Polyalanine Repeat Polymorphism in RUNX2 is Associated with Site-specific Fracture in Post-menopausal Females

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2013 Oct 3

PMID 24086263

Citations 6

Authors

Nigel A Morrison

Alexandre S Stephens

Motomi Osato

Julie A Pasco

Nicolette Fozzard

Gary S Stein

Patsie Polly

Lyn R Griffiths

Geoff C Nicholson

Affiliations

Soon will be listed here.

Abstract

Runt related transcription factor 2 (RUNX2) is a key regulator of osteoblast differentiation. Several variations within the RUNX2 gene have been found to be associated with significant changes in BMD, which is a major risk factor for fracture. In this study we report that an 18 bp deletion within the polyalanine tract (17A>11A) of RUNX2 is significantly associated with fracture. Carriers of the 11A allele were found to be nearly twice as likely to have sustained fracture. Within the fracture category, there was a significant tendency of 11A carriers to present with fractures of distal radius and bones of intramembranous origin compared to bones of endochondral origin (p = 0.0001). In a population of random subjects, the 11A allele was associated with decreased levels of serum collagen cross links (CTx, p = 0.01), suggesting decreased bone turnover. The transactivation function of the 11A allele showed a minor quantitative decrease. Interestingly, we found no effect of the 11A allele on BMD at multiple skeletal sites. These findings suggest that the 11A allele is a biologically relevant polymorphism that influences serum CTx and confers enhanced fracture risk in a site-selective manner related to intramembranous bone ossification.

Citing Articles

Reassessing the association: Evaluation of a polyalanine deletion variant of RUNX2 in non-syndromic sagittal and metopic craniosynostosis.

Walton I, McCann E, Weber A, Morton J, Noons P, Wilson L J Anat. 2024; 245(6):874-878.

PMID: 38760592 PMC: 11547237. DOI: 10.1111/joa.14052.

Evolution and expansion of the RUNX2 QA repeat corresponds with the emergence of vertebrate complexity.

Newton A, Pask A Commun Biol. 2020; 3(1):771.

PMID: 33319865 PMC: 7738678. DOI: 10.1038/s42003-020-01501-3.

Intrinsic Disorder in Proteins with Pathogenic Repeat Expansions.

Darling A, Uversky V Molecules. 2017; 22(12).

PMID: 29186753 PMC: 6149999. DOI: 10.3390/molecules22122027.

RUNX2 repeat variation does not drive craniofacial diversity in marsupials.

Newton A, Feigin C, Pask A BMC Evol Biol. 2017; 17(1):110.

PMID: 28472940 PMC: 5418715. DOI: 10.1186/s12862-017-0955-6.

Bivariate Genome-Wide Association Study Implicates ATP6V1G1 as a Novel Pleiotropic Locus Underlying Osteoporosis and Age at Menarche.

Tan L, Wang Z, Wu K, Chen X, Zhu H, Lu S J Clin Endocrinol Metab. 2015; 100(11):E1457-66.

PMID: 26312577 PMC: 4702453. DOI: 10.1210/jc.2015-2095.

References

Rosen H, Moses A, Garber J, Iloputaife I, Ross D, Lee S . Serum CTX: a new marker of bone resorption that shows treatment effect more often than other markers because of low coefficient of variability and large changes with bisphosphonate therapy. Calcif Tissue Int. 2000; 66(2):100-3. DOI: 10.1007/pl00005830. View

Meyer M, Kircher M, Gansauge M, Li H, Racimo F, Mallick S . A high-coverage genome sequence from an archaic Denisovan individual. Science. 2012; 338(6104):222-6. PMC: 3617501. DOI: 10.1126/science.1224344. View

Franz-Odendaal T . Induction and patterning of intramembranous bone. Front Biosci (Landmark Ed). 2011; 16(7):2734-46. DOI: 10.2741/3882. View

Morrison N, Stephens A, Osato M, Polly P, Tan T, Yamashita N . Glutamine repeat variants in human RUNX2 associated with decreased femoral neck BMD, broadband ultrasound attenuation and target gene transactivation. PLoS One. 2012; 7(8):e42617. PMC: 3418257. DOI: 10.1371/journal.pone.0042617. View

Sanders K, Seeman E, Ugoni A, Pasco J, Martin T, Skoric B . Age- and gender-specific rate of fractures in Australia: a population-based study. Osteoporos Int. 1999; 10(3):240-7. DOI: 10.1007/s001980050222. View

Ermakov S, Malkin I, Kobyliansky E, Livshits G . Variation in femoral length is associated with polymorphisms in RUNX2 gene. Bone. 2005; 38(2):199-205. DOI: 10.1016/j.bone.2005.08.008. View

Vaughan T, Pasco J, Kotowicz M, Nicholson G, Morrison N . Alleles of RUNX2/CBFA1 gene are associated with differences in bone mineral density and risk of fracture. J Bone Miner Res. 2002; 17(8):1527-34. DOI: 10.1359/jbmr.2002.17.8.1527. View

Green R, Krause J, Briggs A, Maricic T, Stenzel U, Kircher M . A draft sequence of the Neandertal genome. Science. 2010; 328(5979):710-722. PMC: 5100745. DOI: 10.1126/science.1188021. View

Doecke J, Day C, Stephens A, Carter S, Daal A, Kotowicz M . Association of functionally different RUNX2 P2 promoter alleles with BMD. J Bone Miner Res. 2006; 21(2):265-73. DOI: 10.1359/JBMR.051013. View

10.

Yoshida T, Kanegane H, Osato M, Yanagida M, Miyawaki T, Ito Y . Functional analysis of RUNX2 mutations in Japanese patients with cleidocranial dysplasia demonstrates novel genotype-phenotype correlations. Am J Hum Genet. 2002; 71(4):724-38. PMC: 378531. DOI: 10.1086/342717. View

11.

Estrada K, Styrkarsdottir U, Evangelou E, Hsu Y, Duncan E, Ntzani E . Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet. 2012; 44(5):491-501. PMC: 3338864. DOI: 10.1038/ng.2249. View

12.

Otto F, Thornell A, Crompton T, Denzel A, Gilmour K, Rosewell I . Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell. 1997; 89(5):765-71. DOI: 10.1016/s0092-8674(00)80259-7. View

13.

Ducy P, Zhang R, Geoffroy V, Ridall A, Karsenty G . Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell. 1997; 89(5):747-54. DOI: 10.1016/s0092-8674(00)80257-3. View

14.

Ermakov S, Malkin I, Keter M, Kobyliansky E, Livshits G . Family-based association study of polymorphisms in the RUNX2 locus with hand bone length and hand BMD. Ann Hum Genet. 2008; 72(Pt 4):510-8. DOI: 10.1111/j.1469-1809.2008.00441.x. View

15.

Chan M, Nguyen N, Center J, Eisman J, Nguyen T . Absolute fracture-risk prediction by a combination of calcaneal quantitative ultrasound and bone mineral density. Calcif Tissue Int. 2011; 90(2):128-36. DOI: 10.1007/s00223-011-9556-3. View

16.

Sears K, Goswami A, Flynn J, Niswander L . The correlated evolution of Runx2 tandem repeats, transcriptional activity, and facial length in carnivora. Evol Dev. 2007; 9(6):555-65. DOI: 10.1111/j.1525-142X.2007.00196.x. View

17.

Sanders K, Pasco J, Ugoni A, Nicholson G, Seeman E, Martin T . The exclusion of high trauma fractures may underestimate the prevalence of bone fragility fractures in the community: the Geelong Osteoporosis Study. J Bone Miner Res. 1998; 13(8):1337-42. DOI: 10.1359/jbmr.1998.13.8.1337. View

18.

Carter D, Bouxsein M, Marcus R . New approaches for interpreting projected bone densitometry data. J Bone Miner Res. 1992; 7(2):137-45. DOI: 10.1002/jbmr.5650070204. View

19.

Zhang S, Xiao Z, Luo J, He N, Mahlios J, Quarles L . Dose-dependent effects of Runx2 on bone development. J Bone Miner Res. 2009; 24(11):1889-904. PMC: 2765932. DOI: 10.1359/jbmr.090502. View

20.

Zhang Y, Yasui N, Ito K, Huang G, Fujii M, Hanai J . A RUNX2/PEBP2alpha A/CBFA1 mutation displaying impaired transactivation and Smad interaction in cleidocranial dysplasia. Proc Natl Acad Sci U S A. 2000; 97(19):10549-54. PMC: 27062. DOI: 10.1073/pnas.180309597. View