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Open Access 01-12-2005 | Research article

Association between a variation in the phosphodiesterase 4D gene and bone mineral density

Authors: Richard H Reneland, Steven Mah, Stefan Kammerer, Carolyn R Hoyal, George Marnellos, Scott G Wilson, Philip N Sambrook, Tim D Spector, Matthew R Nelson, Andreas Braun

Published in: BMC Medical Genetics | Issue 1/2005

Abstract

Background

Fragility fractures caused by osteoporosis are a major cause of morbidity and mortality in aging populations. Bone mineral density (BMD) is a useful surrogate marker for risk of fracture and is a highly heritable trait. The genetic variants underlying this genetic contribution are largely unknown.

Methods

We performed a large-scale association study investigating more than 25,000 single nucleotide polymorphisms (SNPs) located within 16,000 genes. Allele frequencies were estimated in contrasting DNA pools from white females selected for low (<0.87 g/cm², n = 319) and high (> 1.11 g/cm², n = 321) BMD at the lumbar spine. Significant findings were verified in two additional sample collections.

Results

Based on allele frequency differences between DNA pools and subsequent individual genotyping, one of the candidate loci indicated was the phosphodiesterase 4D (PDE4D) gene region on chromosome 5q12. We subsequently tested the marker SNP, rs1498608, in a second sample of 138 white females with low (<0.91 g/cm²) and 138 females with high (>1.04 g/cm²) lumbar spine BMD. Odds ratios were 1.5 (P = 0.035) in the original sample and 2.1 (P = 0.018) in the replication sample. Association fine mapping with 80 SNPs located within 50 kilobases of the marker SNP identified a 20 kilobase region of association containing exon 6 of PDE4D. In a second, family-based replication sample with a preponderance of females with low BMD, rs1498608 showed an opposite relationship with BMD at different sites (p = 0.00044-0.09). We also replicated the previously reported association of the Ser37Ala polymorphism in BMP2, known to interact biologically with PDE4D, with BMD.

Conclusion

This study indicates that variants in the gene encoding PDE4D account for some of the genetic contribution to bone mineral density variation in humans. The contrasting results from different samples indicate that the effect may be context-dependent. PDE4 inhibitors have been shown to increase bone mass in normal and osteopenic mice, but up until now there have been no reports implicating any member of the PDE4 gene family in human osteoporosis.

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Ray NF, Chan JK, Thamer M, Melton LJ: Medical expenditures for the treatment of osteoporotic fractures in the United States in 1995: report from the National Osteoporosis Foundation. J Bone Miner Res. 1997, 12: 24-35.CrossRefPubMed

Cummings SR, Nevitt MC, Browner WS, Stone K, Fox KM, Ensrud KE, Cauley J, Black D, Vogt TM: Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N Engl J Med. 1995, 332: 767-773. 10.1056/NEJM199503233321202.CrossRefPubMed

Espallargues M, Sampietro-Colom L, Estrada MD, Sola M, del Rio L, Setoain J, Granados A: Identifying bone-mass-related risk factors for fracture to guide bone densitometry measurements: a systematic review of the literature. Osteoporos Int. 2001, 12: 811-822. 10.1007/s001980170031.CrossRefPubMed

Kanis JA: Diagnosis of osteoporosis and assessment of fracture risk. Lancet. 2002, 359: 1929-1936. 10.1016/S0140-6736(02)08761-5.CrossRefPubMed

Jordan KM, Cooper C: Epidemiology of osteoporosis. Best Pract Res Clin Rheumatol. 2002, 16: 795-806. 10.1053/berh.2002.0264.CrossRefPubMed

Arden NK, Baker J, Hogg C, Baan K, Spector TD: The heritability of bone mineral density, ultrasound of the calcaneus and hip axis length: a study of postmenopausal twins. J Bone Miner Res. 1996, 11: 530-534.CrossRefPubMed

Hunter DJ, de Lange M, Andrew T, Snieder H, MacGregor AJ, Spector TD: Genetic variation in bone mineral density and calcaneal ultrasound: a study of the influence of menopause using female twins. Osteoporos Int. 2001, 12: 406-411. 10.1007/s001980170110.CrossRefPubMed

Pocock NA, Eisman JA, Hopper JL, Yeates MG, Sambrook PN, Eberl S: Genetic determinants of bone mass in adults. A twin study. J Clin Invest. 1987, 80: 706-710.CrossRefPubMedPubMedCentral

Efstathiadou Z, Kranas V, Ioannidis JP, Georgiou I, Tsatsoulis A: The Sp1 COLIA1 gene polymorphism, and not vitamin D receptor or estrogen receptor gene polymorphisms, determines bone mineral density in postmenopausal Greek women. Osteoporos Int. 2001, 12: 326-331. 10.1007/s001980170123.CrossRefPubMed

10.

Efstathiadou Z, Tsatsoulis A, Ioannidis JP: Association of collagen Ialpha 1 Sp1 polymorphism with the risk of prevalent fractures: a meta-analysis. J Bone Miner Res. 2001, 16: 1586-1592.CrossRefPubMed

11.

Mann V, Hobson EE, Li B, Stewart TL, Grant SF, Robins SP, Aspden RM, Ralston SH: A COL1A1 Sp1 binding site polymorphism predisposes to osteoporotic fracture by affecting bone density and quality. J Clin Invest. 2001, 107: 899-907.CrossRefPubMedPubMedCentral

12.

Devoto M, Shimoya K, Caminis J, Ott J, Tenenhouse A, Whyte MP, Sereda L, Hall S, Considine E, Williams CJ, Tromp G, Kuivaniemi H, Ala-Kokko L, Prockop DJ, Spotila LD: First-stage autosomal genome screen in extended pedigrees suggests genes predisposing to low bone mineral density on chromosomes 1p, 2p and 4q. Eur J Hum Genet. 1998, 6: 151-157. 10.1038/sj.ejhg.5200169.CrossRefPubMed

13.

Niu T, Chen C, Cordell H, Yang J, Wang B, Wang Z, Fang Z, Schork NJ, Rosen CJ, Xu X: A genome-wide scan for loci linked to forearm bone mineral density. Hum Genet. 1999, 104: 226-233. 10.1007/s004390050940.CrossRefPubMed

14.

Koller DL, Econs MJ, Morin PA, Christian JC, Hui SL, Parry P, Curran ME, Rodriguez LA, Conneally PM, Joslyn G, Peacock M, Johnston CC, Foroud T: Genome screen for QTLs contributing to normal variation in bone mineral density and osteoporosis. J Clin Endocrinol Metab. 2000, 85: 3116-3120. 10.1210/jc.85.9.3116.PubMed

15.

Deng HW, Xu FH, Liu YZ, Shen H, Deng H, Huang QY, Liu YJ, Conway T, Li JL, Davies KM, Recker RR: A whole-genome linkage scan suggests several genomic regions potentially containing QTLs underlying the variation of stature. Am J Med Genet. 2002, 113: 29-39. 10.1002/ajmg.10742.CrossRefPubMed

16.

Karasik D, Myers RH, Cupples LA, Hannan MT, Gagnon DR, Herbert A, Kiel DP: Genome screen for quantitative trait loci contributing to normal variation in bone mineral density: the Framingham Study. J Bone Miner Res. 2002, 17: 1718-1727.CrossRefPubMed

17.

Wilson SG, Reed PW, Bansal A, Chiano M, Lindersson M, Langdown M, Prince RL, Thompson D, Thompson E, Bailey M, Kleyn PW, Sambrook P, Shi MM, Spector TD: Comparison of genome screens for two independent cohorts provides replication of suggestive linkage of bone mineral density to 3p21 and 1p36. Am J Hum Genet. 2003, 72: 144-155. 10.1086/345819.CrossRefPubMed

18.

Econs MJ, Koller DL, Hui SL, Fishburn T, Conneally PM, Johnston CCJ, Peacock M, Foroud TM: Confirmation of linkage to chromosome 1q for peak vertebral bone mineral density in premenopausal white women. Am J Hum Genet. 2004, 74: 223-228. 10.1086/381401.CrossRefPubMedPubMedCentral

19.

Peacock M, Koller DL, Hui S, Johnston CC, Foroud T, Econs MJ: Peak bone mineral density at the hip is linked to chromosomes 14q and 15q. Osteoporos Int. 2004, 15: 489-496. 10.1007/s00198-003-1560-7.CrossRefPubMed

20.

Styrkarsdottir U, Cazier JB, Kong A, Rolfsson O, Larsen H, Bjarnadottir E, Johannsdottir VD, Sigurdardottir MS, Bagger Y, Christiansen C, Reynisdottir I, Grant SF, Jonasson K, Frigge ML, Gulcher JR, Sigurdsson G, Stefansson K: Linkage of Osteoporosis to Chromosome 20p12 and Association to BMP2. PLoS Biol. 2003, 1: E69-10.1371/journal.pbio.0000069.CrossRefPubMedPubMedCentral

21.

Risch NJ: Searching for genetic determinants in the new millennium. Nature. 2000, 405: 847-856. 10.1038/35015718.CrossRefPubMed

22.

Wakabayashi S, Tsutsumimoto T, Kawasaki S, Kinoshita T, Horiuchi H, Takaoka K: Involvement of phosphodiesterase isozymes in osteoblastic differentiation. J Bone Miner Res. 2002, 17: 249-256.CrossRefPubMed

23.

Kinoshita T, Kobayashi S, Ebara S, Yoshimura Y, Horiuchi H, Tsutsumimoto T, Wakabayashi S, Takaoka K: Phosphodiesterase inhibitors, pentoxifylline and rolipram, increase bone mass mainly by promoting bone formation in normal mice. Bone. 2000, 27: 811-817. 10.1016/S8756-3282(00)00395-1.CrossRefPubMed

24.

Andrew T, Mak YT, Reed P, MacGregor AJ, Spector TD: Linkage and association for bone mineral density and heel ultrasound measurements with a simple tandem repeat polymorphism near the osteocalcin gene in female dizygotic twins. Osteoporos Int. 2002, 13: 745-754. 10.1007/s001980200102.CrossRefPubMed

25.

Nelson MR, Marnellos G, Kammerer S, Hoyal CR, Shi MM, Cantor CR, Braun A: Large-scale validation of single nucleotide polymorphisms in gene regions. Genome Res. 2004, 14: 1664-1668. 10.1101/gr.2421604.CrossRefPubMedPubMedCentral

26.

Bansal A, van den Boom D, Kammerer S, Honisch C, Adam G, Cantor CR, Kleyn P, Braun A: Association testing by DNA pooling: an effective initial screen. Proc Natl Acad Sci U S A. 2002, 99: 16871-16874. 10.1073/pnas.262671399.CrossRefPubMedPubMedCentral

27.

Barratt BJ, Payne F, Rance HE, Nutland S, Todd JA, Clayton DG: Identification of the sources of error in allele frequency estimations from pooled DNA indicates an optimal experimental design. Ann Hum Genet. 2002, 66: 393-405. 10.1046/j.1469-1809.2002.00125.x.CrossRefPubMed

28.

Agresti A: Categorical data analysis. 2002, New York, Wiley-Interscience, xv, 710-2ndCrossRef

29.

Slager SL, Schaid DJ, Wang L, Thibodeau SN: Candidate-gene association studies with pedigree data: controlling for environmental covariates. Genet Epidemiol. 2003, 24: 273-283. 10.1002/gepi.10228.CrossRefPubMed

30.

Yan J, Fine J: Estimating equations for association structures. Stat Med. 2004, 23: 859-74; discussion 875-7,879-80. 10.1002/sim.1650.CrossRefPubMed

31.

Kammerer S, Burns-Hamuro LL, Ma Y, Hamon SC, Canaves JM, Shi MM, Nelson MR, Sing CF, Cantor CR, Taylor SS, Braun A: Amino acid variant in the kinase binding domain of dual-specific A kinase-anchoring protein 2: a disease susceptibility polymorphism. Proc Natl Acad Sci U S A. 2003, 100: 4066-4071. 10.1073/pnas.2628028100.CrossRefPubMedPubMedCentral

32.

Buetow KH, Edmonson M, MacDonald R, Clifford R, Yip P, Kelley J, Little DP, Strausberg R, Koester H, Cantor CR, Braun A: High-throughput development and characterization of a genomewide collection of gene-based single nucleotide polymorphism markers by chip-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Proc Natl Acad Sci U S A. 2001, 98: 581-584. 10.1073/pnas.021506298.CrossRefPubMedPubMedCentral

33.

Mohlke KL, Erdos MR, Scott LJ, Fingerlin TE, Jackson AU, Silander K, Hollstein P, Boehnke M, Collins FS: High-throughput screening for evidence of association by using mass spectrometry genotyping on DNA pools. Proc Natl Acad Sci U S A. 2002, 99: 16928-16933. 10.1073/pnas.262661399.CrossRefPubMedPubMedCentral

34.

Manganiello VC, Murata T, Taira M, Belfrage P, Degerman E: Diversity in cyclic nucleotide phosphodiesterase isoenzyme families. Arch Biochem Biophys. 1995, 322: 1-13. 10.1006/abbi.1995.1429.CrossRefPubMed

35.

Beavo JA: Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol Rev. 1995, 75: 725-748.PubMed

36.

Farndale RW, Sandy JR, Atkinson SJ, Pennington SR, Meghji S, Meikle MC: Parathyroid hormone and prostaglandin E2 stimulate both inositol phosphates and cyclic AMP accumulation in mouse osteoblast cultures. Biochem J. 1988, 252: 263-268.CrossRefPubMedPubMedCentral

37.

Kumegawa M, Ikeda E, Tanaka S, Haneji T, Yora T, Sakagishi Y, Minami N, Hiramatsu M: The effects of prostaglandin E2, parathyroid hormone, 1,25 dihydroxycholecalciferol, and cyclic nucleotide analogs on alkaline phosphatase activity in osteoblastic cells. Calcif Tissue Int. 1984, 36: 72-76.CrossRefPubMed

38.

Ishizuya T, Yokose S, Hori M, Noda T, Suda T, Yoshiki S, Yamaguchi A: Parathyroid hormone exerts disparate effects on osteoblast differentiation depending on exposure time in rat osteoblastic cells. J Clin Invest. 1997, 99: 2961-2970.CrossRefPubMedPubMedCentral

39.

Partridge NC, Bloch SR, Pearman AT: Signal transduction pathways mediating parathyroid hormone regulation of osteoblastic gene expression. J Cell Biochem. 1994, 55: 321-327.CrossRefPubMed

40.

Jee WS, Ueno K, Deng YP, Woodbury DM: The effects of prostaglandin E2 in growing rats: increased metaphyseal hard tissue and cortico-endosteal bone formation. Calcif Tissue Int. 1985, 37: 148-157.CrossRefPubMed

41.

Jee WS, Ueno K, Kimmel DB, Woodbury DM, Price P, Woodbury LA: The role of bone cells in increasing metaphyseal hard tissue in rapidly growing rats treated with prostaglandin E2. Bone. 1987, 8: 171-178. 10.1016/8756-3282(87)90017-2.CrossRefPubMed

42.

High WB: Effects of orally administered prostaglandin E-2 on cortical bone turnover in adult dogs: a histomorphometric study. Bone. 1987, 8: 363-373. 10.1016/8756-3282(87)90068-8.CrossRefPubMed

43.

Whitfield JF, Morley P: Small bone-building fragments of parathyroid hormone: new therapeutic agents for osteoporosis. Trends Pharmacol Sci. 1995, 16: 382-386. 10.1016/S0165-6147(00)89079-3.CrossRefPubMed

44.

Reeve J: PTH: a future role in the management of osteoporosis?. J Bone Miner Res. 1996, 11: 440-445.CrossRefPubMed

45.

Finkelstein JS, Klibanski A, Schaefer EH, Hornstein MD, Schiff I, Neer RM: Parathyroid hormone for the prevention of bone loss induced by estrogen deficiency. N Engl J Med. 1994, 331: 1618-1623. 10.1056/NEJM199412153312404.CrossRefPubMed

46.

Casperson GF, Bourne HR: Biochemical and molecular genetic analysis of hormone-sensitive adenylyl cyclase. Annu Rev Pharmacol Toxicol. 1987, 27: 371-384. 10.1146/annurev.pa.27.040187.002103.CrossRefPubMed

47.

Miyamoto K, Waki Y, Horita T, Kasugai S, Ohya K: Reduction of bone loss by denbufylline, an inhibitor of phosphodiesterase 4. Biochem Pharmacol. 1997, 54: 613-617. 10.1016/S0006-2952(97)00211-6.CrossRefPubMed

48.

Waki Y, Horita T, Miyamoto K, Ohya K, Kasugai S: Effects of XT-44, a phosphodiesterase 4 inhibitor, in osteoblastgenesis and osteoclastgenesis in culture and its therapeutic effects in rat osteopenia models. Jpn J Pharmacol. 1999, 79: 477-483. 10.1254/jjp.79.477.CrossRefPubMed

49.

Gretarsdottir S, Thorleifsson G, Reynisdottir ST, Manolescu A, Jonsdottir S, Jonsdottir T, Gudmundsdottir T, Bjarnadottir SM, Einarsson OB, Gudjonsdottir HM, Hawkins M, Gudmundsson G, Gudmundsdottir H, Andrason H, Gudmundsdottir AS, Sigurdardottir M, Chou TT, Nahmias J, Goss S, Sveinbjornsdottir S, Valdimarsson EM, Jakobsson F, Agnarsson U, Gudnason V, Thorgeirsson G, Fingerle J, Gurney M, Gudbjartsson D, Frigge ML, Kong A, Stefansson K, Gulcher JR: The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat Genet. 2003, 35: 131-138. 10.1038/ng1245.CrossRefPubMed

50.

Ghiselli G, Gregg RE, Zech LA, Schaefer EJ, Brewer HBJ: Phenotype study of apolipoprotein E isoforms in hyperlipoproteinaemic patients. Lancet. 1982, 2: 405-407. 10.1016/S0140-6736(82)90439-1.CrossRefPubMed

51.

Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA: Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993, 261: 921-923.CrossRefPubMed

52.

Peacock M, Turner CH, Econs MJ, Foroud T: Genetics of osteoporosis. Endocr Rev. 2002, 23: 303-326. 10.1210/er.23.3.303.CrossRefPubMed

53.

Houslay MD, Adams DR: PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization. Biochem J. 2003, 370: 1-18. 10.1042/BJ20021698.CrossRefPubMedPubMedCentral

54.

Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN: Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet. 2003, 33: 177-182. 10.1038/ng1071.CrossRefPubMed

55.

Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG: Replication validity of genetic association studies. Nat Genet. 2001, 29: 306-309. 10.1038/ng749.CrossRefPubMed

56.

Trikalinos TA, Ntzani EE, Contopoulos-Ioannidis DG, Ioannidis JP: Establishment of genetic associations for complex diseases is independent of early study findings. Eur J Hum Genet. 2004, 12: 762-769. 10.1038/sj.ejhg.5201227.CrossRefPubMed

The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/6/9/prepub

Title: Association between a variation in the phosphodiesterase 4D gene and bone mineral density
Authors: Richard H Reneland
Steven Mah
Stefan Kammerer
Carolyn R Hoyal
George Marnellos
Scott G Wilson
Philip N Sambrook
Tim D Spector
Matthew R Nelson
Andreas Braun
Publication date: 01-12-2005
Publisher: BioMed Central
Published in: BMC Medical Genetics / Issue 1/2005
Electronic ISSN: 1471-2350
DOI: https://doi.org/10.1186/1471-2350-6-9

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Association between a variation in the phosphodiesterase 4D gene and bone mineral density

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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