Association of the C –509 →T polymorphism, alone or in combination with the T 869 →C polymorphism, of the transforming growth factor-β 1 gene with bone mineral density and genetic susceptibility to osteoporosis in Japanese women

Transforming growth factor-β 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-β 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-β 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-β 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.