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Published in: Osteoporosis International 4/2011

01-04-2011 | Original Article

Associations of APOE gene polymorphisms with bone mineral density and fracture risk: a meta-analysis

Authors: I. Peter, M. D. Crosier, M. Yoshida, S. L. Booth, L. A. Cupples, B. Dawson-Hughes, D. Karasik, D. P. Kiel, J. M. Ordovas, T. A. Trikalinos

Published in: Osteoporosis International | Issue 4/2011

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Abstract

Summary

To determine the association of the Apolipoprotein E (APOE) E4 gene polymorphism with bone mineral density (BMD) and fractures we conducted a meta-analysis of 17 reports. Despite lower trochanteric and lumbar BMD in APOE4 carriers, there is insufficient evidence to support a consistent association of APOE with bone health.

Introduction

APOE has been studied for its potential role in osteoporosis risk. It is hypothesized that genetic variation at APOE locus, known as E2, E3, and E4, may modulate BMD through its effects on lipoproteins and vitamin K transport. The purpose of this study was to determine the association of the APOE-E4 gene polymorphism with bone-related phenotypes.

Methods

We conducted a meta-analysis that combined newly analyzed individual data from two community-based cohorts, the Framingham Offspring Study (N = 1,495) and the vitamin K clinical trial (N = 377), with 15 other eligible published reports. Bone phenotypes included BMD measurements of the hip (total hip and trochanteric and femoral neck sites) and lumbar spine (from the L2 to L4 vertebrae) and prevalence or incidence of vertebral, hip, and other fractures.

Results

In sex-pooled analyses, APOE4 carriers had a 0.018 g/cm2 lower weighted mean trochanteric BMD than non carriers (p = 0.0002) with no evidence for between-study heterogeneity. A significant association was also detected with lumbar spine BMD (p = 0.006); however, inter-study heterogeneity was observed. Associations with lumbar spine and trochanteric BMD were observed predominantly in women and became less significant in meta-regression (p = 0.055 and 0.01, respectively). There were no consistent associations of APOE4 genotype with BMD at other skeletal sites or with fracture risk.

Conclusions

Based on these findings, there is insufficient evidence to support a strong and consistent association of the APOE genotype with BMD and fracture incidence.
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Literature
1.
go back to reference Eichner JE, Dunn ST, Perveen G, Thompson DM, Stewart KE, Stroehla BC (2002) Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review. Am J Epidemiol 155:487–495PubMedCrossRef Eichner JE, Dunn ST, Perveen G, Thompson DM, Stewart KE, Stroehla BC (2002) Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review. Am J Epidemiol 155:487–495PubMedCrossRef
2.
go back to reference Schilling AF, Schinke T, Munch C, Gebauer M, Niemeier A, Priemel M, Streichert T, Rueger JM, Amling M (2005) Increased bone formation in mice lacking apolipoprotein E. J Bone Miner Res 20:274–282PubMedCrossRef Schilling AF, Schinke T, Munch C, Gebauer M, Niemeier A, Priemel M, Streichert T, Rueger JM, Amling M (2005) Increased bone formation in mice lacking apolipoprotein E. J Bone Miner Res 20:274–282PubMedCrossRef
3.
go back to reference Long JR, Liu PY, Liu YJ, Lu Y, Shen H, Zhao LJ, Xiong DH, Deng HW (2004) APOE haplotypes influence bone mineral density in Caucasian males but not females. Calcif Tissue Int 75:299–304PubMedCrossRef Long JR, Liu PY, Liu YJ, Lu Y, Shen H, Zhao LJ, Xiong DH, Deng HW (2004) APOE haplotypes influence bone mineral density in Caucasian males but not females. Calcif Tissue Int 75:299–304PubMedCrossRef
4.
go back to reference Shiraki M, Shiraki Y, Aoki C, Hosoi T, Inoue S, Kaneki M, Ouchi Y (1997) Association of bone mineral density with apolipoprotein E phenotype. J Bone Miner Res 12:1438–1445PubMedCrossRef Shiraki M, Shiraki Y, Aoki C, Hosoi T, Inoue S, Kaneki M, Ouchi Y (1997) Association of bone mineral density with apolipoprotein E phenotype. J Bone Miner Res 12:1438–1445PubMedCrossRef
5.
go back to reference Johnston JM, Cauley JA, Ganguli M (1999) APOE 4 and hip fracture risk in a community-based study of older adults. J Am Geriatr Soc 47:1342–1345PubMed Johnston JM, Cauley JA, Ganguli M (1999) APOE 4 and hip fracture risk in a community-based study of older adults. J Am Geriatr Soc 47:1342–1345PubMed
6.
go back to reference Macdonald HM, McGuigan FE, Lanham-New SA, Fraser WD, Ralston SH, Reid DM (2008) Vitamin K1 intake is associated with higher bone mineral density and reduced bone resorption in early postmenopausal Scottish women: no evidence of gene-nutrient interaction with apolipoprotein E polymorphisms. Am J Clin Nutr 87:1513–1520PubMed Macdonald HM, McGuigan FE, Lanham-New SA, Fraser WD, Ralston SH, Reid DM (2008) Vitamin K1 intake is associated with higher bone mineral density and reduced bone resorption in early postmenopausal Scottish women: no evidence of gene-nutrient interaction with apolipoprotein E polymorphisms. Am J Clin Nutr 87:1513–1520PubMed
7.
go back to reference Pluijm SM, Dik MG, Jonker C, Deeg DJ, van Kamp GJ, Lips P (2002) Effects of gender and age on the association of apolipoprotein E epsilon4 with bone mineral density, bone turnover and the risk of fractures in older people. Osteoporos Int 13:701–709PubMedCrossRef Pluijm SM, Dik MG, Jonker C, Deeg DJ, van Kamp GJ, Lips P (2002) Effects of gender and age on the association of apolipoprotein E epsilon4 with bone mineral density, bone turnover and the risk of fractures in older people. Osteoporos Int 13:701–709PubMedCrossRef
8.
go back to reference von Muhlen DG, Barrett-Connor E, Schneider DL, Morin PA, Parry P (2001) Osteoporosis and apolipoprotein E genotype in older adults: the Rancho Bernardo study. Osteoporos Int 12:332–335CrossRef von Muhlen DG, Barrett-Connor E, Schneider DL, Morin PA, Parry P (2001) Osteoporosis and apolipoprotein E genotype in older adults: the Rancho Bernardo study. Osteoporos Int 12:332–335CrossRef
9.
go back to reference Schoofs MW, van der Klift M, Hofman A, van Duijn CM, Stricker BH, Pols HA, Uitterlinden AG (2004) ApoE gene polymorphisms, BMD, and fracture risk in elderly men and women: the Rotterdam study. J Bone Miner Res 19:1490–1496PubMedCrossRef Schoofs MW, van der Klift M, Hofman A, van Duijn CM, Stricker BH, Pols HA, Uitterlinden AG (2004) ApoE gene polymorphisms, BMD, and fracture risk in elderly men and women: the Rotterdam study. J Bone Miner Res 19:1490–1496PubMedCrossRef
10.
go back to reference Efstathiadou Z, Koukoulis G, Stakias N, Challa A, Tsatsoulis A (2004) Apolipoprotein E polymorphism is not associated with spinal bone mineral density in peri- and postmenopausal Greek women. Maturitas 48:259–264PubMedCrossRef Efstathiadou Z, Koukoulis G, Stakias N, Challa A, Tsatsoulis A (2004) Apolipoprotein E polymorphism is not associated with spinal bone mineral density in peri- and postmenopausal Greek women. Maturitas 48:259–264PubMedCrossRef
11.
go back to reference Stulc T, Ceska R, Horinek A, Stepan J (2000) Bone mineral density in patients with apolipoprotein E type 2/2 and 4/4 genotype. Physiol Res 49:435–439PubMed Stulc T, Ceska R, Horinek A, Stepan J (2000) Bone mineral density in patients with apolipoprotein E type 2/2 and 4/4 genotype. Physiol Res 49:435–439PubMed
12.
go back to reference Cupples LA, D’Agostino RB, Anderson K, Kannel WB (1988) Comparison of baseline and repeated measure covariate techniques in the Framingham Heart Study. Stat Med 7:205–222PubMedCrossRef Cupples LA, D’Agostino RB, Anderson K, Kannel WB (1988) Comparison of baseline and repeated measure covariate techniques in the Framingham Heart Study. Stat Med 7:205–222PubMedCrossRef
13.
go back to reference Booth SL, Dallal G, Shea MK, Gundberg C, Peterson JW, Dawson-Hughes B (2008) Effect of vitamin K supplementation on bone loss in elderly men and women. J Clin Endocrinol Metab 93:1217–1223PubMedCrossRef Booth SL, Dallal G, Shea MK, Gundberg C, Peterson JW, Dawson-Hughes B (2008) Effect of vitamin K supplementation on bone loss in elderly men and women. J Clin Endocrinol Metab 93:1217–1223PubMedCrossRef
14.
go back to reference Kannel WB, Feinleib M, McNamara PM, Garrison RJ, Castelli WP (1979) An investigation of coronary heart disease in families. The Framingham Offspring Study. Am J Epidemiol 110:281–290PubMed Kannel WB, Feinleib M, McNamara PM, Garrison RJ, Castelli WP (1979) An investigation of coronary heart disease in families. The Framingham Offspring Study. Am J Epidemiol 110:281–290PubMed
15.
go back to reference Araujo AB, Travison TG, Harris SS, Holick MF, Turner AK, McKinlay JB (2007) Race/ethnic differences in bone mineral density in men. Osteoporos Int 18:943–953PubMedCrossRef Araujo AB, Travison TG, Harris SS, Holick MF, Turner AK, McKinlay JB (2007) Race/ethnic differences in bone mineral density in men. Osteoporos Int 18:943–953PubMedCrossRef
16.
go back to reference McNamara JR, Schaefer EJ (1987) Automated enzymatic standardized lipid analyses for plasma and lipoprotein fractions. Clin Chim Acta 166:1–8PubMedCrossRef McNamara JR, Schaefer EJ (1987) Automated enzymatic standardized lipid analyses for plasma and lipoprotein fractions. Clin Chim Acta 166:1–8PubMedCrossRef
17.
go back to reference Washburn RA, Ficker JL (1999) Physical Activity Scale for the Elderly (PASE): the relationship with activity measured by a portable accelerometer. J Sports Med Phys Fit 39:336–340 Washburn RA, Ficker JL (1999) Physical Activity Scale for the Elderly (PASE): the relationship with activity measured by a portable accelerometer. J Sports Med Phys Fit 39:336–340
18.
go back to reference Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215PubMedCrossRef Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215PubMedCrossRef
19.
go back to reference Hixson JE, Vernier DT (1990) Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res 31:545–548PubMed Hixson JE, Vernier DT (1990) Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res 31:545–548PubMed
20.
21.
go back to reference Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558PubMedCrossRef Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558PubMedCrossRef
22.
go back to reference Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG (2001) Replication validity of genetic association studies. Nat Genet 29:306–309PubMedCrossRef Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG (2001) Replication validity of genetic association studies. Nat Genet 29:306–309PubMedCrossRef
23.
go back to reference Trikalinos TA, Salanti G, Khoury MJ, Ioannidis JP (2006) Impact of violations and deviations in Hardy-Weinberg equilibrium on postulated gene-disease associations. Am J Epidemiol 163:300–309PubMedCrossRef Trikalinos TA, Salanti G, Khoury MJ, Ioannidis JP (2006) Impact of violations and deviations in Hardy-Weinberg equilibrium on postulated gene-disease associations. Am J Epidemiol 163:300–309PubMedCrossRef
24.
go back to reference Wallace, B., Schmid CH, Lau J, Trikalinos TA. (2009) Meta-analyst: software for meta-analysis of binary, continuous and diagnostic data. BMC Med Research Methodol 9:80 Wallace, B., Schmid CH, Lau J, Trikalinos TA. (2009) Meta-analyst: software for meta-analysis of binary, continuous and diagnostic data. BMC Med Research Methodol 9:80
25.
go back to reference Lee SI, Lee SY, Yoo WH (2005) Association of apolipoprotein E polymorphism with bone mineral density in postmenopausal women with rheumatoid arthritis. Rheumatol 44:1067–1068CrossRef Lee SI, Lee SY, Yoo WH (2005) Association of apolipoprotein E polymorphism with bone mineral density in postmenopausal women with rheumatoid arthritis. Rheumatol 44:1067–1068CrossRef
26.
go back to reference Theppeang K, Glass TA, Bandeen-Roche K, Todd AC, Rohde CA, Links JM, Schwartz BS (2008) Associations of bone mineral density and lead levels in blood, tibia, and patella in urban-dwelling women. Environ Health Perspect 116:784–790PubMedCrossRef Theppeang K, Glass TA, Bandeen-Roche K, Todd AC, Rohde CA, Links JM, Schwartz BS (2008) Associations of bone mineral density and lead levels in blood, tibia, and patella in urban-dwelling women. Environ Health Perspect 116:784–790PubMedCrossRef
27.
go back to reference Bachner D, Schroder D, Betat N, Ahrens M, Gross G (1999) Apolipoprotein E (ApoE), a Bmp-2 (bone morphogenetic protein) upregulated gene in mesenchymal progenitors (C3H10T1/2), is highly expressed in murine embryonic development. Biofactors 9:11–17PubMedCrossRef Bachner D, Schroder D, Betat N, Ahrens M, Gross G (1999) Apolipoprotein E (ApoE), a Bmp-2 (bone morphogenetic protein) upregulated gene in mesenchymal progenitors (C3H10T1/2), is highly expressed in murine embryonic development. Biofactors 9:11–17PubMedCrossRef
28.
go back to reference Hirasawa H, Tanaka S, Sakai A, Tsutsui M, Shimokawa H, Miyata H, Moriwaki S, Niida S, Ito M, Nakamura T (2007) ApoE gene deficiency enhances the reduction of bone formation induced by a high-fat diet through the stimulation of p53-mediated apoptosis in osteoblastic cells. J Bone Miner Res 22:1020–1030PubMedCrossRef Hirasawa H, Tanaka S, Sakai A, Tsutsui M, Shimokawa H, Miyata H, Moriwaki S, Niida S, Ito M, Nakamura T (2007) ApoE gene deficiency enhances the reduction of bone formation induced by a high-fat diet through the stimulation of p53-mediated apoptosis in osteoblastic cells. J Bone Miner Res 22:1020–1030PubMedCrossRef
29.
go back to reference Wilson PW, Schaefer EJ, Larson MG, Ordovas JM (1996) Apolipoprotein E alleles and risk of coronary disease. a meta-analysis. Arterioscler Thromb Vasc Biol 16:1250–1255PubMed Wilson PW, Schaefer EJ, Larson MG, Ordovas JM (1996) Apolipoprotein E alleles and risk of coronary disease. a meta-analysis. Arterioscler Thromb Vasc Biol 16:1250–1255PubMed
30.
go back to reference Bagger YZ, Rasmussen HB, Alexandersen P, Werge T, Christiansen C, Tanko LB (2007) Links between cardiovascular disease and osteoporosis in postmenopausal women: serum lipids or atherosclerosis per se? Osteoporos Int 18:505–512PubMedCrossRef Bagger YZ, Rasmussen HB, Alexandersen P, Werge T, Christiansen C, Tanko LB (2007) Links between cardiovascular disease and osteoporosis in postmenopausal women: serum lipids or atherosclerosis per se? Osteoporos Int 18:505–512PubMedCrossRef
31.
go back to reference Szulc P, Samelson EJ, Kiel DP, Delmas PD (2009) Increased bone resorption is associated with increased risk of cardiovascular events in men—the MINOS Study. J Bone Miner Res 24(12):2023–2031PubMedCrossRef Szulc P, Samelson EJ, Kiel DP, Delmas PD (2009) Increased bone resorption is associated with increased risk of cardiovascular events in men—the MINOS Study. J Bone Miner Res 24(12):2023–2031PubMedCrossRef
32.
go back to reference Parhami F, Garfinkel A, Demer LL (2000) Role of lipids in osteoporosis. Arterioscler Thromb Vasc Biol 20:2346–2348PubMed Parhami F, Garfinkel A, Demer LL (2000) Role of lipids in osteoporosis. Arterioscler Thromb Vasc Biol 20:2346–2348PubMed
33.
go back to reference Parhami F, Morrow AD, Balucan J, Leitinger N, Watson AD, Tintut Y, Berliner JA, Demer LL (1997) Lipid oxidation products have opposite effects on calcifying vascular cell and bone cell differentiation. A possible explanation for the paradox of arterial calcification in osteoporotic patients. Arterioscler Thromb Vasc Biol 17:680–687PubMed Parhami F, Morrow AD, Balucan J, Leitinger N, Watson AD, Tintut Y, Berliner JA, Demer LL (1997) Lipid oxidation products have opposite effects on calcifying vascular cell and bone cell differentiation. A possible explanation for the paradox of arterial calcification in osteoporotic patients. Arterioscler Thromb Vasc Biol 17:680–687PubMed
34.
go back to reference Kohlmeier M, Salomon A, Saupe J, Shearer MJ (1996) Transport of vitamin K to bone in humans. J Nutr 126:1192S–1196SPubMed Kohlmeier M, Salomon A, Saupe J, Shearer MJ (1996) Transport of vitamin K to bone in humans. J Nutr 126:1192S–1196SPubMed
35.
go back to reference Knapen MH, Hamulyak K, Vermeer C (1989) The effect of vitamin K supplementation on circulating osteocalcin (bone Gla protein) and urinary calcium excretion. Ann Intern Med 111:1001–1005PubMed Knapen MH, Hamulyak K, Vermeer C (1989) The effect of vitamin K supplementation on circulating osteocalcin (bone Gla protein) and urinary calcium excretion. Ann Intern Med 111:1001–1005PubMed
36.
go back to reference Rivadeneira F, Styrkarsdottir U, Estrada K, Halldorsson BV, Hsu YH, Richards JB, Zillikens MC, Kavvoura FK, Amin N, Aulchenko YS, Cupples LA, Deloukas P, Demissie S, Grundberg E, Hofman A, Kong A, Karasik D, van Meurs JB, Oostra B, Pastinen T, Pols HA, Sigurdsson G, Soranzo N, Thorleifsson G, Thorsteinsdottir U, Williams FM, Wilson SG, Zhou Y, Ralston SH, van Duijn CM, Spector T, Kiel DP, Stefansson K, Ioannidis JP, Uitterlinden AG (2009) Twenty bone mineral density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet 41:1199–1206PubMedCrossRef Rivadeneira F, Styrkarsdottir U, Estrada K, Halldorsson BV, Hsu YH, Richards JB, Zillikens MC, Kavvoura FK, Amin N, Aulchenko YS, Cupples LA, Deloukas P, Demissie S, Grundberg E, Hofman A, Kong A, Karasik D, van Meurs JB, Oostra B, Pastinen T, Pols HA, Sigurdsson G, Soranzo N, Thorleifsson G, Thorsteinsdottir U, Williams FM, Wilson SG, Zhou Y, Ralston SH, van Duijn CM, Spector T, Kiel DP, Stefansson K, Ioannidis JP, Uitterlinden AG (2009) Twenty bone mineral density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet 41:1199–1206PubMedCrossRef
37.
go back to reference Richards JB, Kavvoura FK, Rivadeneira F, Styrkarsdottir U, Estrada K, Halldorsson BV, Hsu YH, Zillikens MC, Wilson SG, Mullin BH, Amin N, Aulchenko YS, Cupples LA, Deloukas P, Demissie S, Hofman A, Kong A, Karasik D, van Meurs JB, Oostra BA, Pols HA, Sigurdsson G, Thorsteinsdottir U, Soranzo N, Williams FM, Zhou Y, Ralston SH, Thorleifsson G, van Duijn CM, Kiel DP, Stefansson K, Uitterlinden AG, Ioannidis JP, Spector TD (2009) Collaborative meta-analysis: associations of 150 candidate genes with osteoporosis and osteoporotic fracture. Ann Intern Med 151:528–537PubMed Richards JB, Kavvoura FK, Rivadeneira F, Styrkarsdottir U, Estrada K, Halldorsson BV, Hsu YH, Zillikens MC, Wilson SG, Mullin BH, Amin N, Aulchenko YS, Cupples LA, Deloukas P, Demissie S, Hofman A, Kong A, Karasik D, van Meurs JB, Oostra BA, Pols HA, Sigurdsson G, Thorsteinsdottir U, Soranzo N, Williams FM, Zhou Y, Ralston SH, Thorleifsson G, van Duijn CM, Kiel DP, Stefansson K, Uitterlinden AG, Ioannidis JP, Spector TD (2009) Collaborative meta-analysis: associations of 150 candidate genes with osteoporosis and osteoporotic fracture. Ann Intern Med 151:528–537PubMed
38.
go back to reference Chan AW, Hrobjartsson A, Haahr MT, Gotzsche PC, Altman DG (2004) Empirical evidence for selective reporting of outcomes in randomized trials: comparison of protocols to published articles. JAMA 291:2457–2465PubMedCrossRef Chan AW, Hrobjartsson A, Haahr MT, Gotzsche PC, Altman DG (2004) Empirical evidence for selective reporting of outcomes in randomized trials: comparison of protocols to published articles. JAMA 291:2457–2465PubMedCrossRef
39.
go back to reference Yerges, L.M., Klei, L., Cauley, J.A., Roeder, K., Kammerer, C.M., Ensrud, K.E., Nestlerode, C.S., Lewis, C., Lang, T.F., Barrett-Connor, E., Moffett, S.P., Hoffman, A.R., Ferrell, R.E., Orwoll, E.S., Zmuda, J.M. (2010) Candidate gene analysis of femoral neck trabecular and cortical volumetric bone mineral density in older men. J Bone Miner Res 25:330–338 Yerges, L.M., Klei, L., Cauley, J.A., Roeder, K., Kammerer, C.M., Ensrud, K.E., Nestlerode, C.S., Lewis, C., Lang, T.F., Barrett-Connor, E., Moffett, S.P., Hoffman, A.R., Ferrell, R.E., Orwoll, E.S., Zmuda, J.M. (2010) Candidate gene analysis of femoral neck trabecular and cortical volumetric bone mineral density in older men. J Bone Miner Res 25:330–338
40.
go back to reference Yerges LM, Klei L, Cauley JA, Roeder K, Kammerer CM, Moffett SP, Ensrud KE, Nestlerode CS, Marshall LM, Hoffman AR, Lewis C, Lang TF, Barrett-Connor E, Ferrell RE, Orwoll ES, Zmuda JM (2009) A high-density association study of 383 candidate genes for volumetric bone density at the femoral neck and lumbar spine among older men. J Bone Miner Res 24:2039–2049PubMedCrossRef Yerges LM, Klei L, Cauley JA, Roeder K, Kammerer CM, Moffett SP, Ensrud KE, Nestlerode CS, Marshall LM, Hoffman AR, Lewis C, Lang TF, Barrett-Connor E, Ferrell RE, Orwoll ES, Zmuda JM (2009) A high-density association study of 383 candidate genes for volumetric bone density at the femoral neck and lumbar spine among older men. J Bone Miner Res 24:2039–2049PubMedCrossRef
41.
go back to reference Eastell R (2003) Pathogenesis of postmenopausal osteoporosis. In: Favus MJ (ed) Primer on the metabolic bone diseases and disorders of mineral metabolism. American Society for Bone and Mineral Research, Washington, pp 314–316 Eastell R (2003) Pathogenesis of postmenopausal osteoporosis. In: Favus MJ (ed) Primer on the metabolic bone diseases and disorders of mineral metabolism. American Society for Bone and Mineral Research, Washington, pp 314–316
42.
go back to reference Rochira V, Balestrieri A, Madeo B, Zirilli L, Granata AR, Carani C (2006) Osteoporosis and male age-related hypogonadism: role of sex steroids on bone (patho)physiology. Eur J Endocrinol 154:175–185PubMedCrossRef Rochira V, Balestrieri A, Madeo B, Zirilli L, Granata AR, Carani C (2006) Osteoporosis and male age-related hypogonadism: role of sex steroids on bone (patho)physiology. Eur J Endocrinol 154:175–185PubMedCrossRef
43.
go back to reference Kohlmeier M, Saupe J, Schaefer K, Asmus G (1998) Bone fracture history and prospective bone fracture risk of hemodialysis patients are related to apolipoprotein E genotype. Calcif Tissue Int 62:278–281PubMedCrossRef Kohlmeier M, Saupe J, Schaefer K, Asmus G (1998) Bone fracture history and prospective bone fracture risk of hemodialysis patients are related to apolipoprotein E genotype. Calcif Tissue Int 62:278–281PubMedCrossRef
44.
go back to reference Weisgraber KH, Mahley RW (1996) Human apolipoprotein E: the Alzheimer’s disease connection. FASEB J 10:1485–1494PubMed Weisgraber KH, Mahley RW (1996) Human apolipoprotein E: the Alzheimer’s disease connection. FASEB J 10:1485–1494PubMed
45.
go back to reference Contois JH, Anamani DE, Tsongalis GJ (1996) The underlying molecular mechanism of apolipoprotein E polymorphism: relationships to lipid disorders, cardiovascular disease, and Alzheimer’s disease. Clin Lab Med 16:105–123PubMed Contois JH, Anamani DE, Tsongalis GJ (1996) The underlying molecular mechanism of apolipoprotein E polymorphism: relationships to lipid disorders, cardiovascular disease, and Alzheimer’s disease. Clin Lab Med 16:105–123PubMed
46.
go back to reference Bersano A, Ballabio E, Bresolin N, Candelise L (2008) Genetic polymorphisms for the study of multifactorial stroke. Hum Mutat 29:776–795PubMedCrossRef Bersano A, Ballabio E, Bresolin N, Candelise L (2008) Genetic polymorphisms for the study of multifactorial stroke. Hum Mutat 29:776–795PubMedCrossRef
47.
go back to reference Bauer DC, Mundy GR, Jamal SA, Black DM, Cauley JA, Ensrud KE, van der Klift M, Pols HA (2004) Use of statins and fracture: results of 4 prospective studies and cumulative meta-analysis of observational studies and controlled trials. Arch Intern Med 164:146–152PubMedCrossRef Bauer DC, Mundy GR, Jamal SA, Black DM, Cauley JA, Ensrud KE, van der Klift M, Pols HA (2004) Use of statins and fracture: results of 4 prospective studies and cumulative meta-analysis of observational studies and controlled trials. Arch Intern Med 164:146–152PubMedCrossRef
48.
go back to reference Greenow K, Pearce NJ, Ramji DP (2005) The key role of apolipoprotein E in atherosclerosis. J Mol Med 83:329–342PubMedCrossRef Greenow K, Pearce NJ, Ramji DP (2005) The key role of apolipoprotein E in atherosclerosis. J Mol Med 83:329–342PubMedCrossRef
49.
go back to reference Langdahl BL, Uitterlinden AG, Ralston SH, Trikalinos TA, Balcells S, Brandi ML, Scollen S, Lips P, Lorenc R, Obermayer-Pietsch B, Reid DM, Armas JB, Arp PP, Bassiti A, Bustamante M, Husted LB, Carey AH, Perez Cano R, Dobnig H, Dunning AM, Fahrleitner-Pammer A, Falchetti A, Karczmarewicz E, Kruk M, van Leeuwen JP, Masi L, van Meurs JB, Mangion J, McGuigan FE, Mellibovsky L, Mosekilde L, Nogues X, Pols HA, Reeve J, Renner W, Rivadeneira F, van Schoor NM, Ioannidis JP (2008) Large-scale analysis of association between polymorphisms in the transforming growth factor beta 1 gene (TGFB1) and osteoporosis: the GENOMOS study. Bone 42:969–981PubMedCrossRef Langdahl BL, Uitterlinden AG, Ralston SH, Trikalinos TA, Balcells S, Brandi ML, Scollen S, Lips P, Lorenc R, Obermayer-Pietsch B, Reid DM, Armas JB, Arp PP, Bassiti A, Bustamante M, Husted LB, Carey AH, Perez Cano R, Dobnig H, Dunning AM, Fahrleitner-Pammer A, Falchetti A, Karczmarewicz E, Kruk M, van Leeuwen JP, Masi L, van Meurs JB, Mangion J, McGuigan FE, Mellibovsky L, Mosekilde L, Nogues X, Pols HA, Reeve J, Renner W, Rivadeneira F, van Schoor NM, Ioannidis JP (2008) Large-scale analysis of association between polymorphisms in the transforming growth factor beta 1 gene (TGFB1) and osteoporosis: the GENOMOS study. Bone 42:969–981PubMedCrossRef
50.
go back to reference van Meurs JB, Trikalinos TA, Ralston SH, Balcells S, Brandi ML, Brixen K, Kiel DP, Langdahl BL, Lips P, Ljunggren O, Lorenc R, Obermayer-Pietsch B, Ohlsson C, Pettersson U, Reid DM, Rousseau F, Scollen S, Van Hul W, Agueda L, Akesson K, Benevolenskaya LI, Ferrari SL, Hallmans G, Hofman A, Husted LB, Kruk M, Kaptoge S, Karasik D, Karlsson MK, Lorentzon M, Masi L, McGuigan FE, Mellstrom D, Mosekilde L, Nogues X, Pols HA, Reeve J, Renner W, Rivadeneira F, van Schoor NM, Weber K, Ioannidis JP, Uitterlinden AG (2008) Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis. JAMA 299:1277–1290PubMedCrossRef van Meurs JB, Trikalinos TA, Ralston SH, Balcells S, Brandi ML, Brixen K, Kiel DP, Langdahl BL, Lips P, Ljunggren O, Lorenc R, Obermayer-Pietsch B, Ohlsson C, Pettersson U, Reid DM, Rousseau F, Scollen S, Van Hul W, Agueda L, Akesson K, Benevolenskaya LI, Ferrari SL, Hallmans G, Hofman A, Husted LB, Kruk M, Kaptoge S, Karasik D, Karlsson MK, Lorentzon M, Masi L, McGuigan FE, Mellstrom D, Mosekilde L, Nogues X, Pols HA, Reeve J, Renner W, Rivadeneira F, van Schoor NM, Weber K, Ioannidis JP, Uitterlinden AG (2008) Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis. JAMA 299:1277–1290PubMedCrossRef
51.
go back to reference Heikkinen AM, Kroger H, Niskanen L, Komulainen MH, Ryynanen M, Parviainen MT, Tuppurainen MT, Honkanen R, Saarikoski S (2000) Does apolipoprotein E genotype relate to BMD and bone markers in postmenopausal women? Maturitas 34:33–41PubMedCrossRef Heikkinen AM, Kroger H, Niskanen L, Komulainen MH, Ryynanen M, Parviainen MT, Tuppurainen MT, Honkanen R, Saarikoski S (2000) Does apolipoprotein E genotype relate to BMD and bone markers in postmenopausal women? Maturitas 34:33–41PubMedCrossRef
52.
go back to reference Booth SL, Tucker KL, Chen H, Hannan MT, Gagnon DR, Cupples LA, Wilson PW, Ordovas J, Schaefer EJ, Dawson-Hughes B, Kiel DP (2000) Dietary vitamin K intakes are associated with hip fracture but not with bone mineral density in elderly men and women. Am J Clin Nutr 71:1201–1208PubMed Booth SL, Tucker KL, Chen H, Hannan MT, Gagnon DR, Cupples LA, Wilson PW, Ordovas J, Schaefer EJ, Dawson-Hughes B, Kiel DP (2000) Dietary vitamin K intakes are associated with hip fracture but not with bone mineral density in elderly men and women. Am J Clin Nutr 71:1201–1208PubMed
53.
go back to reference Cauley JA, Zmuda JM, Yaffe K, Kuller LH, Ferrell RE, Wisniewski SR, Cummings SR (1999) Apolipoprotein E polymorphism: a new genetic marker of hip fracture risk—the study of osteoporotic fractures. J Bone Miner Res 14:1175–1181PubMedCrossRef Cauley JA, Zmuda JM, Yaffe K, Kuller LH, Ferrell RE, Wisniewski SR, Cummings SR (1999) Apolipoprotein E polymorphism: a new genetic marker of hip fracture risk—the study of osteoporotic fractures. J Bone Miner Res 14:1175–1181PubMedCrossRef
54.
go back to reference Dick IM, Devine A, Marangou A, Dhaliwal SS, Laws S, Martins RN, Prince RL (2002) Apolipoprotein E4 is associated with reduced calcaneal quantitative ultrasound measurements and bone mineral density in elderly women. Bone 31:497–502PubMedCrossRef Dick IM, Devine A, Marangou A, Dhaliwal SS, Laws S, Martins RN, Prince RL (2002) Apolipoprotein E4 is associated with reduced calcaneal quantitative ultrasound measurements and bone mineral density in elderly women. Bone 31:497–502PubMedCrossRef
55.
go back to reference Gerdes LU, Vestergaard P, Hermann AP, Mosekilde L (2001) Regional and hormone-dependent effects of apolipoprotein E genotype on changes in bone mineral in perimenopausal women. J Bone Miner Res 16:1906–1916PubMedCrossRef Gerdes LU, Vestergaard P, Hermann AP, Mosekilde L (2001) Regional and hormone-dependent effects of apolipoprotein E genotype on changes in bone mineral in perimenopausal women. J Bone Miner Res 16:1906–1916PubMedCrossRef
56.
go back to reference Salamone LM, Cauley JA, Zmuda J, Pasagian-Macaulay A, Epstein RS, Ferrell RE, Black DM, Kuller LH (2000) Apolipoprotein E gene polymorphism and bone loss: estrogen status modifies the influence of apolipoprotein E on bone loss. J Bone Miner Res 15:308–314PubMedCrossRef Salamone LM, Cauley JA, Zmuda J, Pasagian-Macaulay A, Epstein RS, Ferrell RE, Black DM, Kuller LH (2000) Apolipoprotein E gene polymorphism and bone loss: estrogen status modifies the influence of apolipoprotein E on bone loss. J Bone Miner Res 15:308–314PubMedCrossRef
57.
go back to reference Zajickova K, Zofkova I, Hill M, Horinek A, Novakova A (2003) Apolipoprotein E 4 allele is associated with low bone density in postmenopausal women. J Endocrinol Invest 26:312–315PubMed Zajickova K, Zofkova I, Hill M, Horinek A, Novakova A (2003) Apolipoprotein E 4 allele is associated with low bone density in postmenopausal women. J Endocrinol Invest 26:312–315PubMed
Metadata
Title
Associations of APOE gene polymorphisms with bone mineral density and fracture risk: a meta-analysis
Authors
I. Peter
M. D. Crosier
M. Yoshida
S. L. Booth
L. A. Cupples
B. Dawson-Hughes
D. Karasik
D. P. Kiel
J. M. Ordovas
T. A. Trikalinos
Publication date
01-04-2011
Publisher
Springer-Verlag
Published in
Osteoporosis International / Issue 4/2011
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI
https://doi.org/10.1007/s00198-010-1311-5

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