Low-Density Lipoprotein Receptor–Related Protein 5 (LRP5) Gene Polymorphisms Are Associated With Bone Mass in Both Chinese and Whites

Authors

  • Dong-Hai Xiong,

    1. Osteoporosis Research Center and Department of Biomedical Sciences, Creighton University, Omaha, Nebraska, USA
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    • These authors contributed equally to this study

  • Shu-Feng Lei,

    1. Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China
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    • These authors contributed equally to this study

  • Fang Yang,

    1. Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China
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  • Liang Wang,

    1. The Key Laboratory of Biomedical Information Engineering of Ministry of Education and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China
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  • Yu-Mei Peng,

    1. The Key Laboratory of Biomedical Information Engineering of Ministry of Education and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China
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  • Wei Wang,

    1. The Key Laboratory of Biomedical Information Engineering of Ministry of Education and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China
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  • Robert R Recker,

    1. Osteoporosis Research Center and Department of Biomedical Sciences, Creighton University, Omaha, Nebraska, USA
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  • Hong-Wen Deng PhD

    Corresponding author
    1. Osteoporosis Research Center and Department of Biomedical Sciences, Creighton University, Omaha, Nebraska, USA
    2. Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China
    3. The Key Laboratory of Biomedical Information Engineering of Ministry of Education and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China
    4. Departments of Orthopedic Surgery and Basic Medical Sciences, University of Missouri–Kansas City, Kansas City, Missouri, USA
    • Departments of Orthopedic Surgery and Basic Medical Sciences, University of Missouri–Kansas City, 2411 Holmes Street, Room M3-C03, Kansas City, MO 64108-2792, USA
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  • The authors state that they have no conflicts of interest.

Abstract

In this study, the associations of novel LRP5 variants with BMD variation were detected and some replicated in the two ethnic groups of Chinese and white origins, respectively. These data support the concept that LRP5 variation can contribute to minor and major variation in bone structure.

Introduction: Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene have been shown to cause both high and low bone mass. However, it is still controversial whether LRP5 is associated with normal BMD variation. This study explored the association of LRP5 with BMD phenotypes at three clinically important skeletal sites—the spine, hip, and ultradistal radius (UD)—in two independent populations of Chinese and white ethnicities, respectively.

Materials and Methods: The Chinese sample consisted of 733 unrelated subjects. The white sample was made up of 1873 subjects from 405 nuclear families. High-density single nucleotide polymorphisms (SNPs) across the whole LRP5 gene were genotyped and analyzed in both samples.

Results: Linkage disequilibrium (LD) analyses showed that the haplotype structures of LRP5 between Chinese and whites were in good agreement. Association tests showed that polymorphisms in block 5 spanning intron 7 to intron 19 of LRP5 significantly associated with spine BMD variation in both samples. Particularly, the significant association of SNP rs491347 in intron 7 with spine BMD in the Chinese sample (p = 0.002) was replicated in whites, even after adjusting for multiple testing (p = 0.005). Its strongly associated SNP rs1784235 could cause the loss of an estrogen receptor α (ERα) binding site in LRP5, which could partially explain the above replicated association. However, we did not observe any significant replication with BMD variation at the hip and UD. After accounting for multiple testing, associations with BMD variation at these two sites were mainly found in Chinese. Sex-stratified analyses further revealed that the LRP5 associations with BMD in Chinese and whites were driven by male and female subjects, respectively.

Conclusions: Our work supported LRP5 genetic variants as possible susceptibility factors for osteoporosis and fractures in humans. Especially, the SNP rs491347 and its strongly associated SNPs (e.g., rs1784235) could be important to human osteoporosis phenotypes.

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