Association of the 163A/G and 1181G/C Osteoprotegerin Polymorphism with Bone Mineral Density

Abstract

The aim of the study was to investigate the distribution of 163 A/G osteoprotegerin gene promoter and 1181 G/C osteoprotegerin exon 1 polymorphisms in a group of women with different hormonal status and to analyze their relationship with BMD. Osteoprotegerin polymorphisms and BMD were analyzed in 332 women (69 premenopausal and 263 postmenopausal). BMD was quantified at the lumbar spine (L_2-4), femoral neck, and total hip. Genotyping for the presence of different polymorphisms was performed using the Custom Taqman^® SNP Genotyping assays. There were not significant differences in BMD according to 163 A/G genotype. However, significant differences in lumbar spine BMD were found according to 1181 G/C alleles. Thus, women with CC genotype had significant higher BMD at the lumbar spine than those with GC or GG genotype. No differences were found in femoral neck and total hip BMD. In age-adjusted models, the 1181 G/C OPG polymorphism explained 2.2% of BMD variance at the spine, 0.3% at the femoral neck, and 0.9% at the total hip in the whole group. In the subgroup of premenopausal women, the polymorphism was strongly related to spine BMD, and explained 11.5% of the variance, whereas body weight explained 7.9%. The 1181 G/C polymorphism was associated with lumbar spine BMD in Spanish women. Premenopausal women with the CC genotype had a higher BMD.

osteoprotegerin - single nucleotide polymorphisms - 1181 G/C - 163 A/G - bone mineral density

References

• 1 Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis.  Am J Med. 1993;  94 646-650
• 2 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
• 3 Ciguere Y, Rousseau F. The genetics of osteoporosis: “complexities and difficulties”.  Clin Genet. 2000;  57 161-169
• 4 Peacock M, Turner C, Econs M, Foroud T. Genetics of osteoporosis.  Endocr Rev. 2002;  23 303-326
• 5 Ralston SH. Genetic control of susceptibility to osteoporosis.  J Clin Endocrinol Metab. 2002;  87 2460-2466
• 6 Morrison NA, Qi JC, Tokita A, Kelly PJ, Crofts L, Nguyen TV, Sambrook PN, Eisman JA. Prediction of bone density from vitamin D receptor alleles.  Nature. 1994;  367 284-287
• 7 Uitterlinden AG, Pols AHP, Burger H, Huang Q, Daele PL van, Dujin CM Van, Hofman A, Birkenhager JC, Leeuwen JP Van. A large scale population-based study of the association of vitamin D receptor gene polymorphisms with bone mineral density.  J Bone Miner Res. 1996;  11 1242-1248
• 8 Grant SFA, Reid DM, Blake G, Herd R, Fogelman J, Ralston SH. Reduced bone density and osteoporosis associated with a polymorphic Sp1 binding site in the collagen type Iα1 gene.  Nat Genet. 1996;  14 203-205
• 9 Uitterlinden AG, Burger H, Huang Q, Yue F, Mac Guigan FE, Grant SF, Hofman A, Leeuwen JP Van, Pols AH, Ralston SH. Relation of alleles of the collagen type Iα1 gene to bone density and the risk of osteoporotic fractures in postmenopausal women.  N Engl J Med. 1998;  338 1016-1021
• 10 Kobayashi S, Inoue S, Hosoi T, Ouchi Y, Shiraki M, Orimo H. Association of bone mineral density with polymorphism of the estrogen receptor gene.  J Bone Miner Res. 1996;  11 306-311
• 11 Meuers JB Van, Schuit SC, Weel AE, Kilft M Van der, Bergink AP, Arp PP, Colin EM, Fang Y, Hofman A, Duijn CM van, Leeuwen JP van, Pols HA, Uitterlinden AG. Association of 5′ estrogen receptor alpha gene polymorphisms with bone mineral density, vertebral bone area and fracture risk.  Hum Mol Genet. 2003;  12 1745-1754
• 12 Ota N, Nakajima T, Nakazawa I, Suzuki T, Hosoi T, Orimo H, Inoue S, Shirai Y, Emi M. A nucleotide variant in the promoter region of the interleukin-6 gene associated with decreased bone mineral density.  J Hum Genet. 2001;  46 267-272
• 13 Zarrabeitia MT, Hernández JL, Valero C, Zarrabeitia AL, García-Unzueta M, Amado JA, González-Macías J, Riancho JA. A common polymorphism in the 5′-untranslated region of the aromatase gene influences bone mass and fracture risk.  Eur J Endocrinol. 2004;  50 699-704
• 14 Hofbauer LC, Küne CA, Viereck V. The OPG/RANKL/RANK system in metabolic bone diseases.  J Musculoskelet Neuronal Interact. 2004;  4 268-275
• 15 Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Goto M, Mochizuki SI, Tsuda E, Morinaga T, Udagawa N, Tahahashi N, Suda T, Higashio K. A novel molecular mechanism modulating osteoclast differentiation and function.  Bone. 1999;  25 109-113
• 16 Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Heghes TM, Hill D, Pattison W, Campbell P. Osteoprotegerin: A novel secreted protein involved in the regulation of bone density.  Cell. 1997;  89 309-313
• 17 Fiore CE, Pennisi P, Ferro G, Ximenes B, Privitelli L, Mangiafico RA, Santoro F, Parisi N, Lombardo T. Altered osteoprotegerin/RANKL ratio and low bone mineral density in celiac patients on long-term treatment with gluten-free diet.  Horm Metab Res. 2006;  38 417-422
• 18 Kaji H, Kanatani M, Sugimoto T, Chihara K. Statins modulate the levels of osteoprotegerin/receptor activator of NFκB ligand mRNA in mouse bone-cell cultures.  Horm Metab Res. 2005;  12 589-592
• 19 Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Caparelli C, Scully S, Tan HL, Xu W, Lacey DL, Boyle WJ, Simonet WS. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification.  Genes Dev. 1998;  12 1260-1268
• 20 Morinaga T, Nakagawa N, Yasuda H, Tsuda E, Higashio K. Cloning and characterization of the gene encoding human osteoprotegerin/osteoclastogenesis inhibitory factor.  Eur J Biochem. 1998;  254 685-691
• 21 Hofbauer LC, Schoppet M. Osteoprotegerin gene polymorphism and the risk of osteoporosis and vascular disease.  J Clin Endocrinol Metab. 2002;  87 4078-4079
• 22 Arko B, Prezelj J, Komel R, Kocijancic A, Hudler P, Marc J. Sequence variations in the osteoprotegerin gene promoter in patients with postmenopausal osteoporosis.  J Clin Endocrinol Metab. 2002;  87 4080-4084
• 23 Langdahl BL, Carstens M, Stenkjaer L, Eriksen EF. Polymorphisms in the osteoprotegerin gene are associated with osteoporotic fractures.  J Bone Miner Res. 2002;  17 1245-1255
• 24 Arko B, Prezelj J, Kocijancic A, Komel R, Marc J. Association of the osteoprotegerin gene polymorphisms with bone mineral density in postmenopausal women.  Maturitas. 2005;  51 270-279
• 25 Yamada Y, Ando F, Niino N, Shimokata H. Association of polymorphisms of the osteoprotegerin gene with bone mineral density in Japanese women but not men.  Mol Genet Metab. 2003;  80 344-349
• 26 Jorgensen HL, Kusk P, Madsen B, Fenger M, Lauritzen JB. Serum osteoprotegerin (OPG) and the A163G polymorphism in the OPG promoter region are related to peripheral measures of bone mass and fracture odds ratios.  J Bone Miner Metab. 2004;  22 132-138
• 27 Brändström H, Gerdhem P, Stiger F, Obrant KJ, Melhus H, Ljunggren Ö, Kindmark A, Akesson K. Single nucleotide polymorphisms in the human gene for osteoprotegerin are not related to bone mineral density or fracture in elderly women.  Calcif Tissue Int. 2004;  74 18-24
• 28 Zhao H, Liu J, Ning G, Zhao Y, Zhang L, Sun L, Xu M, Uitterlinden AG, Chen J. The influence of Lys3Asn polymorphism in the osteoprotegerin gene of bone mineral density in Chinese postmenopausal women.  Osteoporos Int. 2005;  16 1519-1524
• 29 Choi JY, Shin A, Park SK, Chung HW, Cho SI, Shin CS, Kim H, Lee KM, Lee KH, Kang C, Cho DY, Kang D. Genetic polymorphisms of OPG, RANK, and ESR1, and bone mineral density in Korean postmenopausal women.  Calcif Tissue Int. 2005;  77 152-159
• 30 Wynne F, Drummond F, O’Sullivan K, Daly M, Shanahan F, Molloy MG, Quane KA. Investigation of the genetic influence of the OPG, VDR (Fok1), and COLIA1 Sp1 polymorphisms on BMD in the Irish population.  Calcif Tissue Int. 2002;  71 26-35
• 31 Ohmori H, Makita Y, Funamizu K, Hirooka K, Hosoi T, Orimo H, Suzuki T, Ikari K, Nakajima T, Inoue I, Hata A. Linkage and association analyses of the osteoprotegerin genes locus with human osteoporosis.  J Hum Genet. 2000;  47 400-406
• 32 Hsu Y-H, Niu T, Terwedow HA, Xu XHA, Feng Y, Li Z, Brain JD, Rosen CJ, Laird N, Xu X. Variation in genes involved in the RANKL/RANK/OPG bone remodelling pathway are associated with bone mineral density at different skeletal sites in men.  Hum Genet. 2006;  118 568-577
• 33 Nakajima T, Cheng T, Rohrwasser A, Bloem LJ, Pratt JH, Inoue I, Lalouel JM. Functional analysis of a mutation occurring between the two in-frame AUG codons of human angiotensinogen.  J Biol Chem. 1999;  274 35749-35755

Correspondence