Abstract
Aim:
To determine the associations between HOXD4 gene polymorphisms with peak bone mineral density (BMD) throughing measuring three tagging single nucleotide polymorphisms (tagSNPs), including rs1867863, rs13418078, and rs4972504, in HOXD4.
Methods:
Four hundred Chinese nuclear families with male offspring (1215 subjects) and 401 Chinese nuclear families with female offspring (1260 subjects) were recruited. BMD of the lumbar spine 1-4 (L1-4) and left proximal femur including total hip and femoral neck were measured by dual-energy X-ray absorptiometry. The quantitative transmission disequilibrium test (QTDT) was performed to investigate the association among the tagging SNPs, haplotypes and peak BMD.
Results:
Only the CC genotype was identified in rs13418078 in the Chinese population, unlike other populations. We failed to find significant within-family association among these SNPs, haplotypes and peak BMD at any bone site in either male- or female-offspring nuclear families.
Conclusion:
The results suggest that genetic polymorphisms in HOXD4 may not be a major contributor to the observed variability in peak BMD in the lumbar spine and the hip in Chinese men and women.
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References
Miller PD, Siris ES, Barrett-Connor E, Faulkner KG, Wehren LE, Abbott TA, et al. Prediction of fracture risk in postmenopausal white women with peripheral bone densitometry: evidence from the National Osteoporosis Risk Assessment. J Bone Miner Res 2002; 17: 2222–30.
Brown LB, Streeten EA, Shapiro JR, McBride D, Shuldiner AR, Peyser PA, et al. Genetic and environmental influences on bone mineral density in pre- and post-menopausal women. Osteoporos Int 2005; 16: 1849–56.
Flicker L, Hopper JL, Rodgers L, Kaymakci B, Green RM, Wark JD . Bone density determinants in elderly women: a twin study. J Bone Miner Res 1995; 10: 1607–13.
Ralston SH, Galwey N, MacKay I, Albagha OM, Cardon L, Comnston JE, et al. Loci for regulation of bone mineral density in men and women identified by genome wide linkage scan: The FAMOS study. Hum Mol Genet 2005; 14: 943–51.
Styrkarsdottir U, Halldorsson BV, Gretarsdottir S, Gudbjartsson DF, Walters GB, Ingvarsson T, et al. Multiple genetic loci for bone mineral density and fractures. N Engl J Med 2008; 358: 2355–65.
Xiao P, Shen H, Guo YF, Xiong DH, Liu YZ, Liu YJ, et al. Genomic regions identified for BMD in a large sample including epistatic interactions and gender-specific effects. J Bone Miner Res 2006; 21: 1536–44.
Zhang ZL, He JW, Qin YJ, Hu YQ, Li M, Zhang H, et al. Association between myostatin gene polymorphisms and peak BMD variation in Chinese nuclear families. Osteoporos Int 2008; 19: 39–47.
Dlugaszewska B, Silahtaroglu A, Menzel C, Kübart S, Cohen M, Mundlos S, et al. Breakpoints around the HOXD cluster result in various limb malformations. J Med Genet 2006; 43: 111–8.
Shi X, Yang X, Chen D, Chang Z, Cao X . Smad1 interacts with homeobox DNA-binding proteins in bone morphogenetic protein signaling. J Biol Chem 1999; 274: 13711–7.
Li X, Cao X . BMP signaling and skeletogenesis. Ann N Y Acad Sci 2006; 1068: 26–40.
Liu Z, Shi W, Ji X, Sun C, Jee WS, Wu Y, et al. Molecules mimicking Smad1 interacting with HOX stimulate bone formation. J Biol Chem 2004; 279: 11313–9.
Kappen C, Mello MA, Finnell RH, Salbaum JM . Folate modulates HOXD gene-controlled skeletal phenotypes. Genesis 2004; 39: 155–66.
Oliver G, Sidell N, Fiske W, Heinzmann C, Mohandas T, Sparkes RS, et al. Complementary homeo protein gradients in developing limb buds. Genes Dev 1989; 3: 641–50.
Mavilio F, Simeone A, Giampaolo A, Faiella A, Zappavigna V, Acampora D, et al. Differential and stage-related expression in embryonic tissues of a new human homoeobox gene. Nature 1986; 324: 664–8.
van Scherpenzeel Thim V, Remacle S, Picard J, Cornu G, Gofflot F, Rezsohazy R, et al. Mutation analysis of the HOXD paralogous 4-13 genes in children with acute lymphoid malignancies: identification of a novel germline mutation of HOXD4 leading to a partial loss of function. Human Mutation 2005; 25: 384–95.
Qin YJ, Shen H, Huang QR, Zhao LJ, Zhou Q, Li MX, et al. Estrogen receptor alpha gene polymorphisms and peak bone density in Chinese nuclear families. J Bone Miner Res 2003; 18: 1028–35.
Zhang ZL, He JW, Qin YJ, Hu YQ, Li M, Liu YJ, et al. Association between SNP and haplotypes in PPARGC1 and adiponectin genes and bone mineral density in Chinese nuclear families. Acta Pharmacol Sin 2007; 28: 287–95.
Liu XH, Liu YJ, Jiang DK, Li YM, Li MX, Qin YJ, et al. No evidence for linkage and/or association of human alpha2-HS glycoprotein gene with bone mineral density variation in Chinese nuclear families. Calcif Tissue Int 2003; 73: 244–50.
Urano T, Shiraki M, Ezura Y, Fujita M, Sekine E, Hoshino S, et al. Association of a single-nucleotide polymorphism in low-density lipoprotein receptor-related protein 5 gene with bone mineral density. J Bone Miner Metab 2004; 22: 341–5.
Peacock M, Koller DL, Fishburn T, Krishnan S, Lai D, Hui S, et al. Sex-specific and non-sex-specific quantitative trait loci contribute to normal variation in bone mineral density in men. J Clin Endocrinol Metab 2005; 90: 3060–6.
Abecasis GR, Cookson WO, Cardon LR . Pedigree tests of transmission disequilibrium. Eur J Hum Genet 2000; 8: 545–51.
Gao G, Zhang ZL, Zhang H, Hu WW, Huang QR, Lu JH, et al. Hip axis length changes in 10 554 males and females and the association with femoral neck fracture. J Clin Densitom 2008; 11: 360–6.
Barrett JC, Fry B, Maller J, Daly MJ . Haploviw: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–5.
Stephens M, Smith NJ, Donnelly P . A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001; 68: 978–89.
Abecasis GR, Cardon LR, Cookson WO . A general test of association for quantitative traits in nuclear families. Am J Hum Genet 2000; 66: 279–92.
Fulker DW, Cherny SS, Sham PC, Hewitt JK . Combined linkage and association sib-pair analysis for quantitative traits. Am J Hum Genet 1999; 64: 259–67.
Zhang ZL, Qin YJ, Huang QR, Hu YQ, Li M, He JW, et al. Bone mineral density of the spine and femur in healthy Chinese men. Asian J Androl 2006; 8: 419–27.
McGuigan FE, Murray L, Gallagher A, Davey-Smith G, Neville CE, Van't Hof R, et al. Genetic and environmental determinants of peak bone mass in young men and women. J Bone Miner Res 2002; 17: 1273–9.
Deng HW, Shen H, Xu FH, Deng HY, Conway T, Zhang HT, et al. Tests of linkage and/or association of genes for vitamin D receptor, osteocalcin, and parathyroid hormone with bone mineral density. J Bone Miner Res 2002; 17: 678–86.
Hogan BL . Bone morphogenetic proteins in development. Curr Opin Genet Dev 1996; 6: 432–8.
Turgeman G, Zilberman Y, Zhou S, Kelly P, Moutsatsos IK, Kharode YP, et al. Systemically administered rhBMP-2 promotes MSC activity and reverses bone and cartilage loss in osteopenic mice. J Cell Biochem 2002; 86: 461–74.
Yang X, Ji X, Shi X, Cao X . Smad1 domains interacting with Hoxc-8 induce osteoblast differentiation. J Biol Chem 2000; 275: 1065–72.
Li X, Nie S, Chang C, Qiu T, Cao X . Smads oppose HOX transcriptional activities. Exp Cell Res 2006; 312: 854–64.
Acknowledgements
The study was supported by the National Natural Science Foundation of China (NSFC) (No 30570891, 30771019, and 30800387) and Program of Shanghai Chief Scientist (No 08XD1403000).
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Zhang, H., He, Jw., Gao, G. et al. Polymorphisms in the HOXD4 gene are not associated with peak bone mineral density in Chinese nuclear families. Acta Pharmacol Sin 31, 977–983 (2010). https://doi.org/10.1038/aps.2010.91
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DOI: https://doi.org/10.1038/aps.2010.91
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