Identification of novel RANK polymorphisms and their putative association with low BMD among postmenopausal women

Osteoporosis International - Tập 18 Số 3 - Trang 323-331 - 2007
Koh, J.-M.1, Park, B. L.2, Kim, D. J.1, Kim, G. S.1, Cheong, H. S.2, Kim, T.-H.3, Hong, J.-M.3, Shin, H.-I.4, Park, E. K.3,4, Kim, S.-Y.3,5, Shin, H. D.2
1Division of Endocrinology and Metabolism, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
2Department of Genetic Epidemiology, SNP Genetics, Inc., Seoul, South Korea
3Skeletal Diseases Genome Research Center, Kyungpook National University Hospital, Daegu, South Korea
4Department of Pathology and Regenerative Medicine,School of Dentistry, Kyungpook National University, Daegu, South Korea
5Department of Orthopedic Surgery, Kyungpook National University School of Medicine, Daegu, South Korea

Tóm tắt

Bone mineral density (BMD) is the major factor for determining bone strength, which is closely correlated to osteoporotic fracture risk and is largely determined by multiple genetic factors. The RANK (TNFRSF11A), receptor for RANKL, is a member of the tumor necrosis factor receptor (TNFR) superfamily and plays a central role in osteoclast development. In order to investigate the effects of RANK polymorphism on BMD and osteoporosis, we directly sequenced the RANK gene in 24 Korean individuals and identified 25 sequence variants. Eleven of these polymorphisms were selected and genotyped in a larger-scale study of postmenopausal women (n = 560). Areal BMD (g/cm2) of the anterior–posterior lumbar spine and the nondominant proximal femur were measured using dual-energy X-ray absorptiometry. We found that two intronic polymorphisms in the RANK gene [RANK + 34863G > A (rs12458117) and RANK + 35928insdelC (new polymorphism found in this study) in intron 6] were significantly associated with the BMD of the lumbar spine, i.e., rare alleles were significantly associated with low BMD of the lumbar spine among Korean postmenopausal women (p = 0.04 and 0.02, respectively). These polymorphisms were also associated with low BMD of proximal femur sites, including Ward’s triangle, trochanter, and total femur. Our results suggest that +34863G > A and +35928insdelC polymorphisms in RANK are possible genetic factors for low BMD in postmenopausal women.

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citation_journal_title=JAMA; citation_title=Osteoporosis prevention, diagnosis, and therapy; citation_author=; citation_volume=285; citation_publication_date=2001; citation_pages=785-795; citation_doi=10.1001/jama.285.6.785; citation_id=CR1

citation_journal_title=J Bone Miner Res; citation_title=Genetic influences on muscle strength, lean body mass, and bone mineral density: a twin study; citation_author=NK Arden, TD Spector; citation_volume=12; citation_publication_date=1997; citation_pages=2076-2081; citation_doi=10.1359/jbmr.1997.12.12.2076; citation_id=CR2

citation_journal_title=Endocr Rev; citation_title=Genetics of osteoporosis; citation_author=JA Eisman; citation_volume=20; citation_publication_date=1999; citation_pages=788-804; citation_doi=10.1210/er.20.6.788; citation_id=CR3

citation_journal_title=J Bone Miner Res; citation_title=The diagnosis of osteoporosis; citation_author=JA Kanis, LJ Melton, C Christiansen, CC Johnston, N Khaltaev; citation_volume=9; citation_publication_date=1994; citation_pages=1137-1141; citation_id=CR4

citation_journal_title=Nat Med; citation_title=Arming the osteoclast; citation_author=R Baron; citation_volume=10; citation_publication_date=2004; citation_pages=458-460; citation_doi=10.1038/nm0504-458; citation_id=CR5

citation_journal_title=BMC Cell Biol; citation_title=Polyphosphoinositides-dependent regulation of the osteoclast actin cytoskeleton and bone resorption; citation_author=RN Biswas, DN Baker, KN Hruska, MN Chellaiah; citation_volume=5; citation_publication_date=2004; citation_pages=19; citation_doi=10.1186/1471-2121-5-19; citation_id=CR6

citation_journal_title=J Cell Physiol; citation_title=Roles of stromal cell RANKL, OPG, and M-CSF expression in biphasic TGF-beta regulation of osteoclast differentiation; citation_author=M Karst, G Gorny, RJ Galvin, MJ Oursler; citation_volume=200; citation_publication_date=2004; citation_pages=99-106; citation_doi=10.1002/jcp.20036; citation_id=CR7

citation_journal_title=Science; citation_title=Bone resorption by osteoclasts; citation_author=SL Teitelbaum; citation_volume=289; citation_publication_date=2000; citation_pages=1504-1508; citation_doi=10.1126/science.289.5484.1504; citation_id=CR8

citation_journal_title=Cell; citation_title=The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development; citation_author=JE Fata, YY Kong, J Li, T Sasaki, J Irie-Sasaki, RA Moorehead, R Elliott, S Scully, EB Voura, DL Lacey, WJ Boyle, R Khokha, JM Penninger; citation_volume=103; citation_publication_date=2000; citation_pages=41-50; citation_doi=10.1016/S0092-8674(00)00103-3; citation_id=CR9

citation_journal_title=Proc Natl Acad Sci USA; citation_title=Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand; citation_author=H Hsu, DL Lacey, CR Dunstan, I Solovyev, A Colombero, E Timms, HL Tan, G Elliott, MJ Kelley, I Sarosi, L Wang, XZ Xia, R Elliott, L Chiu, T Black, S Scully, C Capparelli, S Morony, G Shimamoto, MB Bass, WJ Boyle; citation_volume=96; citation_publication_date=1999; citation_pages=3540-3545; citation_doi=10.1073/pnas.96.7.3540; citation_id=CR10

citation_journal_title=J Biol Chem; citation_title=TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells; citation_author=BR Wong, J Rho, J Arron, E Robinson, J Orlinick, M Chao, S Kalachikov, E Cayani, FS Bartlett, WN Frankel, SY Lee, Y Choi; citation_volume=272; citation_publication_date=1997; citation_pages=25190-25194; citation_doi=10.1074/jbc.272.40.25190; citation_id=CR11

citation_journal_title=J Biol Chem; citation_title=The involvement of multiple tumor necrosis factor receptor (TNFR)-associated factors in the signaling mechanisms of receptor activator of NF-kappaB, a member of the TNFR superfamily; citation_author=L Galibert, ME Tometsko, DM Anderson, D Cosman, WC Dougall; citation_volume=273; citation_publication_date=1998; citation_pages=34120-34127; citation_doi=10.1074/jbc.273.51.34120; citation_id=CR12

citation_journal_title=J Biol Chem; citation_title=Characterization of the intracellular domain of receptor activator of NF-kappaB (RANK). Interaction with tumor necrosis factor receptor- associated factors and activation of NF-kappab and c-Jun N-terminal kinase; citation_author=BG Darnay, V Haridas, J Ni, PA Moore, BB Aggarwal; citation_volume=273; citation_publication_date=1998; citation_pages=20551-20555; citation_doi=10.1074/jbc.273.32.20551; citation_id=CR13

citation_journal_title=J Bone Miner Res; citation_title=Possible involvement of IkappaB kinase 2 and MKK7 in osteoclastogenesis induced by receptor activator of nuclear factor kappaB ligand; citation_author=A Yamamoto, T Miyazaki, Y Kadono, H Takayanagi, T Miura, H Nishina, T Katada, K Wakabayashi, H Oda, K Nakamura, S Tanaka; citation_volume=17; citation_publication_date=2002; citation_pages=612-621; citation_doi=10.1359/jbmr.2002.17.4.612; citation_id=CR14

citation_journal_title=J Biol Chem; citation_title=Activation of NF-kappaB by RANK requires tumor necrosis factor receptor- associated factor (TRAF) 6 and NF-kappaB-inducing kinase. Identification of a novel TRAF6 interaction motif; citation_author=BG Darnay, J Ni, PA Moore, BB Aggarwal; citation_volume=274; citation_publication_date=1999; citation_pages=7724-7731; citation_doi=10.1074/jbc.274.12.7724; citation_id=CR15

citation_journal_title=Mol Cell Biol; citation_title=The macrophage transcription factor PU.1 directs tissue-specific expression of the macrophage colony-stimulating factor receptor; citation_author=DE Zhang, CJ Hetherington, HM Chen, DG Tenen; citation_volume=14; citation_publication_date=1994; citation_pages=373-381; citation_id=CR16

citation_journal_title=J Bone Miner Res; citation_title=Identification of a novel tandem duplication in exon 1 of the TNFRSF11A gene in two unrelated patients with familial expansile osteolysis; citation_author=TL Johnson-Pais, FR Singer, HG Bone, CT McMurray, MF Hansen, RJ Leach; citation_volume=18; citation_publication_date=2003; citation_pages=376-380; citation_doi=10.1359/jbmr.2003.18.2.376; citation_id=CR17

citation_journal_title=Nat Genet; citation_title=Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis; citation_author=AE Hughes, SH Ralston, J Marken, C Bell, H MacPherson, RG Wallace, W Hul, MP Whyte, K Nakatsuka, L Hovy, DM Anderson; citation_volume=24; citation_publication_date=2000; citation_pages=45-48; citation_doi=10.1038/71667; citation_id=CR18

citation_journal_title=Am J Hum Genet; citation_title=Genetic linkage of Paget disease of the bone to chromosome 18q; citation_author=JD Cody, FR Singer, GD Roodman, B Otterund, TB Lewis, M Leppert, RJ Leach; citation_volume=61; citation_publication_date=1997; citation_pages=1117-1122; citation_doi=10.1086/301601; citation_id=CR19

citation_journal_title=Am J Hum Genet; citation_title=Linkage of Paget disease of bone to a novel region on human chromosome 18q23; citation_author=DA Good, F Busfield, BH Fletcher, DL Duffy, JB Kesting, J Andersen, JT Shaw; citation_volume=70; citation_publication_date=2002; citation_pages=517-525; citation_doi=10.1086/338658; citation_id=CR20

citation_journal_title=Calcif Tissue Int; citation_title=Genetic polymorphisms of OPG, RANK, and ESR1 and bone mineral density in Korean postmenopausal women; citation_author=JY Choi, A Shin, SK Park, HW Chung, SI Cho, CS Shin, H Kim, KM Lee, KH Lee, C Kang, DY Cho, D Kang; citation_volume=77; citation_publication_date=2005; citation_pages=152-159; citation_doi=10.1007/s00223-004-0264-0; citation_id=CR21

citation_journal_title=Hum Genet; citation_title=Variation in genes involved in the RANKL/RANK/OPG bone remodeling pathway are associated with bone mineral density at different skeletal sites in men; citation_author=YH Hsu, T Niu, HA Terwedow, X Xu, Y Feng, Z Li, JD Brain, CJ Rosen, N Laird, X Xu; citation_volume=118; citation_publication_date=2006; citation_pages=568-577; citation_doi=10.1007/s00439-005-0062-4; citation_id=CR22

citation_journal_title=J Bone Joint Surg Am; citation_title=Osteophytes of the vertebral column: an anatomical study of their development according to age, race, and sex with considerations as to their etiology and significance; citation_author=H Nathan; citation_volume=44A; citation_publication_date=1962; citation_pages=243-268; citation_id=CR23

citation_journal_title=J Bone Miner Res; citation_title=Assessing vertebral fractures. National Osteoporosis Foundation Working Group on Vertebral Fractures; citation_author=D Kiel; citation_volume=10; citation_publication_date=1995; citation_pages=518-523; citation_doi=10.1002/jbmr.5650100719; citation_id=CR24

citation_journal_title=Genet Anal; citation_title=Allelic discrimination using fluorogenic probes and the 5’ nuclease assay; citation_author=KJ Livak; citation_volume=14; citation_publication_date=1999; citation_pages=143-149; citation_id=CR25

citation_journal_title=Genetics; citation_title=Gametic disequilibrium measures: proceed with caution; citation_author=PW Hedrick; citation_volume=117; citation_publication_date=1987; citation_pages=331-341; citation_id=CR26

citation_journal_title=Eur J Hum Genet; citation_title=Mutation and linkage disequilibrium in human mtDNA; citation_author=P Hedrick, S Kumar; citation_volume=9; citation_publication_date=2001; citation_pages=969-972; citation_doi=10.1038/sj.ejhg.5200735; citation_id=CR27

citation_journal_title=Am J Hum Genet; citation_title=A new statistical method for haplotype reconstruction from population data; citation_author=M Stephens, NJ Smith, P Donnelly; citation_volume=68; citation_publication_date=2001; citation_pages=978-989; citation_doi=10.1086/319501; citation_id=CR28

citation_journal_title=J Bone Miner Res; citation_title=Association of bone mineral density with polymorphism of the estrogen receptor gene; citation_author=S Kobayashi, S Inoue, T Hosoi, Y Ouchi, M Shiraki, H Orimo; citation_volume=11; citation_publication_date=1996; citation_pages=306-311; citation_doi=10.1002/jbmr.5650110304; citation_id=CR29

citation_journal_title=J Mol Med; citation_title=Association of the C-509-> T polymorphism, alone of in combination with the T869-> C polymorphism, of the transforming growth factor-beta1 gene with bone mineral density and genetic susceptibility to osteoporosis in Japanese women; citation_author=Y Yamada, A Miyauchi, Y Takagi, M Tanaka, M Mizuno, A Harada; citation_volume=79; citation_publication_date=2001; citation_pages=149-156; citation_doi=10.1007/s001090100190; citation_id=CR30

citation_journal_title=Bone; citation_title=Allelic variation at the interleukin-1 receptor antagonist gene is associated with early postmenopausal bone loss at the spine; citation_author=RW Keen, KL Woodford-Richens, JS Lanchbury, TD Spector; citation_volume=23; citation_publication_date=1998; citation_pages=367-371; citation_doi=10.1016/S8756-3282(98)00109-4; citation_id=CR31

citation_journal_title=Bone; citation_title=Polymorphisms of the interleukin-6 gene are associated with bone mineral density; citation_author=RE Murray, F McGuigan, SF Grant, DM Reid, SH Ralston; citation_volume=21; citation_publication_date=1997; citation_pages=89-92; citation_doi=10.1016/S8756-3282(97)00081-1; citation_id=CR32

citation_journal_title=J Bone Miner Res; citation_title=Two new single-nucleotide polymorphisms in the COL1A1 upstream regulatory region and their relationship to bone mineral density; citation_author=N Garcia-Giralt, X Nogues, A Enjuanes, J Puig, L Mellibovsky, A Bay-Jensen, R Carreras, S Balcells, A Diez-Perez, D Grinberg; citation_volume=17; citation_publication_date=2002; citation_pages=384-393; citation_doi=10.1359/jbmr.2002.17.3.384; citation_id=CR33

citation_journal_title=J Clin Endocrinol Metab; citation_title=Sequence variations in the osteoprotegerin gene promoter in patients with postmenopausal osteoporosis; citation_author=B Arko, J Prezelj, R Komel, A Kocijancic, P Hudler, J Marc; citation_volume=87; citation_publication_date=2002; citation_pages=4080-4084; citation_doi=10.1210/jc.2002-020124; citation_id=CR34

citation_journal_title=Proc Natl Acad Sci USA; citation_title=Contribution of trans-acting factor alleles to normal physiological variability: vitamin D receptor gene polymorphism and circulating osteocalcin; citation_author=NA Morrison, R Yeoman, PJ Kelly, JA Eisman; citation_volume=89; citation_publication_date=1992; citation_pages=6665-6669; citation_doi=10.1073/pnas.89.15.6665; citation_id=CR35

citation_journal_title=Nature; citation_title=Prediction of bone density from vitamin D receptor alleles; citation_author=NA Morrison, JC Qi, A Tokita, PJ Kelly, L Crofts, TV Nguyen, PN Sambrook, JA Eisman; citation_volume=367; citation_publication_date=1994; citation_pages=284-287; citation_doi=10.1038/367284a0; citation_id=CR36

citation_journal_title=J Bone Miner Res; citation_title=Association of the OSCAR promoter polymorphism with BMD in postmenopausal women; citation_author=GS Kim, JM Koh, JS Chang, BL Park, LH Kim, EK Park, SY Kim, HD Shin; citation_volume=20; citation_publication_date=2005; citation_pages=1342-1348; citation_doi=10.1359/JBMR.050320; citation_id=CR37

citation_journal_title=Nature; citation_title=Osteoclast differentiation and activation; citation_author=WJ Boyle, WS Simonet, DL Lacey; citation_volume=423; citation_publication_date=2003; citation_pages=337-342; citation_doi=10.1038/nature01658; citation_id=CR38

citation_journal_title=J Exp Med; citation_title=TRANCE, a tumor necrosis factor family member critical for CD40 ligand-independent T helper cell activation; citation_author=MF Bachmann, BR Wong, R Josien, RM Steinman, A Oxenius, Y Choi; citation_volume=189; citation_publication_date=1999; citation_pages=1025-1031; citation_doi=10.1084/jem.189.7.1025; citation_id=CR39

citation_journal_title=Nature; citation_title=A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function; citation_author=DM Anderson, E Maraskovsky, WL Billingsley, WC Dougall, ME Tometsko, ER Roux, MC Tepe, RF DuBose, D Cosman, L Galibert; citation_volume=390; citation_publication_date=1997; citation_pages=175-179; citation_doi=10.1038/36593; citation_id=CR40

citation_journal_title=J Cell Biochem; citation_title=Regulation of osteoclastogenesis and RANK expression by TGF-beta1; citation_author=T Yan, BL Riggs, WJ Boyle, S Khosla; citation_volume=83; citation_publication_date=2001; citation_pages=320-325; citation_doi=10.1002/jcb.1200; citation_id=CR41

citation_journal_title=J Exp Med; citation_title=Commitment and differentiation of osteoclast precursor cells by the sequential expression of c-Fms and receptor activator of nuclear factor kappaB (RANK) receptors; citation_author=F Arai, T Miyamoto, O Ohneda, T Inada, T Sudo, K Brasel, T Miyata, DM Anderson, T Suda; citation_volume=190; citation_publication_date=1999; citation_pages=1741-1754; citation_doi=10.1084/jem.190.12.1741; citation_id=CR42

citation_journal_title=Bone; citation_title=Expression of RANK is dependent upon differentiation into the macrophage/osteoclast lineage: induction by 1alpha, 25-dihydroxyvitamin D3 and TPA in a human myelomonocytic cell line, HL60; citation_author=S Kido, D Inoue, K Iliura, W Javier, Y Ito, T Matsumoto; citation_volume=32; citation_publication_date=2003; citation_pages=621-629; citation_doi=10.1016/S8756-3282(03)00049-8; citation_id=CR43

citation_journal_title=Mol Cells; citation_title=Receptor activator of nuclear factor-kappaB is induced by a rottlerin-sensitive and p38 MAP kinase-dependent pathway during monocyte differentiation; citation_author=HS Kang, EK Park, KH Kim, JY Park, JY Choi, HI Shin, CD Jun, SS Kang, SY Kim; citation_volume=17; citation_issue=3; citation_publication_date=2004; citation_pages=438-445; citation_id=CR44

citation_journal_title=Nat Rev Genet; citation_title=How did alternative splicing evolve?; citation_author=G Ast; citation_volume=5; citation_publication_date=2004; citation_pages=773-782; citation_doi=10.1038/nrg1451; citation_id=CR45

citation_journal_title=BMJ; citation_title=Genetic factors and osteoporotic fractures in elderly people. Twin data support genetic contribution to risk of fracture.; citation_author=A MacGregor, H Snieder, TD Spector; citation_volume=320; citation_publication_date=2000; citation_pages=1669-1670; citation_doi=10.1136/bmj.320.7250.1669; citation_id=CR46

citation_journal_title=J Bone Miner Res; citation_title=Genetic determination of Colles’ fracture and differential bone mass in women with and without Colles’ fracture; citation_author=HW Deng, WM Chen, S Recker, MR Stegman, JL Li, KM Davies, Y Zhou, H Deng, R Heaney, RR Recker; citation_volume=15; citation_publication_date=2000; citation_pages=1243-1252; citation_doi=10.1359/jbmr.2000.15.7.1243; citation_id=CR47

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Osteoporosis International

Tập 18 Số 3

323-331

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