Copy Number Variation in CNP267 Region May Be Associated with Hip Bone Size

Shan-Lin Liu,Shu-Feng Lei,Hong-Wen Deng,Rong Liu,Yong-Jun Liu,Yao-Zhong Liu,Shan Nie,Fei-Yan Deng,Yan Guo,Qing Tian,Xi Li,Xiao-Gang Liu,Jian Li,Hui Shen,Tie-Lin Yang,Fang Yang,Brian P Chadwick

doi:10.1371/journal.pone.0022035

Shan-Lin Liu, Shu-Feng Lei + Show 15 more

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https://doi.org/10.1371/journal.pone.0022035

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Osteoporotic hip fracture (HF) is a serious global public health problem associated with high morbidity and mortality. Hip bone size (BS) has been identified as one of key measurable risk factors for HF, independent of bone mineral density (BMD). Hip BS is highly genetically determined, but genetic factors underlying BS variation are still poorly defined. Here, we performed an initial genome-wide copy number variation (CNV) association analysis for hip BS in 1,627 Chinese Han subjects using Affymetrix GeneChip Human Mapping SNP 6.0 Array and a follow-up replicate study in 2,286 unrelated US Caucasians sample. We found that a copy number polymorphism (CNP267) located at chromosome 2q12.2 was significantly associated with hip BS in both initial Chinese and replicate Caucasian samples with p values of 4.73E-03 and 5.66E-03, respectively. An important candidate gene, four and a half LIM domains 2 (FHL2), was detected at the downstream of CNP267, which plays important roles in bone metabolism by binding to several bone formation regulator, such as insulin-like growth factor-binding protein 5 (IGFBP-5) and androgen receptor (AR). Our findings suggest that CNP267 region may be associated with hip BS which might influence the FHL2 gene downstream.

Highlights

Osteoporosis is a serious global public health problem especially in the elderly, which is characterized by low bone mineral density (BMD) and low trauma fracture
In the initial genome-wide copy number variation (CNV) analysis in Chinese sample, four Copy number polymorphisms (CNPs) were associated with hip bone size (BS) at significant level of p,0.01 (CNP11164 P = 6.18E-04, CNP182 P = 1.05E-03, CNP267 P = 4.73E-03, CNP10799 P = 7.23E-03) (Table 2)
Due to allele frequency (AF) of CNP11164 (AF = 0.0031) and CNP10799 (AF = 0.003) is smaller than 1%, only CNP182 and CNP267 were analyzed for replicate association and reached p values at 2.39E-01 and 5.66E-03, respectively (Table 2)

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Introduction

Osteoporosis is a serious global public health problem especially in the elderly, which is characterized by low bone mineral density (BMD) and low trauma fracture. In recent years, an increasing aging Chinese population has resulted in even more OFs in China [3]. BMD, as an important risk factor for OFs, has been extensively investigated for identifying the genetic factors underlying BMD variation [4]. BMD is not the only risk factor for osteoporotic fracture, and recent studies suggested that bone size (BS) is another important risk factor for OFs independent of BMD [5,6]. A genetically homogenous inbred mouse strain has higher bone mass but smaller bone size, and is less sensitive in adapting to mechanical loading to increase bone strength when compared with another inbred mouse strain [10]. Only a few of genes such as VDR [11,12], ER, COL1A2 [13], CYP17 [14], PTH [15], were tested in association with BS, and most of the genetic factors for BS largely remain unknown

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