509-->T polymorphism in the study population were 24%, 49%, and 27%, respectively A significant association of C-(509)-->T genotype with bone mineral density was detected: lumbar spine (L2-L4) and total body bone mineral density values were 7% and 5% lower, respectively, in individuals with the TT genotype than in those with the CT or CC genotype. The serum concentration of transforming growth factor-beta (1) did not vary with C-509-->T genotype. Multivariable logistic regression analysis, with adjustment for age, height, body weight, time since menopause, smoking status, body fat mass, and lean mass, revealed a significantly higher frequency of the TT genotype of the C-509-->T polymorphism in 286 individuals with osteoporosis than in 170 normal controls. Analysis of combined C-509-->T and T-869-->C genotypes showed that L2-L4 bone mineral density decreases and the prevalence of osteoporosis increases with the number of T alleles. These results suggest that the C-509-->T polymorphism, alone or in combination with the T-869-->C polymorphism, of the transforming growth factor-beta (1) gene is a genetic determinant of bone mass, and that the number of T alleles in the combined genotype is a risk factor for the genetic susceptibility to osteoporosis in postmenopausal Japanese women.