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Transforming Growth Factor-1 Gene Polymorphism and Bone Mineral Density

To the Editor: Transforming growth factor 1 (TGF-1) regulates bone metabolism by acting under partial control of estrogen and cooperatively with vitamin D.^1-2 The Leu10Pro polymorphism of the TGF-1 gene is located in the signal peptide sequence,³ which is thought to target newly synthesized protein molecules to the endoplasmic reticulum. Our previous observation that the serum concentration of TGF-1 increases with the number of C alleles suggests that the Leu10Pro polymorphism may affect the function of the signal peptide, possibly influencing intracellular trafficking or export efficiency of the protein.⁴

In a previous case-control study we found that a T869C (Leu10Pro) polymorphism of the TGF-1 gene is associated with reduced bone mineral density (BMD) at the lumbar spine and increased rate of bone loss in postmenopausal Japanese women. Thus, the T allele appears to represent a genetic risk factor for the development of osteoporosis.^4-5 We report a test of this hypothesis in a population-based cohort study.

Methods
The Japanese National Institute for Longevity Sciences–Longitudinal Study of Aging (NILS-LSA) is a population-based prospective cohort study of aging and age-related diseases that began in 1997. We measured the association of the T869CC polymorphism of the TGF-1 gene with BMD in 2241 NILS-LSA participants (1115 women and 1126 men) who were community-dwelling Japanese individuals aged 40 to 79 years and who were randomly recruited from regions close to the National Institute for Longevity Sciences.

Bone mineral density at the distal radius was measured by peripheral quantitative computed tomography and expressed as D50 (BMD for the inner 50% of the cross-sectional area, which mostly comprises cancellous bone) and D100 (BMD for the entire cross-sectional area, including both cancellous and cortical bone). The TGF-1 genotype was determined with an allele-specific polymerase chain reaction assay.⁴

Results
The distribution of TGF-1 genotypes was 30% TT, 52% TC, and 18% CC in women, and 27% TT, 51% TC, and 22% CC in men; both distributions are consistent with a Hardy-Weinberg equilibrium. Age, height, body weight, body mass index, physical activity, and smoking status did not differ by TGF-1 genotypes in women or men. Both D50 and D100 were similar in women with the TC and TT genotypes, but D50 was significantly lower in women with the T allele than in those with the CC genotype (Table 1). Evaluation of BMD by successive age groups revealed that, for women aged 70 years and older, D50 was 18% (P = .01) lower in individuals with the T allele than in those with the CC genotype. No significant differences in D50 or D100 among TGF-1 genotypes were detected for men.

View this table: [in this window] [in a new window] Table. Characteristics of 1115 Community-Dwelling Women Stratified by Age and Transforming Growth Factor-1 Genotype*

Comment
Our results show that the T869C (Leu10Pro) polymorphism of the TGF-1 gene may be associated with distal radius BMD in community-dwelling women and that BMD is greater in women aged 70 years or older with the CC genotype compared with those with the T allele. The greater difference in BMD among TGF-1 genotypes in these individuals may be related to the age-dependent decrease in serum concentrations of estrogen and 1,25-dihydroxyvitamin D₃.

AUTHOR INFORMATION
Funding/Support: This work was supported in part by a Research Grant for Longevity Sciences (12C-01) from the Ministry of Health and Welfare of Japan (Drs Yamada and Shimokata).

Yoshiji Yamada, MD,PhD
Department of Gene Therapy
Gifu International Institute of Biotechnology and Institute of Applied Biochemistry
Mitake, Gifu, Japan

Fujiko Ando, MD,PhD; Naoakira Niino, MD,PhD; Hiroshi Shimokata, MD,PhD
Department of Epidemiology
National Institute for Longevity Sciences
Obu, Aichi, Japan

1. Hughes DE, Dai A, Tiffee JC, et al. Estrogen promotes apoptosis of murine osteoclasts mediated by TGF-. Nature Med. 1996;2:1132-1136. FULL TEXT | WEB OF SCIENCE | PUBMED 2. Yanagisawa J, Yanagi Y, Masuhiro Y, et al. Convergence of transforming growth factor- and vitamin D signaling pathways on SMAD transcriptional coactivators. Science. 1999;283:1317-1321. FREE FULL TEXT 3. Derynck R, Jarrett JA, Chen EY, et al. Human transforming growth factor- complementary DNA sequence and expression in normal and transformed cells. Nature. 1985;316:701-705. FULL TEXT | PUBMED 4. Yamada Y, Miyauchi A, Goto J, et al. Association of a polymorphism of the transforming growth factor- gene with genetic susceptibility to osteoporosis in postmenopausal Japanese women. J Bone Miner Res. 1998;13:1569-1576. FULL TEXT | WEB OF SCIENCE | PUBMED 5. Yamada Y, Harada A, Hosoi T, et al. Association of transforming growth factor 1 genotype with therapeutic response to active vitamin D for postmenopausal osteoporosis. J Bone Miner Res. 2000;15:415-420. FULL TEXT | WEB OF SCIENCE | PUBMED

Letters Section Editor: Stephen J. Lurie, MD, PhD, Senior Editor.

JAMA. 2001;285:167-168.

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