Association Between Genetic Polymorphisms Of TIMP-4 And The Risk Of Steroid-induced Osteonecrosis Of The Femoral Head

Background: ONFH(osteonecrosis of the femoral head)is a common disease in orthopaedics.Due to the disruption of the blood supply to the femoral head,the microstructural changes in the femoral head are mainly caused by hip pain and joint dysfunction.The pathological process of the disease is very complicated.Although there are many new studies and explorations at home and abroad,its pathogenesis is still not completely clear.In our clinical study,we found that only a few people suffered from steroid-induced ONFH after taking steroids for a period of time.This indicates that the genetic background of individuals plays an important role in determining the susceptibility of hormone-induced ONFH.According to relevant literature,matrix metalloproteinase3(MMP3),MMP8,and MMP9 genes are closely related to the risk of ONFH in northern China.As an endogenous inhibitor of matrix metalloproteinases(MMPs)in the extracellular matrix,the expression of tissue inhibitors of metalloprotease-4(TIMP4)plays an essential role in cartilage and bone tissue damage and remodeling,vasculitis formation,intravascular thrombosis,and lipid metabolism.The aim of this study was to explore whether there was a potential association between TIMP4 gene polymorphism and the risk of steroid-induced ONFH in northern China.Methods: In this trial,we collected 286 blood samples from patients with steroid-induced ONFH from the Han population in northern China,and 309 blood samples from healthy Chinese Han population in northern China.The single nucleotide polymorphisms of TIMP4 gene were selected from HapMap database by case-control study.The gene model was analyzed by Massarray.The data were analyzed by chi-square test and linear regression analysis.Results: We performed allelic model analysis and found that allele C at rs99365 locus,allele A at rs308952 locus,allele C at rs3817004 locus,allele C at rs2279750 locus and allele C at rs3755724 locus were associated with decreased steroid-induced ONFH(rs99365,OR=0.73,95%CI=0.559-0.954,p=0.02;rs308952,OR=0.75,95%CI=0.571-0.973,p=0.03;rs3817004,OR=0.76,95%CI=0.582-0.988,p=0.04;rs2279750,OR=0.72,95%CI=0.55-0.936,p=0.01;rs3755724,OR=0.78,95%CI=0.621-0.985,p=0.04,respectively).Rs2279750 showed a significant association with decreased risk of steroid-induced ONFH in the Dominant and Log-additive models(OR=0.68,95%CI=0.49-0.94,p=0.021;adjusted OR=0.70,95%CI=0.50-0.99,p=0.042;OR=0.71,95%CI=0.55-0.93,p=0.014;adjusted OR=0.73,95%CI=0.55-0.97,p=0.028,respectively),and rs9935,rs30892,and rs3817004 were associated with decreased risk in the Log-additive model(rs99365,OR=0.73,95%CI=0.55-0.95,p=0.02,adjusted OR = 0.74,95%CI=0.56-0.99,p=0.038;rs308952,OR=0.74,95%CI=0.57-0.97,p=0.03,adjusted OR=0.75,95%CI=0.56-0.99,p =0.044;rs3817004,OR = 0.75,95%CI=0.58-0.99,p=0.038,adjusted OR=0.75,95%CI=0.56-0.99,p=0.042,respectively).In further stratification analysis,TIMP4 gene variants showed a significant association with steroid-induced ONFH in gender under the genotypes.Haplotype analysis also revealed that “CCGGAA” and “TCAGAC”sequences have protective effect on steroid-induced ONFH(CCGAAA,adjusted OR=0.31,95%CI=0.10-0.98,p=0.046;TCAGAC,OR=0.71,95%CI=0.53-0.95,p=0.021,adjusted OR=0.73,95% CI=0.54-0.99,p=0.04).Conclusion: Our results indicate that five TIMP4 SNPs(rs99365,rs308952,rs3817004,rs2279750,and rs3755724)are significantly associated with decreased risk of steroid-induced ONFH in the population of northern China.