Genetic Determinants of Trabecular and Cortical Volumetric Bone Mineral Densities and Bone Microstructure

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Most previous genetic epidemiology studies within the field of osteoporosis have focused on the genetics of the complex trait areal bone mineral density (aBMD), not being able to differentiate genetic determinants of cortical volumetric BMD (vBMD), trabecular vBMD, and bone microstructural traits. The objective of this study was to separately identify genetic determinants of these bone traits as analysed by peripheral quantitative computed tomography (pQCT). Separate GWA meta-analyses for cortical and trabecular vBMDs were performed. The cortical vBMD GWA meta-analysis (n = 5,878) followed by replication (n = 1,052) identified genetic variants in four separate loci reaching genome-wide significance (RANKL, rs1021188, p = 3.6×10⁻¹⁴; LOC285735, rs271170, p = 2.7×10⁻¹²; OPG, rs7839059, p = 1.2×10⁻¹⁰; and ESR1/C6orf97, rs6909279, p = 1.1×10⁻⁹). The trabecular vBMD GWA meta-analysis (n = 2,500) followed by replication (n = 1,022) identified one locus reaching genome-wide significance (FMN2/GREM2, rs9287237, p = 1.9×10⁻⁹). High-resolution pQCT analyses, giving information about bone microstructure, were available in a subset of the GOOD cohort (n = 729). rs1021188 was significantly associated with cortical porosity while rs9287237 was significantly associated with trabecular bone fraction. The genetic variant in the FMN2/GREM2 locus was associated with fracture risk in the MrOS Sweden cohort (HR per extra T allele 0.75, 95% confidence interval 0.60–0.93) and GREM2 expression in human osteoblasts. In conclusion, five genetic loci associated with trabecular or cortical vBMD were identified. Two of these (FMN2/GREM2 and LOC285735) are novel bone-related loci, while the other three have previously been reported to be associated with aBMD. The genetic variants associated with cortical and trabecular bone parameters differed, underscoring the complexity of the genetics of bone parameters. We propose that a genetic variant in the RANKL locus influences cortical vBMD, at least partly, via effects on cortical porosity, and that a genetic variant in the FMN2/GREM2 locus influences GREM2 expression in osteoblasts and thereby trabecular number and thickness as well as fracture risk.

Vyšlo v časopise: Genetic Determinants of Trabecular and Cortical Volumetric Bone Mineral Densities and Bone Microstructure. PLoS Genet 9(2): e32767. doi:10.1371/journal.pgen.1003247
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003247

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Zdroje

1. DuncanEL, DanoyP, KempJP, LeoPJ, McCloskeyE, et al. (2011) Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk. PLoS Genet 7: e1001372 doi:10.1371/journal.pgen.1001372.

2. EstradaK, StyrkarsdottirU, EvangelouE, HsuYH, DuncanEL, et al. (2012) Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet 44: 491–501.

3. RivadeneiraF, StyrkarsdottirU, EstradaK, HalldorssonBV, HsuYH, et al. (2009) Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet 41: 1199–1206.

4. StyrkarsdottirU, HalldorssonBV, GretarsdottirS, GudbjartssonDF, WaltersGB, et al. (2008) Multiple genetic loci for bone mineral density and fractures. N Engl J Med 358: 2355–2365.

5. StyrkarsdottirU, HalldorssonBV, GretarsdottirS, GudbjartssonDF, WaltersGB, et al. (2009) New sequence variants associated with bone mineral density. Nat Genet 41: 15–17.

6. RichardsJB, RivadeneiraF, InouyeM, PastinenTM, SoranzoN, et al. (2008) Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet 371: 1505–1512.

7. SievanenH (2000) A physical model for dual-energy X-ray absorptiometry–derived bone mineral density. Invest Radiol 35: 325–330.

8. NicksKM, AminS, AtkinsonEJ, RiggsBL, MeltonLJ3rd, et al. (2012) Relationship of age to bone microstructure independent of areal bone mineral density. J Bone Miner Res 27: 637–644.

9. ZebazeRM, Ghasem-ZadehA, BohteA, Iuliano-BurnsS, MiramsM, et al. (2010) Intracortical remodelling and porosity in the distal radius and post-mortem femurs of women: a cross-sectional study. Lancet 375: 1729–1736.

10. PaternosterL, LorentzonM, VandenputL, KarlssonMK, LjunggrenO, et al. (2010) Genome-wide association meta-analysis of cortical bone mineral density unravels allelic heterogeneity at the RANKL locus and potential pleiotropic effects on bone. PLoS Genet 6: e1001217 doi:10.1371/journal.pgen.1001217.

11. HavillLM, MahaneyMC, TLB, SpeckerBL (2007) Effects of genes, sex, age, and activity on BMC, bone size, and areal and volumetric BMD. J Bone Miner Res 22: 737–746.

12. LaibA, RuegseggerP (1999) Calibration of trabecular bone structure measurements of in vivo three-dimensional peripheral quantitative computed tomography with 28-microm-resolution microcomputed tomography. Bone 24: 35–39.

13. MacNeilJA, BoydSK (2007) Accuracy of high-resolution peripheral quantitative computed tomography for measurement of bone quality. Med Eng Phys 29: 1096–1105.

14. YangJ, BenyaminB, McEvoyBP, GordonS, HendersAK, et al. (2010) Common SNPs explain a large proportion of the heritability for human height. Nat Genet 42: 565–569.

15. GrundbergE, AdoueV, KwanT, GeB, DuanQL, et al. (2011) Global analysis of the impact of environmental perturbation on cis-regulation of gene expression. PLoS Genet 7: e1001279 doi:10.1371/journal.pgen.1001279.

16. GrundbergE, KwanT, GeB, LamKC, KokaV, et al. (2009) Population genomics in a disease targeted primary cell model. Genome Res 19: 1942–1952.

17. Consensus Development Conference on Osteoporosis. Hong Kong, April 1–2, 1993. Am J Med 95: 1S–78S.

18. ZhengHF, TobiasJH, DuncanE, EvansDM, ErikssonJ, et al. (2012) WNT16 Influences Bone Mineral Density, Cortical Bone Thickness, Bone Strength, and Osteoporotic Fracture Risk. PLoS Genet 8: e1002745 doi:10.1371/journal.pgen.1002745.

19. EstradaK, AbuseirisA, GrosveldFG, UitterlindenAG, KnochTA, et al. (2009) GRIMP: a web- and grid-based tool for high-speed analysis of large-scale genome-wide association using imputed data. Bioinformatics 25: 2750–2752.

20. GrundbergE, SmallKS, HedmanAK, NicaAC, BuilA, et al. (2012) Mapping cis- and trans-regulatory effects across multiple tissues in twins. Nat Genet 44: 1084–1089.

21. CummingsSR, San MartinJ, McClungMR, SirisES, EastellR, et al. (2009) Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 361: 756–765.

22. SeemanE, DelmasPD, HanleyDA, SellmeyerD, CheungAM, et al. (2010) Microarchitectural deterioration of cortical and trabecular bone: differing effects of denosumab and alendronate. J Bone Miner Res 25: 1886–1894.

23. KostenuikPJ, NguyenHQ, McCabeJ, WarmingtonKS, KuraharaC, et al. (2009) Denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and increases BMD in knock-in mice that express chimeric (murine/human) RANKL. J Bone Miner Res 24: 182–195.

24. KhoslaS, MeltonLJ3rd, RiggsBL (2011) The unitary model for estrogen deficiency and the pathogenesis of osteoporosis: is a revision needed? J Bone Miner Res 26: 441–451.

25. MellstromD, VandenputL, MallminH, HolmbergAH, LorentzonM, et al. (2008) Older men with low serum estradiol and high serum SHBG have an increased risk of fractures. J Bone Miner Res 23: 1552–1560.

26. SmithEP, BoydJ, FrankGR, TakahashiH, CohenRM, et al. (1994) Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 331: 1056–1061.

27. VandenputL, OhlssonC (2009) Estrogens as regulators of bone health in men. Nat Rev Endocrinol 5: 437–443.

28. VanderschuerenD, VandenputL, BoonenS, LindbergMK, BouillonR, et al. (2004) Androgens and bone. Endocr Rev 25: 389–425.

29. LeaderB, LimH, CarabatsosMJ, HarringtonA, EcsedyJ, et al. (2002) Formin-2, polyploidy, hypofertility and positioning of the meiotic spindle in mouse oocytes. Nat Cell Biol 4: 921–928.

30. Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447: 661–678.

31. IdenoH, TakanabeR, ShimadaA, ImaizumiK, ArakiR, et al. (2009) Protein related to DAN and cerberus (PRDC) inhibits osteoblastic differentiation and its suppression promotes osteogenesis in vitro. Exp Cell Res 315: 474–484.

32. ImJ, KimH, KimS, JhoEH (2007) Wnt/beta-catenin signaling regulates expression of PRDC, an antagonist of the BMP-4 signaling pathway. Biochem Biophys Res Commun 354: 296–301.

33. BeamerWG, ShultzKL, Ackert-BicknellCL, HortonLG, DelahuntyKM, et al. (2007) Genetic dissection of mouse distal chromosome 1 reveals three linked BMD QTLs with sex-dependent regulation of bone phenotypes. J Bone Miner Res 22: 1187–1196.

34. EdderkaouiB, BaylinkDJ, BeamerWG, ShultzKL, WergedalJE, et al. (2007) Genetic regulation of femoral bone mineral density: complexity of sex effect in chromosome 1 revealed by congenic sublines of mice. Bone 41: 340–345.

35. IshimoriN, StylianouIM, KorstanjeR, MarionMA, LiR, et al. (2008) Quantitative trait loci for BMD in an SM/J by NZB/BlNJ intercross population and identification of Trps1 as a probable candidate gene. J Bone Miner Res 23: 1529–1537.

36. OrwollES, BelknapJK, KleinRF (2001) Gender specificity in the genetic determinants of peak bone mass. J Bone Miner Res 16: 1962–1971.

37. KarasikD, CupplesLA, HannanMT, KielDP (2003) Age, gender, and body mass effects on quantitative trait loci for bone mineral density: the Framingham Study. Bone 33: 308–316.

38. IoannidisJP, NgMY, ShamPC, ZintzarasE, LewisCM, et al. (2007) Meta-analysis of genome-wide scans provides evidence for sex- and site-specific regulation of bone mass. J Bone Miner Res 22: 173–183.

39. OhlssonC, WallaschofskiH, LunettaKL, StolkL, PerryJR, et al. (2011) Genetic determinants of serum testosterone concentrations in men. PLoS Genet 7: e1002313 doi:10.1371/journal.pgen.1002313.

40. VidalO, LindbergMK, HollbergK, BaylinkDJ, AnderssonG, et al. (2000) Estrogen receptor specificity in the regulation of skeletal growth and maturation in male mice. Proc Natl Acad Sci U S A 97: 5474–5479.

41. HenryYM, FatayerjiD, EastellR (2004) Attainment of peak bone mass at the lumbar spine, femoral neck and radius in men and women: relative contributions of bone size and volumetric bone mineral density. Osteoporos Int 15: 263–273.

42. OhlssonC, DarelidA, NilssonM, MelinJ, MellstromD, et al. (2011) Cortical consolidation due to increased mineralization and endosteal contraction in young adult men: a five-year longitudinal study. J Clin Endocrinol Metab 96: 2262–2269.

43. LarocheM (2012) Pattern of bone mineral density in idiopathic male osteoporosis. Rheumatol Int 32: 3093–3096.

44. LeslieWD, LixLM, JohanssonH, OdenA, McCloskeyE, et al. (2011) Spine-hip discordance and fracture risk assessment: a physician-friendly FRAX enhancement. Osteoporos Int 22: 839–847.

45. LorentzonM, MellstromD, OhlssonC (2005) Age of attainment of peak bone mass is site specific in Swedish men–The GOOD study. J Bone Miner Res 20: 1223–1227.

46. LorentzonM, SwansonC, AnderssonN, MellstromD, OhlssonC (2005) Free testosterone is a positive, whereas free estradiol is a negative, predictor of cortical bone size in young Swedish men: the GOOD study. J Bone Miner Res 20: 1334–1341.

47. NilssonM, OhlssonC, SundhD, MellstromD, LorentzonM (2010) Association of physical activity with trabecular microstructure and cortical bone at distal tibia and radius in young adult men. J Clin Endocrinol Metab 95: 2917–2926.

48. BurghardtAJ, KazakiaGJ, RamachandranS, LinkTM, MajumdarS (2010) Age- and gender-related differences in the geometric properties and biomechanical significance of intracortical porosity in the distal radius and tibia. J Bone Miner Res 25: 983–993.

49. NishiyamaKK, MacdonaldHM, BuieHR, HanleyDA, BoydSK (2010) Postmenopausal women with osteopenia have higher cortical porosity and thinner cortices at the distal radius and tibia than women with normal aBMD: an in vivo HR-pQCT study. J Bone Miner Res 25: 882–890.

50. BurghardtAJ, BuieHR, LaibA, MajumdarS, BoydSK (2010) Reproducibility of direct quantitative measures of cortical bone microarchitecture of the distal radius and tibia by HR-pQCT. Bone 47: 519–528.

51. RaitakariOT, JuonalaM, RonnemaaT, Keltikangas-JarvinenL, RasanenL, et al. (2008) Cohort profile: the cardiovascular risk in Young Finns Study. Int J Epidemiol 37: 1220–1226.

52. BoydA, GoldingJ, MacleodJ, LawlorDA, FraserA, et al. (2012) Cohort Profile: The ‘Children of the 90s’–the index offspring of the Avon Longitudinal Study of Parents and Children. Int J Epidemiol

53. JonesRW, RingS, TyfieldL, HamvasR, SimmonsH, et al. (2000) A new human genetic resource: a DNA bank established as part of the Avon longitudinal study of pregnancy and childhood (ALSPAC). Eur J Hum Genet 8: 653–660.

54. MellstromD, JohnellO, LjunggrenO, ErikssonAL, LorentzonM, et al. (2006) Free testosterone is an independent predictor of BMD and prevalent fractures in elderly men: MrOS Sweden. J Bone Miner Res 21: 529–535.

55. LiYA, G.R. (2006) Mach 1.0: Rapid haplotype reconstruction and missing genotype inference. Am J Hum Genet S79: 2290.

56. JutbergerH, LorentzonM, Barrett-ConnorE, JohanssonH, KanisJA, et al. (2010) Smoking predicts incident fractures in elderly men: Mr OS Sweden. J Bone Miner Res 25: 1010–1016.

57. AulchenkoYS, StruchalinMV, van DuijnCM (2010) ProbABEL package for genome-wide association analysis of imputed data. BMC Bioinformatics 11: 134.