Background/Aims: The purpose of this study was to investigate the association between single nucleotide polymorphisms (SNPs) in sclerostin (SOST), dickkopf (DKK), secreted frizzled-related protein (sFRP) genes and bone mineral density (BMD) in postmenopausal Korean women. Methods: The SOST, Wnt inhibitory factor 1 (WIF1), sFRP1,sFRP2,sFRP3, sFRP4, sFRP5, DKK1, DKK2 and DKK3 polymorphisms were analyzed in 399 postmenopausal Korean women. Serum levels of bone turnover markers were measured, and BMDs at the lumbar spine and femoral neck were also examined. Results: No significant differences in adjusted BMD at the lumbar spine and femoral neck were noted according to any single and combined polymorphisms measured in SOST, DKK s and sFRP s. However, osteoporosis at the femoral neck was 2.35 times more frequently observed in the AA genotype of the sFRP4 c.958C>A polymorphism compared to the non-AA genotype (95% CI 1.09-5.08, p = 0.03). Also, the CC genotype of the sFRP3 c.970C>G polymorphism had a higher rate of osteoporosis at the femoral neck compared to the GC genotype (OR 8.47, 95% CI 1.37-52.63, p = 0.049). Conclusions: Our results suggest that the sFRP3 c.970C>G and sFRP4 c.958C>A polymorphisms may be genetic factors associated with the prevalence of osteoporosis at the femoral neck in postmenopausal Korean women.

NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy: Osteoporosis prevention, diagnosis, and therapy. JAMA 2001;285:785-795.
Jouanny P, Guillemin F, Kuntz C, Jeandel C, Pourel J: Environmental and genetic factors affecting bone mass. Similarity of bone density among members of healthy families. Arthritis Rheum 1995;38:61-67.
Gong G, Haynatzki G: Association between bone mineral density and candidate genes in different ethnic populations and its implications. Calcif Tissue Int 2003;72:113-123.
Ralston SH, Uitterlinden AG: Genetics of osteoporosis. Endocr Rev 2010;31:629-662.
Kang S, Shi YY, Li Y, Wang N, Lu YC, Zhou RM, Zhao XW: Association between genetic variants of the VEGFR-2 gene and the risk of developing endometriosis in northern Chinese women. Gynecol Obstet Invest 2013;76:32-37.
Song C, Xie S, Wang J, Lian J, Diao B, Tang Y: Association of angiotensinogen gene polymorphisms and angiogenic factors with preeclampsia in Chinese women. Gynecol Obstet Invest 2013;76:64-68.
Yuan R, Le AW: A study on the estrogen receptor-α gene polymorphism and its expression in thin endometrium of unknown etiology. Gynecol Obstet Invest 2012;74:13-20.
Kim H, Chun S, Ku SY, Suh CS, Choi YM, Kim JG: Association between polymorphisms in tumor necrosis factor (TNF) and TNF receptor genes and circulating TNF, soluble TNF receptor levels, and bone mineral density in postmenopausal Korean women. Menopause 2009;16:1014-1020.
Kim JG, Kim JH, Kim JY, Ku SY, Jee BC, Suh CS, Kim SH, Choi YM: Association between osteoprotegerin (OPG), receptor activator of nuclear factor-κB (RANK), and rank ligand (RANKL) gene polymorphisms and circulating OPG, soluble RANKL levels, and bone mineral density in Korean postmenopausal women. Menopause 2007;14:913-918.
Kim JG, Kwon JH, Kim SH, Choi YM, Moon SY, Lee JY: Association between vitamin D receptor gene haplotypes and bone mass in postmenopausal Korean women. Am J Obstet Gynecol 2003;189:1234-1240.
Kim JG, Lim KS, Kim EK, Choi YM, Lee JY: Association of vitamin D receptor and estrogen receptor gene polymorphisms with bone mass in postmenopausal Korean women. Menopause 2001;8:222-228.
Kim JG, Roh KR, Lee JY: The relationship among serum insulin-like growth factor-I, insulin-like growth factor-1 gene polymorphism, and bone mineral density in postmenopausal women in Korea. Am J Obstet Gynecol 2002;186:345-350.
Baron R, Rawadi G, Roman-Roman S: Wnt signaling: a key regulator of bone mass. Curr Top Dev Biol 2006;76:103-127.
Westendorf JJ, Kahler RA, Schroeder TM: Wnt signaling in osteoblasts and bone diseases. Gene 2004;341:19-39.
Bovolenta P, Esteve P, Ruiz JM, Cisneros E, Lopez-Rios J: Beyond Wnt inhibition: new functions of secreted frizzled-related proteins in development and disease. J Cell Sci 2008;121:737-746.
Kawano Y, Kypta R: Secreted antagonists of the Wnt signalling pathway. J Cell Sci 2003;116:2627-2634.
Ott SM: Sclerostin and Wnt signaling - the pathway to bone strength. J Clin Endocrinol Metab 2005;90:6741-6743.
Van Bezooijen RL, ten Dijke P, Papapoulos SE, Lowik CW: SOST/sclerostin, an osteocyte-derived negative regulator of bone formation. Cytokine Growth Factor Rev 2005;16:319-327.
Nakanishi R, Akiyama H, Kimura H, Otsuki B, Shimizu M, Tsuboyama T, Nakamura T: Osteoblast-targeted expression of Sfrp4 in mice results in low bone mass. J Bone Miner Res 2008;23:271-277.
Nakanishi R, Shimizu M, Mori M, Akiyama H, Okudaira S, Otsuki B, Hashimoto M, Higuchi K, Hosokawa M, Tsuboyama T, Nakamura T: Secreted frizzled-related protein 4 is a negative regulator of peak BMD in SAMP6 mice. J Bone Miner Res 2006;21:1713-1721.
Balemans W, Foernzler D, Parsons C, Ebeling M, Thompson A, Reid DM, Lindpaintner K, Ralston SH, Van Hul W: Lack of association between the SOST gene and bone mineral density in perimenopausal women: analysis of five polymorphisms. Bone 2002;31:515-519.
Gao G, Zhang ZL, He JW, Zhang H, Yue H, Hu WW, Gu JM, Fu WZ, Hu YQ, Li M, Liu YJ, Yu JB: No association of the polymorphisms of the frizzled-related protein gene with peak bone mineral density in Chinese nuclear families. BMC Med Genet 2010;11:1.
Huang QY, Li GH, Kung AW: The -9247 T/C polymorphism in the SOST upstream regulatory region that potentially affects C/EBPα and FOXA1 binding is associated with osteoporosis. Bone 2009;45:289-294.
Lee DY, Kim H, Ku SY, Kim SH, Choi YM, Kim JG: Association between polymorphisms in Wnt signaling pathway genes and bone mineral density in postmenopausal Korean women. Menopause 2010;17:1064-1070.
Lories RJ, Boonen S, Peeters J, de Vlam K, Luyten FP: Evidence for a differential association of the Arg200Trp single-nucleotide polymorphism in FRZB with hip osteoarthritis and osteoporosis. Rheumatology (Oxford) 2006;45:113-114.
Ohnaka K, Yamamoto K, Nakamura K, Adachi M, Kawate H, Kono S, Takayanagi R: Association of single nucleotide polymorphisms in secreted frizzled-related protein 1 gene with bone mineral density in Japanese women. Geriatr Gerontol Int 2009;9:304-309.
Piters E, Balemans W, Nielsen TL, Andersen M, Boudin E, Brixen K, Van Hul W: Common genetic variation in the DKK1 gene is associated with hip axis length but not with bone mineral density and bone turnover markers in young adult men: Results from the Odense Androgen Study. Calcif Tissue Int 2010;86:271-281.
Sims AM, Shephard N, Carter K, Doan T, Dowling A, Duncan EL, Eisman J, Jones G, Nicholson G, Prince R, Seeman E, Thomas G, Wass JA, Brown MA: Genetic analyses in a sample of individuals with high or low BMD shows association with multiple Wnt pathway genes. J Bone Miner Res 2008;23:499-506.
Valero C, Zarrabeitia MT, Hernandez JL, Pineda B, Cano A, Garcia-Perez MA, Riancho JA: Relationship of sclerostin and secreted frizzled protein polymorphisms with bone mineral density: an association study with replication in postmenopausal women. Menopause 2011;18:802-807.
Kanis JA, Melton LJ 3rd, Christiansen C, Johnston CC, Khaltaev N: The diagnosis of osteoporosis. J Bone Miner Res 1994;9:1137-1141.
Loughlin J, Dowling B, Chapman K, Marcelline L, Mustafa Z, Southam L, Ferreira A, Ciesielski C, Carson DA, Corr M: Functional variants within the secreted frizzled-related protein 3 gene are associated with hip osteoarthritis in females. Proc Natl Acad Sci USA 2004;101:9757-9762.
Lettre G, Lange C, Hirschhorn JN: Genetic model testing and statistical power in population-based association studies of quantitative traits. Genet Epidemiol 2007;31:358-362.
Glass DA 2nd, Karsenty G: Canonical Wnt signaling in osteoblasts is required for osteoclast differentiation. Ann NY Acad Sci 2006;1068:117-130.
Spencer GJ, Utting JC, Etheridge SL, Arnett TR, Genever PG: Wnt signalling in osteoblasts regulates expression of the receptor activator of NF-κB ligand and inhibits osteoclastogenesis in vitro. J Cell Sci 2006;119:1283-1296.
Richards JB, Rivadeneira F, Inouye M, Pastinen TM, Soranzo N, Wilson SG, Andrew T, Falchi M, Gwilliam R, Ahmadi KR, Valdes AM, Arp P, Whittaker P, Verlaan DJ, Jhamai M, Kumanduri V, Moorhouse M, van Meurs JB, Hofman A, Pols HA, Hart D, Zhai G, Kato BS, Mullin BH, Zhang F, Deloukas P, Uitterlinden AG, Spector TD: Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet 2008;371:1505-1512.
Styrkarsdottir U, Halldorsson BV, Gretarsdottir S, Gudbjartsson DF, Walters GB, Ingvarsson T, Jonsdottir T, Saemundsdottir J, Center JR, Nguyen TV, Bagger Y, Gulcher JR, Eisman JA, Christiansen C, Sigurdsson G, Kong A, Thorsteinsdottir U, Stefansson K: Multiple genetic loci for bone mineral density and fractures. N Engl J Med 2008;358:2355-2365.
Hirata H, Hinoda Y, Nakajima K, Kikuno N, Yamamura S, Kawakami K, Suehiro Y, Tabatabai ZL, Ishii N, Dahiya R: Wnt antagonist gene polymorphisms and renal cancer. Cancer 2009;115:4488-4503.
Bodine PV, Zhao W, Kharode YP, Bex FJ, Lambert AJ, Goad MB, Gaur T, Stein GS, Lian JB, Komm BS: The Wnt antagonist secreted frizzled-related protein-1 is a negative regulator of trabecular bone formation in adult mice. Mol Endocrinol 2004;18:1222-1237.
Kerkhof JM, Uitterlinden AG, Valdes AM, Hart DJ, Rivadeneira F, Jhamai M, Hofman A, Pols HA, Bierma-Zeinstra SM, Spector TD, van Meurs JB: Radiographic osteoarthritis at three joint sites and FRZB, LRP5, and LRP6 polymorphisms in two population-based cohorts. Osteoarthritis Cartilage 2008;16:1141-1149.
Cho YS, Go MJ, Kim YJ, Heo JY, Oh JH, Ban HJ, Yoon D, Lee MH, Kim DJ, Park M, Cha SH, Kim JW, Han BG, Min H, Ahn Y, Park MS, Han HR, Jang HY, Cho EY, Lee JE, Cho NH, Shin C, Park T, Park JW, Lee JK, Cardon L, Clarke G, McCarthy MI, Lee JY, Oh B, Kim HL: A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat Genet 2009;41:527-534.
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