nach oben

Erschienen in:

01.02.2010 | Original Article

Polymorphisms and haplotypes across the osteoprotegerin gene associated with bone mineral density and osteoporotic fractures

verfasst von: S. Jurado, X. Nogués, L. Agueda, N. Garcia-Giralt, R. Urreizti, G. Yoskovitz, L. Pérez-Edo, G. Saló, R. Carreras, L. Mellibovsky, S. Balcells, D. Grinberg, A. Díez-Pérez

Erschienen in: Osteoporosis International | Ausgabe 2/2010

Einloggen, um Zugang zu erhalten

Abstract

Summary

Osteoprotegerin plays a key role in bone remodelling. We studied the association between 24 polymorphisms and haplotypes on the OPG gene and bone mineral density and fractures. After multiple-testing correction, one SNP and two block-haplotypes were significantly associated with FN BMD. Two other block-haplotypes were associated with fracture.

Introduction and Hypothesis

Osteoprotegerin (OPG) plays a key role in bone remodelling. Here we studied the association between polymorphisms and haplotypes on the OPG gene and bone mineral density (BMD) and fractures.

Methods

Twenty-four single nucleotide polymorphisms (SNPs) were selected to cover six haplotypic blocks and were genotyped in 964 postmenopausal Spanish women. Haplotypes were established with HaploStats. Association was analysed by GLM (for BMD) and logistic regression (for fractures) both at single SNP and haplotype levels.

Results

Upon adjustment for multiple testing (p < 0.0073), one of the SNPs (SNP #17, rs1032129) remained significantly associated with FN BMD (p = 0.001). Four block-haplotypes stood multiple-testing correction. Two remained associated with FN BMD and two with fracture. The association of block-4 haplotype “AC” (of SNPs #18 and #17) with FN BMD (p = 0.0002) was stronger than that of SNP#17 alone and was the best result overall. A global assessment of the results indicated that all the alleles and haplotypes with a protective effect, at p < 0.05, belonged to a frequent long-range haplotype.

Conclusions

In conclusion, these results provide a detailed picture of the involvement of common variants and haplotypes of the OPG gene in bone phenotypes.

Ralston SH (2002) Genetic control of susceptibility to osteoporosis. J Clin Endocrinol Metab 87:2460–2466CrossRefPubMed

Liu YZ, Liu YJ, Recker RR et al (2003) Molecular studies of identification of genes for osteoporosis: the 2002 update. J Endocrinol 177:147–196CrossRefPubMed

Hofbauer LC, Heufelder AE (2001) Role of receptor activator of nuclear factor-kappaB ligand and osteoprotegerin in bone cell biology. J Mol Med 79:243–253CrossRefPubMed

Khosla S (2001) Minireview: the OPG/RANKL/RANK system. Endocrinology 142:5050–5055CrossRefPubMed

Simonet WS, Lacey DL, Dunstan CR et al (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89:309–319CrossRefPubMed

Bucay N, Sarosi I, Dunstan CR et al (1998) osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 12:1260–1268CrossRefPubMed

Arko B, Prezelj J, Komel R et al (2002) Sequence variations in the osteoprotegerin gene promoter in patients with postmenopausal osteoporosis. J Clin Endocrinol Metab 87:4080–4084CrossRefPubMed

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

Ohmori H, Makita Y, Funamizu M et al (2002) Linkage and association analyses of the osteoprotegerin gene locus with human osteoporosis. J Hum Genet 47:400–406CrossRefPubMed

10.

Wynne F, Drummond F, O'Sullivan K et al (2002) Investigation of the genetic influence of the OPG, VDR (Fok1), and COLIA1 Sp1 polymorphisms on BMD in the Irish population. Calcif Tissue Int 71:26–35CrossRefPubMed

11.

Yamada Y, Ando F, Niino N et al (2003) Association of polymorphisms of the osteoprotegerin gene with bone mineral density in Japanese women but not men. Mol Genet Metab 80:344–349CrossRefPubMed

12.

Daroszewska A, Hocking LJ, McGuigan FE et al (2004) Susceptibility to Paget's disease of bone is influenced by a common polymorphic variant of osteoprotegerin. J Bone Miner Res 19:1506–1511CrossRefPubMed

13.

Jorgensen HL, Kusk P, Madsen B et al (2004) Serum osteoprotegerin (OPG) and the A163G polymorphism in the OPG promoter region are related to peripheral measures of bone mass and fracture odds ratios. J Bone Miner Metab 22:132–138CrossRefPubMed

14.

Brandstrom H, Gerdhem P, Stiger F et al (2004) Single nucleotide polymorphisms in the human gene for osteoprotegerin are not related to bone mineral density or fracture in elderly women. Calcif Tissue Int 74:18–24CrossRefPubMed

15.

Soufi M, Schoppet M, Sattler AM et al (2004) Osteoprotegerin gene polymorphisms in men with coronary artery disease. J Clin Endocrinol Metab 89:3764–3768CrossRefPubMed

16.

Arko B, Prezelj J, Kocijancic A et al (2005) Association of the osteoprotegerin gene polymorphisms with bone mineral density in postmenopausal women. Maturitas 51:270–279CrossRefPubMed

17.

Zhao HY, Liu JM, Ning G et al (2005) The influence of Lys3Asn polymorphism in the osteoprotegerin gene on bone mineral density in Chinese postmenopausal women. Osteoporos Int 16:1519–1524CrossRefPubMed

18.

Choi JY, Shin A, Park SK et al (2005) Genetic polymorphisms of OPG, RANK, and ESR1 and bone mineral density in Korean postmenopausal women. Calcif Tissue Int 77:152–159CrossRefPubMed

19.

Vidal C, Brincat M, Xuereb Anastasi A (2005) TNFRSF11B gene variants and bone mineral density in postmenopausal women in Malta. Maturitas

20.

Hsu YH, Niu T, Terwedow HA et al (2006) Variation in genes involved in the RANKL/RANK/OPG bone remodeling pathway are associated with bone mineral density at different skeletal sites in men. Hum Genet 118:568–577CrossRefPubMed

21.

Rhee EJ, Oh KW, Jung CH et al (2006) The relationship between four single nucleotide polymorphisms in the promoter region of the osteoprotegerin gene and aortic calcification or coronary artery disease in Koreans. Clin Endocrinol (Oxf) 64:689–697CrossRef

22.

Ueland T, Bollerslev J, Wilson SG et al (2007) No associations between OPG gene polymorphisms or serum levels and measures of osteoporosis in elderly Australian women. Bone 40:175–181CrossRefPubMed

23.

Styrkarsdottir U, Halldorsson BV, Gretarsdottir S et al (2008) Multiple genetic loci for bone mineral density and fractures. N Engl J Med 358:2355–2365CrossRefPubMed

24.

Richards JB, Rivadeneira F, Inouye M et al (2008) Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet 371:1505–1512CrossRefPubMed

25.

Cardon LR, Abecasis GR (2003) Using haplotype blocks to map human complex trait loci. Trends Genet 19:135–140CrossRefPubMed

26.

Altshuler D, Brooks LD, Chakravarti A et al (2005) A haplotype map of the human genome. Nature 437:1299–1320CrossRef

27.

Morinaga T, Nakagawa N, Yasuda H et al (1998) Cloning and characterization of the gene encoding human osteoprotegerin/osteoclastogenesis-inhibitory factor. Eur J Biochem 254:685–691CrossRefPubMed

28.

Bustamante M, Nogues X, Agueda L et al (2007) Promoter 2–1025 T/C polymorphism in the RUNX2 gene is associated with femoral neck bmd in Spanish postmenopausal women. Calcif Tissue Int 81:327–332CrossRefPubMed

29.

Bustamante M, Nogues X, Mellibovsky L et al (2007) Polymorphisms in the interleukin-6 receptor gene are associated with bone mineral density and body mass index in Spanish postmenopausal women. Eur J Endocrinol 157:677–684CrossRefPubMed

30.

Genant HK, Wu CY, van Kuijk C et al (1993) Vertebral fracture assessment using a semiquantitative technique. J Bone Miner Res 8:1137–1148PubMedCrossRef

31.

Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215CrossRefPubMed

32.

Gabriel SB, Schaffner SF, Nguyen H et al (2002) The structure of haplotype blocks in the human genome. Science 296:2225–2229CrossRefPubMed

33.

Tobler AR, Short S, Andersen MR et al (2005) The SNPlex genotyping system: a flexible and scalable platform for SNP genotyping. J Biomol Tech 16:398–406PubMed

34.

Barrett JC, Fry B, Maller J et al (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265CrossRefPubMed

35.

Lake SL, Lyon H, Tantisira K et al (2003) Estimation and tests of haplotype-environment interaction when linkage phase is ambiguous. Hum Hered 55:56–65CrossRefPubMed

36.

Cheverud JM (2001) A simple correction for multiple comparisons in interval mapping genome scans. Heredity 87:52–58CrossRefPubMed

37.

Li J, Ji L (2005) Adjusting multiple testing in multilocus analyses using the eigenvalues of a correlation matrix. Heredity 95:221–227CrossRefPubMed

38.

Purcell S, Cherny SS, Sham PC (2003) Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 19:149–150CrossRefPubMed

39.

Beyens G, Daroszewska A, de Freitas F et al (2007) Identification of sex-specific associations between polymorphisms of the osteoprotegerin gene, TNFRSF11B, and Paget's disease of bone. J Bone Miner Res 22:1062–1071CrossRefPubMed

Titel: Polymorphisms and haplotypes across the osteoprotegerin gene associated with bone mineral density and osteoporotic fractures
verfasst von: S. Jurado
X. Nogués
L. Agueda
N. Garcia-Giralt
R. Urreizti
G. Yoskovitz
L. Pérez-Edo
G. Saló
R. Carreras
L. Mellibovsky
S. Balcells
D. Grinberg
A. Díez-Pérez
Publikationsdatum: 01.02.2010
Verlag: Springer-Verlag
Erschienen in: Osteoporosis International / Ausgabe 2/2010
Print ISSN: 0937-941X
Elektronische ISSN: 1433-2965
DOI: https://doi.org/10.1007/s00198-009-0956-4

Arthropedia

Grundlagenwissen der Arthroskopie und Gelenkchirurgie. Erweitert durch Fallbeispiele, Videos und Abbildungen.
» Jetzt entdecken

Neu im Fachgebiet Orthopädie und Unfallchirurgie

18.04.2024 | Wirbelsäulenmetastase | Nachrichten

Update Orthopädie und Unfallchirurgie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Polymorphisms and haplotypes across the osteoprotegerin gene associated with bone mineral density and osteoporotic fractures

Abstract

Summary

Introduction and Hypothesis

Methods

Results

Conclusions

Arthropedia

Neu im Fachgebiet Orthopädie und Unfallchirurgie

Stereotaktische Radiatio schlägt konventionelle Bestrahlung

Vorsicht mit hohen NSAR-Dosen bei ankylosierender Spondylitis!

Brustkrebs in der Vorgeschichte macht Gelenkersatz komplikationsträchtiger

„Nur wer sich gut aufgehoben fühlt, kann auch für Patientensicherheit sorgen“

Update Orthopädie und Unfallchirurgie

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Abstract

Summary

Introduction and Hypothesis

Methods

Results

Conclusions

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 2/2010

Martial arts fall training to prevent hip fractures in the elderly

Improvement of trochanteric bone quality in an osteoporosis model after short-term treatment with parathyroid hormone: a new mechanical test for trochanteric region of rat femur

The cost-effectiveness of strontium ranelate in the UK for the management of osteoporosis

Vertebral anti-fracture efficacy of strontium ranelate according to pre-treatment bone turnover

Direct-to-participant feedback and awareness of bone mineral density testing results in a population-based sample of mid-aged Canadians

Association between circulating osteoprogenitor cell numbers and bone mineral density in postmenopausal osteoporosis

Arthropedia

Neu im Fachgebiet Orthopädie und Unfallchirurgie

Stereotaktische Radiatio schlägt konventionelle Bestrahlung

Vorsicht mit hohen NSAR-Dosen bei ankylosierender Spondylitis!

Brustkrebs in der Vorgeschichte macht Gelenkersatz komplikationsträchtiger

„Nur wer sich gut aufgehoben fühlt, kann auch für Patientensicherheit sorgen“

Update Orthopädie und Unfallchirurgie