Abstract
Collagen type I α2 (COL1A2) and parathyroid hormone (PTH)/PTH-related peptide receptor (PTHR1) are two prominent candidate genes for bone mineral density (BMD). To test their importance for BMD variation in Chinese, we recruited 388 nuclear families composed of both parents and at least one healthy daughter with a total of 1,220 individuals, and simultaneously analyzed population stratification, total-family association, and within-family association between BMD at the spine and hip and the (GT) n marker in the intron 1 of the COL1A2 gene and the (AAAG) n marker in the P3 promoter of PTHR1 gene. We also performed these association analyses with haplotypes of the MspI and (GT) n polymorphisms in the COL1A2 gene. Significant within-family association was found between the M(GT) 12 haplotype and trochanter BMD (P<0.001). Individuals with this haplotype have, on average, 9.53% lower trochanter BMD than the non-carriers. Suggestive evidence of the within-family association was detected between the (GT) 17 allele and BMD at the spine (P=0.012), hip (P=0.011), femoral neck (P=0.032), trochanter (P=0.023), and intertrochanter (P=0.034). The association was confirmed by subsequent permutation tests. For the association, the proportion of phenotypic variance explained by the detected markers ranged from 1.2 to 3.9%, with the highest 3.9% at the trochanter for the M(GT) 12 haplotype. This association indicates that there is strong linkage disequilibrium between the polymorphisms (MspI and GT repeat polymorphism) in the COL1A2 gene and a nearby quantitative trait locus (QTL) underlying BMD variation in Chinese, or the markers themselves may have an important effect on the variation of BMD. On the other hand, no significant within-family association, population stratification and total-family association between the PTHR1 polymorphism and BMD were found in our Chinese population.
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Abecasis GR, Cardon LR, Cookson WO (2000) A general test of association for quantitative traits in nuclear families. Am J Hum Genet 66:279–292
Akai J, Kimura A, Hata RI (1999) Transcriptional regulation of the human type I collagen α2 (COL1A2) gene by the combination of two dinucleotide repeats. Gene 239:65–73
Audi L, Garcia-Ramirez M, Carrascosa A (1999) Genetic determinants of bone mass. Horm Res 51:105–123
Bettoun JD, Minagawa M, Hendy GN, Alpert LC, Goodyer CG, Goltzman D, White JH (1998) Developmental upregulation of human parathyroid hormone (PTH)/PTH-related peptide receptor gene expression from conserved and human-specific promoters. J Clin Invest 102:958–967
Brommage R, Hotchkiss CE, Lees CJ, Stancill MW, Hock JM, Jerome CP (1999) Daily treatment with human recombinant parathyroid hormone-(1–34), LY333334, for 1 year increases bone mass in ovariectomized monkeys. J Clin Endocrinol Metab 84:3757–3763
Buckwalter JA, Cooper RR (1987) Bone structure and function. Instr Course Lect 36:27–48
Cardon LR, Garner C, Bennett ST, Mackay IJ, Edwards J, Cornish J, Hegde M, Murray MAP, Reid IR, Cundy T (2000) Evidence for a major gene for bone mineral density in idiopathic osteoporosis families. J Bone Miner Res 15:1132–1137
Cummings SR, Kelsey JL, Nevitt MC, O’Dowd KJ (1985) Epidemiology of osteoporosis and osteoporotic fractures. Epidemiol Rev 7:178–208
Dalgleish R (2000) The human type I collagen mutation database. Nucleic Acids Res 25:181–187
Deng FY, Liu MY, Li MX, Lei SF, Qin YJ, Zhou Q, Liu YJ, Deng HW (2003) Tests of linkage and association of the COL1A2 gene with bone phenotypes’ variation in Chinese nuclear families. Bone 33:614–619
Duncan EL, Brown MA, Sinsheimer J, Bell J, Carr AJ, Wordsworth BP, Wass JA (1999) Suggestive linkage of the parathyroid receptor type 1 to osteoporosis. J Bone Miner Res 14:1993–1999
Flicker L, Hopper JL, Rodgers L, Kaymakci B, Green JD, Wark JD (1995) Bone density determinants in elderly women: a twin study. J Bone Miner Res 10:1607–1613
Gebhardt F, Zanker KS, Brandt B (1999) Modulation of epidermal growth factor receptor gene transcription by a polymorphic dinucleotide repeat in intron 1. J Biol Chem 274:13176–13180
Hansen MA, Overgaard K, Riis BJ, Christiansen C (1991) Role of peak bone mass and bone loss in postmenopausal osteoporosis: 12 year study. BMJ 303:961–964
Ho NC, Jia L, Driscoll CC, Gutter EM, Francomano CA (2000) A skeletal gene database. J Bone Miner Res 15:2095–2122
Hui SL, Slemenda CW, Johnston CC Jr (1990) The contribution of bone loss to postmenopausal osteoporosis. Osteoporos Int 1:30–34
Lei SF, Deng FY, Li MX, Dvornyk V, Deng HW (2004) Bone mineral density in elderly Chinese: effects of age, sex, weight, height, and body mass index. J Bone Miner Metab 22:71–78
Li JL, Deng H, Lai DB, Xu F, Chen J, Gao G, Recker RR, Deng HW (2001) Toward high-throughput genotyping: dynamic and automatic software for manipulating large-scale genotype data using fluorescently labeled dinucleotide markers. Genome Res 11:1304–1314
Liu XH, Liu YJ, Jiang DK, Li YM, Li MX, Qin YJ, Jian WX, Zhou Q, Deng HW (2003) No evidence for linkage and/or association of human α2-HS glycoprotein gene with bone mineral density variation in Chinese nuclear families. Calcif Tissue Int 73:244–250
Liu Z, Piao J, Pang L, Qing X, Nan S, Pan Z, Guo Y, Wang X, Li F, Liu J, Cheng X (2002) The diagnostic criteria for primary osteoporosis and the incidence of osteoporosis in China. J Bone Miner Metab 20:181–189
Livshits G, Karasik D, Otremski I, Kobyliansky E (1998) Genes play an important role in bone aging. Am J Hum Biol 10:421–428
Lu SD (1999) Current Protocols for Molecular Biology, 2nd edn. Peking Union Medical College Press, Beijing, pp 102–108
Manen D, Palmer G, Bonjour JP, Rizzoli R (2000) Positive and negative control of the expression of parathyroid hormone (PTH)/PTH-related protein receptor via proximal promoter P3 in human osteoblast-like cells. J Clin Endocr Metab 85:3376–3382
McIntyre LM, Martin ER, Simonsen KL, Kaplan NL (2000) Circumventing multiple testing: a multilocus Monte Carlo approach to testing for association. Genet Epidemiol 19:18–29
Minagawa M, Yasuda T, Watanabe T, Minamitani K, Takahashi Y, Goltzman D, White JH, Hendy GN, Kohno Y (2002) Association between AAAG repeat polymorphism in the P3 promoter of the human parathyroid hormone (PTH)/PTH-related peptide receptor gene and adult height, urinary pyridinoline excretion, and promoter activity. J Clin Endocrinol Metab 87:1791–1796
Okladnova O, Syagailo YV, Tranitz M, Stober G, Riederer P, Mossner R, Lesch KP (1998) A promoter-associated polymorphic repeat modulates PAX-6 expression in human brain. Biochem Biophys Res Commun 248:402–405
Pepe G (1993) A highly polymorphic (ACT) n VNTR (variable nucleotide of tandem repeats) locus inside intron 12 of COL1A2, one of the two genes involved in dominant osteogenesis imperfecta. Hum Mutat 2:300–305
Pepe G, Rickarcds O, Bue C, Martinez-labarga C, Tartaglia M, De Stefano GF (1994) EcoRI, RsaI and MspI RFLPs of the COL1A2 gene (type I collagen) in the Cayapa, a native American population of Ecuador. Hum Biol 66:979–989
Phillips CL, Bradley DA, Schlotzhauer CL, Bergfeld M, Libreros Minotta C, Gawenis LR, Morris JS, Clarke LL, Hillman LS (2000) Oim mice exhibit altered femur and incisor mineral composition and decreased bone mineral density. Bone 27:219–226
Purcell S, Cherny SS, Sham PC (2003) Genetic power calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 19:149–150
Qin YJ, Shen H, Huang QR, Zhao LJ, Zhou Q, Li MX, He JW, Mo XY, Lu JH, Recker RR, Deng HW (2003) Estrogen receptor α gene polymorphisms and peak bone density in Chinese nuclear families. J Bone Miner Res 18:1028–1035
Spielman RS, McGinnis RE, Ewens WJ (1993) Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 52:506–516
Spotila LD, Colige A, Sereda L, Constantinou-Deltas CD, Whyte MP, Riggs BL, Shaker JL, Spector TD, Hume E, Olsen N (1994) Mutation analysis of coding sequences for type I procollagen in individuals with low bone density. J Bone Miner Res 9:923–932
Spotila LD, Caminis J, Devoto M, Shimoya K, Sereda L, Ott J, Whyte MP, Tenenhouse A, Prockop DJ (1996) Osteopenia in 37 members of seven families: analysis based on a model of dominant inheritance. Mol Med 2:313–324
Suuriniemi M, Mahonen A, Kovanen V, Alen M, Cheng S (2003) Relation of PvuII site polymorphism in the COL1A2 gene to the risk of fractures in prepubertal Finnish girls. Physiol Genomics 14:217–224
Willing MC, Torner JC, Burns TL, Janz KF, Marshall T, Gilmore J, Deschenes SP, Warren JJ, Levy SM (2003) Gene polymorphisms, bone mineral density and bone mineral content in young children: the Iowa bone development study. Osteoporos Int 14:650–658
Zhou XG, Liu YZ, Li MX, Jian WX, Lei SF, Qin YJ, Zhou Q, Deng HW (2003) Parathyroid hormone gene with bone phenotypes in Chinese. Biochem Biophys Res Commun 307:666–671
Acknowledgements
The study was partially supported by a key project grant (30230210), an Outstanding Young Scientist Award (30025025), a general (30170504) from National Science Foundation of China (NSFC), a project from Scientific Research Fund of Hunan Provincial Education Department (02A027), and a Seed Fund (25000106) and a outstanding young award from Huo Ying Dong education foundation (81017). Investigators (H.-W.D., V.D.) were partially supported by grants from Health Future Foundation of USA, grants of National Health Institute (K01 AR02170-01, R01 GM60402-01A1), grants from the State of Nebraska Cancer and Smoking Related Disease Research Program (LB595) and the State of Nebraska Tobacco Settlement Fund (LB692), and US department of Energy grant (DE-FG03-00ER63000/A00). We thank all the study subjects for volunteering to participate in the study. We thank Ms. Qi-Ren Huang, Ms. Yue-Juan Qin, and Ms. Qi Zhou from the Sixth Hospital of Shanghai, China, for coordinating sample recruitment.
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S.-F. Lei and F.-Y. Deng contributed equally to this work
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Lei, SF., Deng, FY., Dvornyk, V. et al. The (GT) n polymorphism and haplotype of the COL1A2 gene, but not the (AAAG) n polymorphism of the PTHR1 gene, are associated with bone mineral density in Chinese. Hum Genet 116, 200–207 (2005). https://doi.org/10.1007/s00439-004-1225-4
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DOI: https://doi.org/10.1007/s00439-004-1225-4