Genetic prediction of osteoporosis in clinical practice

Czech version

Authors: T. Fait ^1,2; M. Koudová ²
Authors‘ workplace: Gynekologicko-porodnická klinika, 1. LF UK a VFN Praha ¹; Klinika GHC Praha, genetické laboratoře GHC GENETICS ²
Published in: Prakt Gyn 2011; 15(3-4): 144-148
Category: Original Article

Overview

Objective:
The aim of the study was to explore the utility of predictive genetic testing in a group of women with a risk of osteoporosis.

Materials and methods:
257 women aged 34–68 years at an increased risk of osteoporosis were evaluated using densinometry, biochemistry and genetics. Eight genetic variants of the COL1A1, ESR1, VDR, LRP5, LRP6 and ALOX12 genes, associated with the risk of osteoporosis, were evaluated. Genetic predisposition was classified protective, high-risk or neutral based on the overall genetic score.

Results:
The tested sample comprised 16% of genetically high-risk women. Most frequently (39.1%), the women carried the high-risk TT genotype of the VDR gene (c.1025–49G>T); this is twice the prevalence in the general population. The protective AA genotypee of the ESR1 gene (c.453–351A>G) was also relatively frequent (37.4% of women). Osteopenia, as a clinical sign of an increased risk of osteoporosis, was diagnosed in 15% of the evaluated women. When correlated, 3% of women had an increased genetic and clinical risk.

Conclusion:
Genetic testing could become one of the predictors of risk of osteoporosis, which would allow early and targeted prevention of osteoporosis even prior to the development of any clinical and densinometric changes.

Key words:
osteoporosis – predictive genetic testing – densitometry

Sources

1. Deng HW, Chen WM, Rocker S et al. Genetics determination of Colles’ fracture and diffe-rential bone mass in women with and without Colles’ fracture. J Bone Miner Res 2000; 15(7): 1243–1252.

2. Andrew T, Antioniades L, Scurrah KJ et al. Risk of wrist fracture in women is heritable and is influenced by genes that are largely independent of those influencing BMD. J Bone Miner Res 2005; 20(1): 67–74.

3. Kannus P, Palvanen M, Kaprio J et al. Genetics factors and osteoporotic fractures in elderly people: prospective 25 year follow up of a nationwide cohort of elderly Finnish twins. BMJ 1999; 319(7221): 1334–1337.

4. Michaëlsson K, Melhus H, Ferm H et al. Genetics liability for fractures in the elderly. Arch Intern Med 2005; 165(16): 1825–1830.

5. Ralston SH. Genetics of osteoporosis. Proc Nutr Soc 2007; 66(2): 158–165.

6. Ferrari S. Human genetics of osteoporosis. Best Pract Res Clin Endocrinol Metanol 2008; 22(5): 723–735.

7. Arai H, Miyamoto KI, Yoshida M et al. The polymorphism in the caudal-related homeodomain protein Cdx-2 binding element in the human vitamin D receptor gene. J Bone Miner Res 2001; 16(7): 1256–1264.

8. Gross C, Eccleshall TR, Malloy PJ et al. The presence of a polymorphism at the translation initiation site of the vitamin D receptor gene is associated with low BMD in postmenopausal Mexican-American women. J Bone Miner Res 1997; 11(12): 1850–1856.

9. Thakkinstian A, D’Este C, Eisman J et al. Meta-analysis of molecular association studies: vitamin D receptor gene polymorphisms and BMD as a case study. J Bone Miner Res 2004; 19(3): 419–428.

10. Grant SF, Reid DM, Blake G et al. Reduced bone density and osteoporosis associated with polymorphic Sp1 binding site in the collagen type I alpha 1 gene. Nat Genet 1996; 14(2): 203–205.

11. Harris SS, Patel MS, Cole DE et al. Association of the collagen type I alpha 1 Sp1 polymorphism with five-year rates of bone loss in older adults. Calcif Tissue Int 2000; 66(4): 268–271.

12. Mann V, Hobson EE, Li B et al. A COL1A1 Sp1 binding site polymorphism predisposes to osteoporotic fracture by affecting bone density and quality. J Clin Invest 2001; 107(7): 899–907.

13. Steward TL, Roschger P, Misof BM et al. Association of COL1A1 Sp1 alleles with defective bone nodule formation in vitro and abnormal bone mineralization in vivo. Calcif Tissue Int 2005; 77(2): 113–118.

14. Albagha OM, Pettersson U, Stewart A et al. Association of oestrogen receptor alpha gene polymorphisms with postmenopausal bone loss, bone mass, and quantitative ultrasound properties of bone. J Med Genet 2005; 42(3): 240–246.

15. Ioannidis JP, Stavrou I, Trikalinos TA et al. Association of polymorphisms of the oestrogen receptor alpha gene with BMD and fracture risk in women: a meta-analysis. J Bone Miner Res 2002; 17(11): 2048–2060.

16. Shah R, Rahaman B, Hurley CK et al. Allelic diversity in the TGFB1 regulatory region: characterization of novel functional single nucleotide polymorphisms. Hum Genet 2006; 119(1–2): 61–74.

17. Yamada Y, Miyauchi A, Takagi Y et al. Association of the C-509T polymorphism, alone of in combination with the T869-C polymorphism, of the transforming growth factor-beta1 gene with BMD ad genetic susceptibility to osteoporosis in Japanese women. J Mol Med 2001; 79(2–3): 149–156.

18. Ferrari SL, Deutsch S, Choudhury U et al. Polymorphism in the low-density lipoprotein receptor-related protein 5 (LPR5) gene are associated with variation in vertebral bone mass, vertebral size, and stature in whites. Am J Hum Genet 2004; 74(5): 866–875.

19. van Meurs JB, Rivadeneira F, Jhamai M et al. Common genetic variation of the low-density lipoprotein receptor-related protein 5 and 6 genes determines fracture risk in elderly white men. J Bone Miner Res 2006; 21(1): 141–150.

20. Uitterlinden AG, Arp PP, Paeper BW et al. Polymorphisms in the sclerosteosis/van Buchem disease gene (SOST) region are associated with BMD in elderly whites. Am J Hum Genet 2004; 75(6): 1032–1045.

21. Sobacchi C, Vezzoni P, Reid DM et al. Association between a polymorphism affecting an AP1 binding site in the promoter of the TCIRG1 gene and bone mass in women. Calcif Tissue Int 2004; 74(1): 35–41.

22. Pettersson U, Albagha OM, Mirolo M et al. Polymorphisms of the CLCN7 gene are associated with BMD in women. J Bone Miner Res 2005; 20(11): 1960–1967.

23. Murray RE, McGuigan F, Grant SF et al. Polymorphism of IL6 gene are associated with BMD. Bone 1997; 21(1): 89–92.

24. Langdahl BL, Carstens M, Stenkjaer L et al. Polymorphisms in the osteoprotegerin gene are associated with osteoporotic fractures. J Bone Miner Res 2002; 17(7): 1245–1255.

25. Harsløt T, Husted LB, Nyegaard M et al. Polymorphisms in the ALOX12 gene and osteoporosis. Osteoporos Int 2011; 22(8): 2249–2255.