Role of genetics in prediction of osteoporosis risk

Česká verzia

Authors: I. Žofková
Authors place of work: Endokrinologický ústav Praha, ředitel doc. MU Dr. Vojtěch Hainer, CSc.
Published in the journal: Vnitř Lék 2011; 57(1): 78-84
Category: Reviews

Summary

Osteoporosis is in 60– 80% a hereditary disease with a characteristic multifactorial pathogenesis during which the effects of many “weak” genes interact with external factors. To date, most information relating to the correlations between genes and bone parameter variability (density, quality and metabolism) has been provided by association studies of candidate genes for osteoporosis. The best known genes related to bone density have been identified as the genes for the vitamin D, estrogen and calcitonin receptor, LRP5 and LRP6. The genes for IL‑1α and osteoprotegerin are responsible for the parameters of bone remodeling. Recently discovered genes related to bone phenotype include identified genes for hypolactasia, tetrafolate reductase and ALDH7A1. Bone size and dimensions are probably partially controlled by the PLCL1 gene. Candidate genes for osteoporosis probably also determine the production of calciotropic hormones (PTH, sex steroids) and even some extra‑osseous phenotypes (inflammation, immunity, susceptibility to malignancies). On the contrary, genes that determine extra‑osseous parameters (e. g. lipoprotein levels) are associated with the bone phenotype (the gene for ApoE is related to bone density). Association studies, though, have serious limitations. Among others, these include the influence of linkage disequilibrium associated with the close proximity of the identified genes within DNA, which may be one of the causes of false positive results. In children, where building of the skeleton is influenced predominantly by external factors (nutrition, physical activity), the relationship between candidate genes and bone mass is less close than in adults. This overview deals with the physiology and sexual differentiation of pubertal bone. It discusses the importance of identifying candidate genes in the prevention and targeted treatment of osteoporosis (pharmacogenetics) as well as the application of the FRAX (WHO) program in the ten‑year prediction of fractures in osteopenic patients.

Key words:
osteoporosis – genetics – candidate genes for osteoporosis – pubertal bone – prevention of osteoporosis – pharmacogenetics

Zdroje

1. Lazcano- Ponce E. Tamaro J, Diaz T et al. Correlation trends for bone mineral density in Mexican women: evidence of familiar predisposition. Salud Publica Mex 2009; 51 (Suppl 1): 93– 99.

2. Peacock M, Turner ChH, Econs MJ et al. Genetics of osteoporosis. Endocrine Reviews 2002; 23: 303– 326.

3. Ralston SH. Genetic control of susceptibility to osteoporosis. J Clin Endocrinol Metab 2002; 87: 2460– 2466.

4. Omelka R, Martiniaková, Žofková I. Genetický výskum osteoporózy: možnosti a experimentálne východiská. Osteologický bulletin 2007; 12: 11– 17.

5. Rauch F, Lalic L, Roughley P et al. Genotype- phenotype correlations in nonlethal osteogenesis imperfecta cause by mutations in the helical domain of collagen type I. Eur J Hum Genet 2010; Jan 20 (Epub ahead of print).

6. 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: 419– 428.

7. Cooper GS, Umbach DM. Are vitamin D receptor polymorphisms associated with bone mineral density? A meta-analysis. J Bone Miner Res 1996; 11: 1841– 1849.

8. Zajickova K, Zofkova I, Bahbouh R et al. Vitamin D receptor gene polymorphisms, bone mineral density and bone turnover: FokI genotype is related to postmenopausal bone mass. Physiol Res 2002; 51: 501– 509.

9. Willing M, Sowers M, Aron D et al. Bone mineral density and its change in white women: estrogen and vitamin D receptor genotypes and thein interaction. J Bone Miner Res 1998; 13: 695– 705.

10. Masi L, Cimaz R, Simonini G et al. Association of low bone mass with vitamin d receptor gene and calcitonin receptor gene polymorphisms in juvenile idiopathic arthritis. J Rheumatol 2002; 29: 2225– 2231.

11. Lee HJ, Kim SY, Kim GS et al. Fracture, bone mineral density, and the effects of calcitonin receptor gene in postmenopausal Koreans. Osteoporosis Int 2009; Nov 28 (Epub ahead of print).

12. Zofkova I, Zajickova K, Hill M et al. Does polymorphism C1377T of the calcitonin receptor gene determine bone mineral density in postmenopausal women? Exp Clin Endocrinol Diabetes 2003; 111: 447– 449.

13. Charapoulos I, Trovas G, Stathopoulou Met al. Lack of association between vitamin D and calcitonin receptor gene polymorphisms and forearm bone values of young Greek males. J Musculoskelet Neuronat Interact 2008; 8: 196– 203.

14. Obermayer- Pietsch B. Genetics of osteoporosis. Sien Med Wochenschr 2006; 156: 162– 163.

15. Ralston SH , Uitterlinden AG, Brandi ML et al. Large- scale evidence for the effect of COLIA1 Sp1 polymorphism on osteoporosis outcomes: The GENOMOS study. PLoS Medicine 2006; 3: 0515– 0522.

16. MacDonald HM, McGuigan FA, New SA et al. COL1A1 Sp1 polymorphism predicts perimenopausal and early postmenopausal spinal bone loss. J Bone Miner Res 2001; 16: 1634– 1641.

17. Fairbrother UL, Tankó LB, Halley AJ et al. Leptin receptor genotype at Gln223Arg is associated with body composition, BMD, and vertebral fracture in postmenopausal Danish women. J Bone Miner Res 2007; 22: 544– 550.

18. Glass DA2nd, Fialek P, Ahn JD et al. Canonical Wnt signaling in diferentiated osteoblasts control osteoclast differentiation. Developmental cell 2005; 8: 751– 764.

19. Grundberg E, Lau EM, Lorentzon M et al. Large- scale association study between two coding LRP5 gene polymorphisms and bone phenotypes and fractures in men. Osteoporosis Int 2008; 19: 829– 837.

20. 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: 141– 150.

21. Czerny B, Kaminski A, Kurzawski M et al. The association of IL-1β, and IL-6 gene polymorphisms with bone mineral density and osteoporosis in postmenopausal women. Eur J Obstet Gynecol Reprod Biol 2010; Jan 6 (Epub ahead of print).

22. Wang C, He JW, Qin YJ et al. Osteoprotegerin gene polymorphism and therapeutic response to alendronate in postmenopausal women with osteoporosis. Zhonghua Yi Xue Za Zhi 2009; 89: 2958– 2962.

23. Ueland T, Bollerslev J, Wilson SG et al. No associations between OPG gene polymorphisms or serum levels and merasures of osteoporosis in elderly Australan women. Bone 2007; 40: 175– 181.

24. Takács I, Lazáry A, Kósa JP et al. Allelic variations of RANKL/ OPG signaling system are related to bone mineral density and in vivo gene expression. Eur J Endocrinol 2010; 162: 423– 431.

25. Richter L, Chevalley T, Manen D et al. Bone mass in prepubertal boys is associated with a Gln223Arg amino acid substitution in the leptin receptor. J Clin Endocrinol Metab 2007; 92: 4380– 4386.

26. Bathum L, von Bornemann Hjelmborg J, Christiansen L et al. Evidence for an association of methylene tetrahydrofolate reductase polymorphism C677T and an increased risk of fractures: results from a population-based Danish twin study. Osteoporosis Int 2004; 15: 659– 664.

27. Ongphiphadanakul B. Osteoporosis: the role of genetics and the environment. Forum Nutr 2007; 60: 158– 167.

28. Guo Y, Tan LJ, Lei SF et al. Geonome- wide association study identifies ALDH7A1 as a novel susceptibility gene for osteoporosis. PLoS Genet 2010; 6: 1000806.

29. Liu YZ, Wilson SG, Wang L et al. Identification of PLCL1 gene for hip bone size variation in females in a geonome- wide association study. PLoS One 2008; 3: 3160.

30. Zofkova I, Hill M, Zajickova K. Association of C/ T polymorphism in the LRP5 gene with circulating follicle stimulating hormone in Caucasian postmenopausal women. Physiol Res 2007; 56: 735– 739.

31. Zajickova K, Hill M, Vankova M et al. Low- density lipoprotein receptor-related protein 5 and vitamin D receptor gene polymorphisms in relation to vitamin D levels in menopause. Clin Chem Lab Med 2006; 44: 1066– 1069.

32. Zofkova I, Zajickova K, Hill M. Postmenopausal serum androstenedione levels are associated with the calcitonin receptor gene polymorphism T1377C. A pilot study. I Endocrinol Invest 2004; 27: 442– 444.

33. Zofkova I, Zajickova K, Hill M. The estrogen receptor alpha gene determines serum androstenedione levels in postmenopausal women. Steroids 2002; 67: 815– 819.

34. Zofkova I, Zajickova K, Hill M. Serum parathyroid hormone levels are associated with FokI polymorphism of the vitamin D receptor gene in untreated postmenopausal women. Eur J Internal Med 2003; 14: 232– 236.

35. Laaksonen MM, Outila TA, Karkkainen MU et al. Association of vitamin D receptor, calcium- sensing receptor and parathyroid hormone gene polymorphisms with calcium homeostasis and peripheral bone density in adult Finns. J Nutrigenet Nutrigenomics 2009; 2: 55– 56.

36. Zajickova K, Zofkova I, Hill M et al. Apolipoprotein E 4 allele is associated with low bone density in postmenopausal women. J Endocrinol Invest 2003; 26: 312– 315.

37. Bonjour JP, Chevalley T, Ferrari S et al. The importance and relevance of peak bone mass in the prevalence of osteoporosis. Salud Publica Mex 2009; 51 (Suppl I): S5– S17.

38. Cheng S, Völgyi E, Tylovsky FA et al. Trait- specific tracking and determinants of body composition: a 7 year follow-up study of pubertal growth in girls. BMC Med 2009; 7: 5.

39. Robling AG, Bellido TM, Turner CH. Mechanical loading reduced osteocyte expression of sclerostin protein. J Bone Miner Res 2006; 21 (Suppl I): S72.

40. Nordstrom A, Karlsson C, Nyquist F et al. Bone loss and fracture risk after reduced physical activity. J Bone Miner Res 2005; 20: 202– 207.

41. Ducher G, Courteix D, Meme S et al. Bone geometry in response to long-term tennis playing and its relationship with muscle volume: a quantitative magnetic resonance imaging in tennis players. Bone 2005; 37: 457– 466.

42. Uitterlinden AG, Ralston SH, Brandi ML et al. The association between common vitamin D receptor gene variations and osteoporosis: a participant- level meta-analysis. Ann Intern Med 2006; 145: 255– 264.

43. Duncan EL, Brown MA. Mapping genes for osteoporosis- old dogs and new tricks. Bone 2010; Jan 11 (Epub ahead of print).

44. Gennari L, De Paola V, Merlotti D et al. Steroid hormone receptor gene polymorphisms and osteoporosis: a pharmacogenomic review. Expert Opin Pharmacother 2007; 8: 537– 553.

45. Massart F, Marcucci G, Brandi ML. Pharmacogenetics of bone treatments: the VDR and ERα gene story. Pharmacogenomics 2008; 9: 733– 746.

46. Ohlendrorff SD, Tofteng CL, Jensen JE et al. Single nucleotide polymorphisms in the P2X7 gene are associated to fracture risk and the effect of estrogen treatment. Pharmacogenet Genomics 2007; 17: 555– 567.

47. Nguyen TV, Center JR, Eisman JA. Pharmacogenetics of osteoporosis and the prospect of individualized prognosis and individualized therapy. Curr Opin Endocrinol Diabetes Obes 2008; 15: 481– 488.

48. Siris ES, Baim S, Nattiv A. Primary care use of FRAX: absolute fracture risk assessment in postmenopausal women and older men. Postgrad Med 2010; 122: 82– 90. www.shef.ac.uk/ FRAX.