Association of LPR5 Polymorphism with Bone Mass Density and Cholesterol Level in Population of Chinese Han

Abstract

Recently, two single nucleotide polymorphisms, rs4355801 near the osteoprotegerin (OPG) gene and rs3736228 in the low-density lipoprotein receptor-related protein 5 (LRP5) gene, were found to be associated with osteoporosis and osteoporotic fractures in Caucasians in a genome wide association study. In the present study, we investigated the association between these two SNPs (rs4355801 and rs3736228) and bone mass density (BMD), whole body T score and metabolic phenotypes (e. g., body mass index, glucose, triglyceride, and total cholesterol) in 425 Chinese Han subjects. We observed a significant association between rs3736228 in LRP5 and hip BMD, total BMD, and T score. The level of hip BMD, total BMD, and T score was significantly reduced with the number of at risk T alleles (p=0.006, p=0.003, and p=0.006, respectively). This finding was still significant after accounting for gender and age. We also observed a significant association between rs3736228 and total cholesterol (CHO) levels in our sample. The CHO levels of the CC, CT, and TT genotypes were 4.71, 4.76, and 5.24, respectively (p=0.031). For OPG rs4355801, the level of hip BMD, spine BMD, and total BMD was consistently reduced in persons with the copy of A allele, but none of these findings were statistically significant. We also did not observe a significant association between the above two polymorphisms and body mass index, glucose, and triglyceride levels in Chinese Han subjects. Thus, our observations support the association between rs3736228 and BMD in Han subjects. We also provide first evidence that the T allele of rs3736228 increases the total cholesterol level in a general Han population.

Key words

bone mineral density - polymorphism - LRP5 - osteoprotegerin - cholesterol

References

• 1 Boom R, Sol CJ, Salimans MM. et al . Rapid and simple method for purification of nucleic acids.  J Clin Microbiol. 1990;  28 495-503
• 2 Brixen K, Beckers S, Peeters A. et al . Polymorphisms in the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with peak bone mass in non-sedentary men: results from the Odense androgen study.  Calcif Tissue Int. 2007;  81 421-429
• 3 Ching-Lung Cheung, Qing-Yang Huang, Vivian Chan. et al . Association of Low-Density Lipoprotein Receptor-Related Protein 5 (LRP5) promoter SNP with peak bone mineral density in Chinese women.  Hum Hered. 2008;  65 232-239
• 4 Emery JG, McDonnell P, Burke MB. et al . Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL.  J Biol Chem. 1998;  273 14363-14367
• 5 Ezura Y, Nakajima T, Urano T. et al . Association of a single-nucleotide variation (A1330 V) in the low-density lipoprotein receptor-related protein 5 gene (LRP5) with bone mineral density in adult Japanese women.  Bone. 2007;  40 997-1005
• 6 Fujino T, Asaba H, Kang MJ. et al . Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion.  Proc Natl Acad Sci. 2003;  100 229-234
• 7 Gong Y, Slee RB, Fukai N. et al . LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development.  Cell. 2001;  107 513-523
• 8 Hey PJ, Twells RC, Phillips MS. et al . Cloning of a novel member of the low-density lipoprotein receptor family.  Gene. 1998;  216 103-111
• 9 Kiel DP, Ferrari SL, Cupples LA. Genetic variation at the low-density lipoprotein receptor-related protein 5 (LRP5) locus modulates Wnt signaling and the relationship of physical activity with bone mineral density in men.  Bone. 2007;  40 587-596
• 10 McCarthy MI, Abecasis GR, Cardon LR. et al . Genome-wide association studies for complex traits: consensus, uncertainty and challenges.  Nat Rev Genet. 2008;  9 356-369
• 11 Richards JB, Rivadeneira F, Inouye M. et al . Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study.  Lancet. 2008;  371 1505-1512
• 12 Saarinen A, Välimäki VV, Välimäki MJ. et al . The A1330V polymorphism of the low-density lipoprotein receptor- related protein 5 gene (LRP5) associates with low peak bone mass in young healthy men.  Bone. 2007;  40 1006-1012
• 13 Simonet WS, Lacey DL, Dunstan CR. et al . Osteoprotegerin: a novel secreted protein involved in the regulation of bone density.  Cell. 1997;  89 309-319
• 14 Tamai K, Semenov M, Kato Y. et al . LDL-receptor-related proteins in Wnt signal transduction.  Nature. 2000;  407 530-535
• 15 Van Meurs JB, Trikalinos TA, Ralston SH. et al . GENOMOS Study. Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis.  JAMA. 2008;  299 1277-1290
• 16 Wehrli M, Dougan ST, Caldwell K. et al . Arrow encodes an LDL-receptor-related protein essential for Wingless signaling.  Nature. 2000;  407 527-530

1 These two authors contributed equally.

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