Association of TIMP4 gene variants with steroid-induced osteonecrosis of the femoral head in the population of northern China

Abstract

BackgroundIn clinical treatment, the use of steroid hormones is an important etiological factor of non-traumatic osteonecrosis of the femoral head (ONFH) risk. 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.MethodsThis study aimed to detect the association between TIMP4 polymorphism and steroid-induced ONFH. We genotyped seven single-nucleotide polymorphisms (SNPs) in TIMP4 genes and analyzed the association with steroid-induced ONFH from 286 steroid-induced ONFH patients and 309 normal individuals.ResultsWe performed allelic model analysis and found that the minor alleles of five SNPs (rs99365, rs308952, rs3817004, rs2279750, and rs3755724) were associated with decreased steroid-induced ONFH (p = 0.02, p = 0.03, p = 0.04, p = 0.01, p = 0.04, respectively). rs2279750 showed a significant association with decreased risk of steroid-induced ONFH in the Dominant and Log-additive models (p = 0.042, p = 0.028, respectively), and rs9935, rs30892, and rs3817004 were associated with decreased risk in the Log-additive model (p = 0.038, p = 0.044, 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 “TCAGAC” and “CCGGAA” sequences have protective effect on steroid-induced ONFH.ConclusionOur 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.

Steroid-induced osteonecrosis

“…Metalloproteinase 2, 8, and 10 polymorphisms contribute to susceptibility [ 27 , 28 ], as RETN (coding for resistin, an adipokine involved in metabolic disorders) and ApoA 5 and APOE (involved in lipid metabolism) SNP [ [29] , [30] , [31] ]. In contrast, metalloproteinase 9 SNPs appears to reduce the risk [ 32 ], similar to the gene for the tissue inhibitor of metalloprotease-4 [ 33 ], while the plasminogen activator inhibitor-1 (PAI-1) SNP has been demonstrated to be associated with an increased risk of steroid-induced osteonecrosis [ 34 ]. Interestingly, the long-chain RNA p53-induced transcript (LncRNA LINC-PINT) has been reported to impact on the risk.…”

“… Gene Risk Ref. ATP-binding cassette subfamily B member 1 (ABCB1) Reduced [ 24 ] Cytochrome P450 Reduced [ 25 ] IL1B Increased or reduced [ 26 ] Metalloproteinase 2, 8, and 10 Increased [ 27 , 28 ] Metalloproteinase 9 Reduced [ 32 ] RETN Increased [ 29 ] APOA5 Increased [ 30 ] APOE Increased [ 31 ] TIMP4 Reduced [ 33 ] PAI-1 Increased [ 34 ] LncRNA LINC-PINT Increased [ 35 ] VEGF Increased [ 13 ] NO Increased [ 13 ] …”