Song Yang, Du Zhenwu, Ren Ming, Yang Qiwei, Wang Qingyu, Chen Gaoyang, Zhao Haiyue, Li Zhaoyan, Wang Jincheng, Zhang Guizhen
Department of Orthopedics of Second Clinical College of Jilin University, Ziqiang Street 218, Changchun 130041,PR China; The Engineering Research Centre of Molecular Diagnosis and Cell Treatment for Metabolic Bone Diseases of Jilin Province, Ziqiang Street 218, Changchun 130041,PR China.
Department of Orthopedics of Second Clinical College of Jilin University, Ziqiang Street 218, Changchun 130041,PR China; Research Centre of Second Clinical College of Jilin University, Ziqiang Street 218, Changchun 130041,PR China; The Engineering Research Centre of Molecular Diagnosis and Cell Treatment for Metabolic Bone Diseases of Jilin Province, Ziqiang Street 218, Changchun 130041,PR China.
Bone. 2017 Aug;101:104-112. doi: 10.1016/j.bone.2017.05.002. Epub 2017 May 2.
The molecular pathogenesis of osteonecrosis of the femoral head (ONFH) has been remained obscure so that its prevalence has been increasing in recent decades. Different transcription factors play critical roles in maintaining the balance between osteogenesis and adipogenesis. However, it has been unclear that the genes variants of the transcription factors exert the effects on the imbalance between steogenesis and adipogenesis during the development of ONFH. Here, we selected the 11SNPs from steogenesis, adipogenesis-specific transcription factors RUNX2, Osterix, and PPARγ genes, chondrogenesis or adipogenesis key factors COL2A1, IGFBP3 genes and analysed the genotypes, alleles, haplotypes and their association with the risk and clinical phenotypes of ONFH through Mass ARRAY® platformin in 200 ONFH patients and 177controls. The patients with ONFH (132 males, 68 females; age: 53.46±11.48yr) were consecutively enrolled at the Department of Orthopedics, the Second Clinical College of Jilin University, from March 2014 to June 2015 and were diagnosed and classified into 10 cases of stage II (5.6%), 54 cases of stage III (30.2%) and 115 cases (64.2%) of stage IV and alcohol-induced (71 cases (39.7%)), idiopathic (64 cases (34.0%)), and steroid-induced osteonecrosis (47 cases (26.3%)) subgroup, respectively. Our results showed that all models of logistical regression analysis, the co-dominants, dominants, and recessives of PPARγrs2920502, significantly associated with the increased risk of ONFH (p=0.004, p=0.013, p=0.016), respectively. Both the minor homozygous CC genotype and the allele C of rs2920502 were evidently correlated with the enhanced risk of ONFH (p=0.005, p=0.0005),respectively. The recessives models of IGFBP3rs2132572 (G/A) as well as RUNX2 rs3763190(G/A) were statistically associated with the higher ONFH risk, p=0.030, p=0.029, respectively; the minor homozygous(AA) of IGFBP3rs2132572 (G/A) was also related to the increased risk of bilateral hips lesions, p=0.039. Moreover, the ages on set of major homozygous(GG) and heterozygous(GT) of COL2A1rs2070739(G/A) were significantly younger than that of the minor homozygous(AA) of the SNP(p=0.008) while the A-T-G-A haplotype of COL2A1 gene revealed significant association with the decreased the risk of bilateral hip lesions, p=0.01, OR:0.258. More important, the serum HDL-c level and the ratio of LDL-c/HDL-c in the ONFH group were significantly decreased and increased compared with those of the control group (p=0.02, p=0.0001), respectively. Particularly, the CC genotype of PPARγ rs2920502 was statistically correlated with the enhanced serum TG level, p=0.011.These results suggest that the variants of PPARγ, RUNX2, COL2A1, and IGFBP3 genes closely associated with the development of ONFH.
股骨头坏死（ONFH）的分子发病机制一直不明，因此其发病率在近几十年呈上升趋势。不同的转录因子在维持成骨和脂肪生成之间的平衡中起关键作用。然而，目前尚不清楚转录因子的基因变异在ONFH发生发展过程中对成骨和脂肪生成失衡是否产生影响。在此，我们从成骨、脂肪生成特异性转录因子RUNX2、Osterix和PPARγ基因，软骨生成或脂肪生成关键因子COL2A1、IGFBP3基因中选取了11个单核苷酸多态性（SNPs），并通过Mass ARRAY®平台分析了200例ONFH患者和177例对照的基因型、等位基因、单倍型及其与ONFH风险和临床表型的关联。2014年3月至2015年6月期间，吉林大学第二临床学院骨科连续纳入ONFH患者（132例男性，68例女性；年龄：53.46±11.48岁），并诊断分类为II期10例（5.6%）、III期54例（30.2%）和IV期115例（64.2%），以及酒精性（71例（39.7%））、特发性（64例（34.0%））和类固醇性骨坏死（47例（26.3%））亚组。我们的结果显示，在所有逻辑回归分析模型中，PPARγ rs2920502的共显性、显性和隐性模型分别与ONFH风险增加显著相关（p = 0.004，p = 0.013，p = 0.016）。rs2920502的次要纯合CC基因型和等位基因C均分别与ONFH风险增加显著相关（p = 0.005，p = 0.0005）。IGFBP3 rs2132572（G/A）以及RUNX2 rs3763190（G/A）的隐性模型分别与较高的ONFH风险在统计学上相关，p分别为0.030和0.029；IGFBP3 rs2132572（G/A）的次要纯合（AA）型也与双侧髋关节病变风险增加相关，p = 0.039。此外，COL2A1 rs2070739（G/A）的主要纯合（GG）型和杂合（GT）型的发病年龄显著低于该单核苷酸多态性（SNP）的次要纯合（AA）型（p = 0.008），而COL2A1基因的A-T-G-A单倍型与双侧髋关节病变风险降低显著相关，p = 0.01，比值比（OR）：0.258。更重要的是，与对照组相比，ONFH组的血清高密度脂蛋白胆固醇（HDL-c）水平显著降低，低密度脂蛋白胆固醇（LDL-c）/HDL-c比值显著升高（p分别为0.02和0.0001）。特别地，PPARγ rs2920502的CC基因型与血清甘油三酯（TG）水平升高在统计学上相关，p = 0.011。这些结果表明，PPARγ、RUNX2、COL2A1和IGFBP3基因的变异与ONFH的发生密切相关。
