rspНаучно-практическая ревматологияRheumatology Science and Practice1995-44841995-4492IMA-PRESS, LLC10.14412/1995-4484-2009-137rsp-472Research ArticleСтатьиArticlesПолиморфизм гена трансформирующего фактора роста бета 1 при постменопаузальном остеопорозеTransforming growth factor β1 gene polymorphism in postmenopausal osteoporosisKrylovM YKrylovM Y-MaslovaK AMaslovaK A-КоротковаТ. А.KorotkovaT A-ToroptsovaN AToroptsovaN A-НикитинскаяО. А.NikitinskayaO A-DeminN VDeminN V-MyakotkinV AMyakotkinV A-БеневоленмкаяЛ. И.BenevolenskayaL I-200915022009471№1 (2009)1823Copyright © Krylov M.Y., Maslova K.A., Короткова Т.А., Toroptsova N.A., Никитинская О.А., Demin N.V., Myakotkin V.A., Беневоленмкая Л.И., 20092009Krylov M.Y., Maslova K.A., Короткова Т.А., Toroptsova N.A., Никитинская О.А., Demin N.V., Myakotkin V.A., Беневоленмкая Л.И.Krylov M.Y., Maslova K.A., Korotkova T.A., Toroptsova N.A., Nikitinskaya O.A., Demin N.V., Myakotkin V.A., Benevolenskaya L.I.This work is licensed under a Creative Commons Attribution 4.0 License.https://rsp.mediar-press.net/rsp/article/view/472

Трансформирующий фактор роста бета-1 (ТФР-β1) представлен в костной ткани в большей степени по сравнению с другими ростовыми факторами. Он продуцируется остеобластами и обладает способностью тормозить пролиферацию остеокластов, активировать и стимулировать пролиферацию и дифференциацию преостеобластов. Описано несколько полиморфизмов этого гена, располагающихся в разных областях его последовательности.Цель. Изучить связи полиморфизма С-509Т, расположенного в промоторной области гена ТФР-β1, с минеральной плотностью костной ткани.Материал и методы. Полиморфизм С-509Т был изучен с помощью ПЦР-ПДРФ анализа среди 159 пациенток с остеопорозом (ОП) и 152 здоровых индивидумов. Минеральная плотность костной ткани (МПКТ) определялась в грудном отделе позвоночника и стандартных областях проксимального отдела бедра с помощью рентгеновского костного денситометра.Результаты. Распределения С-509Т частот аллелей и генотипов были сходными и статистически не отличались между группой с ОП и нормальным контролем.Средний показатель МПКТ шейки бедра женщин с ОП был статистически достоверно выше у носителей гомозиготного генотипа СС и гетерозиготного СТ генотипа по сравнению с носителями мутантного гомозиготного ТТ генотипа: 0,617 ± 0,091 г/см2, 0,626 ± 0,064 г/см2 и 0,555 ± 0,074 г/см2 соответственно (p < 0,005, ANOVA). Сходные различия в средних показателях МПКТ между этими генотипами были найдены в разных областях бедра и всего бедра в целом. Анализ МПКТ у носителей СС + СТ генотипов показал наличие более высоких средних показателей МПКТ всех областей бедра по сравнению с носителями ТТ генотипа среди женщин с ОП. Не установлено связи носительства гомозиготного мутантного генотипа с риском развития переломов.

Objective. Transforming growth factor β1 (TGF β1) prevails among growth factors in bone. It is produced by osteoblasts and is able to hamper osteoclast proliferation, activate and stimulate osteoblasts precursors proliferation and differentiation. At present several polymorphisms located in different regions of its sequence have been described for this gene. Several studies have shown an association between some polymorphisms of this gene and bone mass. The objective of the present study was to examine relationship between C-509T polymorphism located in gene TGF β1 promoter region with bone mineral density(BMD). There are only a few studies of relationship of this polymorphism with bone mass 23in European population. Such data for Russian population are not available.Material and methods. C-509T polymorphism was studied with PCR analysis in 159 pts with osteoporosis and in 152 healthy individuals. BMD was assessed in thoracic spine and standard regions of proximal femur with an X-ray bone densitometer.Results. C-509T allele frequencies and genotypes distribution were similar in osteoporosis and control. Mean femur neck BMD in women with osteoporosis was significantly higher in carriers of homozygote CC and heterozygote CT genotypes in comparison with homozygote TT genotype: 0,617±0,091 g/sm2, 0,626±0,064 g/sm2 and 0,555±0,074 g/sm2 respectively (p<0,005, ANOVA). Similar differences of BMD values between these genotypes were found in different femur regions and the whole femur. BMD analysis in CC+CT genotype carriers revealed presence of higher mean BMD values in all femur regions in comparison with TT genotype carriers among women with osteoporosis. Homozygote mutant genotype was not associated with fracture risk.

остеопорозминеральная плотность костной тканиSNP полиморфизм TGF-β1 генаosteoporosisbone mineral densitySNP TGF β1 gene polymorphismReferences<div><p>Pocock N.A., Eisman J.A., Hoooper J.L. et al. Genetic determinants of bone mass in adults. A twin study. J. Clin.Invest., 1987, 80, 706-10.</p><p>Slemenda C.W., Christian J.C., Williams C.J. et al. Genetic determinants of bone mass in adult women: a reevaluation of the twin model and the potential importance of gene interaction on heriability estimate. J. Bone Mineral. Res., 1991, 6, 561-7.</p><p>Soroko S.B., Barrett-Connor E., Edelstein S.L., et al. Family history of osteoporosis and bone mineral density at the axial skeleton the Rancho Bernardo Study. J. Bone Mineral. Res., 1994, 9,761-9.</p><p>Gueguen R., Jouanny P., Guillemin F. et al. Segregation analysis and variance components analysis of bone mineral density in healthy families. J. Bone Miner. Res., 1995, 10, 2017-22.</p><p>Bonewald L.F. Regulation and regulatory activities of transforming growth factor beta. Crit. Rev. Eukariot Gene Exp., 1999, 9, 33-44.</p><p>Bonewald L.F., Mundy G.R. Role of transforming growth factor-beta in bone remodeling. Clin. Orthop., 1990, 250, 261-70.</p><p>Ivanovic V., Melman A., Davis-Joseph B. et al. Elevated plasma levels of TGFB-beta 1 in patients with invasive prostate cancer. Nat. Med. 1995, 1,282-284.</p><p>Pirce D.F.Jr., Gorska A.E., Chityl A. et al. Mammary tumor suppression by transforming growth factor beta transgenic expression. Proc. Natl. Acad. Sci. USA, 1995, 92, 4254-8.</p><p>Kulkarni A.B., Ward J.M., Yaswen L. et al. Transforming growth factor-beta 1 null mace. An animal model for inflammatory disorders. Am. J. Pathol., 1995,146, 264-75.</p><p>Grainger D.J., Kemp P.R., Liu A.C. et al. Activation of transforming growth factor-beta is inhibited in trans- genic apolipoprotein (a) mice. Nature, 1994, 370, 460-2.</p><p>Grainger D.J., Kemp P.R., Metcalf J.C. et al. The serum concentration of active transforming growth factor-beta is severely depressed in advanced arterio- sclerosis. Nat. Med., 1995, 1, 74-9.</p><p>Grainger D.J., Heaathcote K., Chiano M. et.al. Genetic control of the circulating concentration of transforming growth factor type beta 1. Hum.Mol.Genet., 1999, 8, 93-7.</p><p>Yamada Y., Miyauchi A., Goto J. et al. Association of a polymorphism of the transforming growth factor-beta 1 gene with genetic susceptibility to osteoporosis in postmenopausal Japanese women. J. Bone Miner. Res., 1998, 13,1569-76.</p><p>Yamada Y., Miyauchi A., Takagi Y. et al. Association of a polymorphism of the transforming growth factor-beta 1 gene with prevalent vertebral fractures in Japanese women. Am. J. Med., 2000, 109,244-7.</p><p>Award M.R., El Gamel A., Hasleton P. et al. Genotypic variation in the transforming growth factor-beta 1 gene: association with transforming growth factor-beta</p><p>production, fibrotic lung disease, and graft fibrosis after lung transplantation. Transplantation, 1998, 66, 1014-20.</p><p>Cambien F., Ricard S., Molloy H. et al. Polymorphisms of the transforming growth factor-beta 1 gene in relation to myocardial infarction and blood pressure. The Etude Cas-Temoin de l’Infarctus du Myocard (ECTIM) Study. Hypertension, 1996, 28, 881-7.</p><p>Keen R.W., Snieder H., Molloy H. et al. Evidence of association and linkage disequilibria between a novel polymorphism in the transforming growth factor-beta 1 gene and hip bone mineral density: a study of female twins. Rheumatology (Oxford), 2001, 40, 48-54.</p><p>Polonikov A.V., Ivanov V.P., Belugin D.A. et al. Analysis of common transforming growth factor beta-gene polymorphisms in gastric and duodenal ulcer disease: Pilot study. J. Gastroenterol. Hepotol., 2007, 22(4), 555-64.</p><p>Miller S.A., Dykes D.D., Polesky H.F. A simple salting out procedure for extracting DNA from human nucleated cells Nucleic Acids Res., 1988, 16, 12-5.</p><p>Prasad P., Tiwari A.K., Kumar KM.P. et al. Association of TGFβ1, TNFα, CCR2 and CCR5 gene polymorphisms in type-2 diabetes and renal insuf- ficiency among Asian Indians. BMC Med. Genet., 2007,8,20-7.</p><p>Crilly A.,Hamilton J.,Clark C.J.et al. Analysis of the transforming growth factor β1 gene polymorphisms in patients with systemic sclerosis. Ann. Rheum. Dis., 2002, 61,678-81.</p><p>Pokorny V., Chau J., Wu L. et al. Transforming growth factor beta 1 gene (HSTGFB1) nucleotide T869C (codon 10) polymorphism is not associated with prevalence or severity of rheumatoid arthritis in a Caucasian. Ann. Rheum. Dis., 2003, 62, 907-8.</p><p>Yamada Y., Miyauchi A., Takagi Y. et al. Association of the C-509T polymorphism, alone or in combination with the T869C polymorphism, of the transforming growth factor beta-1 gene with bone mineral density and genetic susceptibility to osteoporosis in Japanese women. J. Mol. Med., 2001, 79,149-6.</p><p>Park B.L., Han I.K., Lee H.S. et al. Identification of novel variants in the transforming growth factor beta-(TGFB1) gene and association analysis with bone mineral density. Hum. Mut., 2003, 22,257-8.</p><p>Langdahl B.L., Carstens M., Stenkjaer L. et al. Polymorphisms in the transforming growth factor beta-gene and osteoporosis. Bone, 2003, 32,297-10.</p><p>McGuigan F.E., Macdonald H.M., Bassiti A. et al. Large-scale population-based study shows no association between common polymorphisms of the TGFB1 gene and BMD in women. J. Bone Miner. Res., 2007, 22(2), 195-202.</p><p>Chou H.T., Chen C.H., Tsai C.H., Tsai F.J. Association between transforming growth factor-beta 1 gene C-509T and T869C polymorphisms and rheumatic heart disease. Am. Heart J., 2004, 148(1), 181-6.</p><p>Koch W., Hoppmann P., Mueller J.C. et al. Association of transforming growth factor-β1 gene polymorphisms with myocardial infarction in patients with angiographically proven coronary heart disease. Arterioscler. Thrombos. Vascul. Biology, 2006, 26, 11-4.</p></div><br /><div><p>Pocock N.A., Eisman J.A., Hoooper J.L. et al. Genetic determinants of bone mass in adults. A twin study. J. Clin.Invest., 1987, 80, 706-10.</p><p>Slemenda C.W., Christian J.C., Williams C.J. et al. Genetic determinants of bone mass in adult women: a reevaluation of the twin model and the potential importance of gene interaction on heriability estimate. J. Bone Mineral. Res., 1991, 6, 561-7.</p><p>Soroko S.B., Barrett-Connor E., Edelstein S.L., et al. Family history of osteoporosis and bone mineral density at the axial skeleton the Rancho Bernardo Study. J. Bone Mineral. Res., 1994, 9,761-9.</p><p>Gueguen R., Jouanny P., Guillemin F. et al. Segregation analysis and variance components analysis of bone mineral density in healthy families. J. Bone Miner. Res., 1995, 10, 2017-22.</p><p>Bonewald L.F. Regulation and regulatory activities of transforming growth factor beta. Crit. Rev. Eukariot Gene Exp., 1999, 9, 33-44.</p><p>Bonewald L.F., Mundy G.R. Role of transforming growth factor-beta in bone remodeling. Clin. Orthop., 1990, 250, 261-70.</p><p>Ivanovic V., Melman A., Davis-Joseph B. et al. Elevated plasma levels of TGFB-beta 1 in patients with invasive prostate cancer. Nat. Med. 1995, 1,282-284.</p><p>Pirce D.F.Jr., Gorska A.E., Chityl A. et al. Mammary tumor suppression by transforming growth factor beta transgenic expression. Proc. Natl. Acad. Sci. USA, 1995, 92, 4254-8.</p><p>Kulkarni A.B., Ward J.M., Yaswen L. et al. Transforming growth factor-beta 1 null mace. An animal model for inflammatory disorders. Am. J. Pathol., 1995,146, 264-75.</p><p>Grainger D.J., Kemp P.R., Liu A.C. et al. Activation of transforming growth factor-beta is inhibited in trans- genic apolipoprotein (a) mice. Nature, 1994, 370, 460-2.</p><p>Grainger D.J., Kemp P.R., Metcalf J.C. et al. The serum concentration of active transforming growth factor-beta is severely depressed in advanced arterio- sclerosis. Nat. Med., 1995, 1, 74-9.</p><p>Grainger D.J., Heaathcote K., Chiano M. et.al. Genetic control of the circulating concentration of transforming growth factor type beta 1. Hum.Mol.Genet., 1999, 8, 93-7.</p><p>Yamada Y., Miyauchi A., Goto J. et al. Association of a polymorphism of the transforming growth factor-beta 1 gene with genetic susceptibility to osteoporosis in postmenopausal Japanese women. J. Bone Miner. Res., 1998, 13,1569-76.</p><p>Yamada Y., Miyauchi A., Takagi Y. et al. Association of a polymorphism of the transforming growth factor-beta 1 gene with prevalent vertebral fractures in Japanese women. Am. J. Med., 2000, 109,244-7.</p><p>Award M.R., El Gamel A., Hasleton P. et al. Genotypic variation in the transforming growth factor-beta 1 gene: association with transforming growth factor-beta</p><p>production, fibrotic lung disease, and graft fibrosis after lung transplantation. Transplantation, 1998, 66, 1014-20.</p><p>Cambien F., Ricard S., Molloy H. et al. Polymorphisms of the transforming growth factor-beta 1 gene in relation to myocardial infarction and blood pressure. The Etude Cas-Temoin de l’Infarctus du Myocard (ECTIM) Study. Hypertension, 1996, 28, 881-7.</p><p>Keen R.W., Snieder H., Molloy H. et al. Evidence of association and linkage disequilibria between a novel polymorphism in the transforming growth factor-beta 1 gene and hip bone mineral density: a study of female twins. Rheumatology (Oxford), 2001, 40, 48-54.</p><p>Polonikov A.V., Ivanov V.P., Belugin D.A. et al. Analysis of common transforming growth factor beta-gene polymorphisms in gastric and duodenal ulcer disease: Pilot study. J. Gastroenterol. Hepotol., 2007, 22(4), 555-64.</p><p>Miller S.A., Dykes D.D., Polesky H.F. A simple salting out procedure for extracting DNA from human nucleated cells Nucleic Acids Res., 1988, 16, 12-5.</p><p>Prasad P., Tiwari A.K., Kumar KM.P. et al. Association of TGFβ1, TNFα, CCR2 and CCR5 gene polymorphisms in type-2 diabetes and renal insuf- ficiency among Asian Indians. BMC Med. Genet., 2007,8,20-7.</p><p>Crilly A.,Hamilton J.,Clark C.J.et al. Analysis of the transforming growth factor β1 gene polymorphisms in patients with systemic sclerosis. Ann. Rheum. Dis., 2002, 61,678-81.</p><p>Pokorny V., Chau J., Wu L. et al. Transforming growth factor beta 1 gene (HSTGFB1) nucleotide T869C (codon 10) polymorphism is not associated with prevalence or severity of rheumatoid arthritis in a Caucasian. Ann. Rheum. Dis., 2003, 62, 907-8.</p><p>Yamada Y., Miyauchi A., Takagi Y. et al. Association of the C-509T polymorphism, alone or in combination with the T869C polymorphism, of the transforming growth factor beta-1 gene with bone mineral density and genetic susceptibility to osteoporosis in Japanese women. J. Mol. Med., 2001, 79,149-6.</p><p>Park B.L., Han I.K., Lee H.S. et al. Identification of novel variants in the transforming growth factor beta-(TGFB1) gene and association analysis with bone mineral density. Hum. Mut., 2003, 22,257-8.</p><p>Langdahl B.L., Carstens M., Stenkjaer L. et al. Polymorphisms in the transforming growth factor beta-gene and osteoporosis. Bone, 2003, 32,297-10.</p><p>McGuigan F.E., Macdonald H.M., Bassiti A. et al. Large-scale population-based study shows no association between common polymorphisms of the TGFB1 gene and BMD in women. J. Bone Miner. Res., 2007, 22(2), 195-202.</p><p>Chou H.T., Chen C.H., Tsai C.H., Tsai F.J. Association between transforming growth factor-beta 1 gene C-509T and T869C polymorphisms and rheumatic heart disease. Am. Heart J., 2004, 148(1), 181-6.</p><p>Koch W., Hoppmann P., Mueller J.C. et al. Association of transforming growth factor-β1 gene polymorphisms with myocardial infarction in patients with angiographically proven coronary heart disease. Arterioscler. Thrombos. Vascul. Biology, 2006, 26, 11-4.</p></div><br />

The authors declare that there are no conflicts of interest present.