整合分析证实骨保护素基因与骨质疏松症的相关性

doi:10.24920/003466

Abstract

Objective This study aimed to verify the association between osteoprotegerin gene (OPG) and its variants with osteoporosis (OP) by performing integrative analysis.Methods We used the KGG software to perform gene-based association analysis, which integrated all publicly available single-nucleotide polymorphism (SNP)-based P values and obtained an overall P value for the OPG. The significant SNPs were screened for expression quantitative trait loci (eQTLs). Meta-analysis was used to combine the associations between the variants of OPG and bone mineral density (BMD) reported in the literatures. Then we performed dual-luciferase reporter gene systems for the functional verification of the variants of OPG in vitro.Results In the gene-based association analysis, the over all P value of OPG was 6.24×10 ^-13for BMD at femoral neck (FN) and 7.37×10 ^-17 for BMD at lumbar spine (LS), indicating the importance of OPG for OP. The publicly available eQTL database identified 5 eQTLs which exert cis-regulation effects on OPG at FN and LS. Literature searching found that rs2073617 (known as T950C) was the hot spot SNP. There were 13 relevant studies on rs2073617 besides the GEFOS-2 study identified from the PubMed. Significant differences among TT, TC and CC genotypes at FN (P= 0.047) and LS (P= 0.025) were shown by meta-analysis, demonstrating the associations between T950C polymorphism and BMD. Luciferase gene expression was significantly higher at the presence of allele C than allele T in the 293T cells (t=-9.47, P<0.01). Conclusion The integrative analysis further confirmed the importance of OPG in OP and the correlation of T950C polymorphism with BMD of OP. The strategy can be used as a reference for functional interpretation of other disease-related genes.

Key words: osteoprotegerin, osteoporosis, single-nucleotide polymorphism, integrative analysis

Funding: Supported by the National Natural Science Foundation of China((No. 31271336).)

Tang Hui,Zhu Xiaowei,Wu Longfei,Mo Xingbo,Deng Feiyan,Lei Shufeng. Integrative Analysis Confirmed the Association between Osteoprotegerin and Osteoporosis[J].Chinese Medical Sciences Journal, 2019, 34(2): 147-156.

Figures/Tables 5

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References 34

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SNP	Position	Score^*	FN P value^#	LS P value^#	Number of studies^?
rs6469789	chr8:120029842..120029842	0.01	4.89×10^-14	1.12×10^-17	0
rs3134063	chr8:120028838..120028838	0.06	3.13×10^-9	8.06×10^-15	1
rs3134058	chr8:120023289..120023289	0.03	1.25×10^-3	4.09×10^-9	0
rs1385503	chr8:120031667..120031667	0.07	1.05×10^-3	4.37×10^-9	0
rs2073617	chr8:120033464..120033464	0.46	2.50×10^-9	6.19×10^-15	13

Study author	Publication year	Country	Study design	Population	Age (year)	Sex	Producer of BMD measurement	Anatomic sites measured
Langdahl BL, et al.^[16]	2002	Denmark	case control	268 osteoporosis patients; 327 normal people	52-72	male/ female	Hologic QDR 1000 or Norland Corp.	LS; FN; TH
Yamada Y, et al.^[17]	2003	Japan	cross- sectional	1095 women	40-79	female	Hologic QDR 4500	TB; LS; FN; TR; WT
Cheng Q, et al.^[18]	2004	China	cross- sectional	259 postmenopausal women	55-71	female	Norland XR -36	LS; FN; TR; WT
Vidal C, et al.^[19]	2006	Britain	cross- sectional	126 postmenopausal women	40-75	female	Norland Corp.	LS; FN; TR; WT
Wynne F, et al.^[20]	2002	Malta	cross- sectional	381 postmenopausal women; 130 premenopausal women	40-70	female	Lunar DPX1Q	LS; FN
Ueland T, et al.^[21]	2007	Australia	cross- sectional	1469 postmenopausal women	75±3	female	Hologic Corp.	FN; TH
Wang C, et al.^[22]	2009	China	cross- sectional	80 postmenopausal women with osteoporosis	>50	female	Hologic QDR 2000	LS; FN; TR; IN; TH

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