Association of MIR17HG and MIR155HG gene variants with steroid-induced osteonecrosis of the femoral head in the population of northern China.

INTRODUCTION: Steroid-induced osteonecrosis of the femoral head (ONFH) is a disease of the bone. Metabolism and genetic factors are generally considered to play an important role. The purpose of this study was to investigate the relationship between single-nucleotide polymorphisms (SNPs) in MIR17HG and MIR155HG and the risk of steroid-induced ONFH in the population of northern China. METHODS: A total of 199 steroid-induced ONFH patients and 506 healthy controls were recruited for the study. Four SNPs of MIR17HG and seven SNPs of MIR155HG were genotyped by Sequenom MassARRAY. ORs and 95% CIs were used to evaluate the relationship between these SNPs and steroid-induced ONFH. RESULTS: In the codominant model, patients with the MIR17HG SNPs (rs7318578) AA genotype had an increased risk of steroid-induced ONFH (OR = 1.79, p = 0.039); in the recessive model, patients with the MIR17HG SNP (rs7318578) AA genotype had an increased risk of steroid-induced ONFH (OR = 1.78, p = 0.032). Stratified analysis showed that a MIR17HG SNP (rs7318578) and the MIR155HG SNPs (rs77218221, rs11911469, rs34904192 and rs4143370) were closely related to different unornamented phenotypes of steroid-induced ONFH. Analysis of the clinical indicators revealed significant differences in high-density lipoprotein (HDL-C) levels between the ONFH group and the control group (p = 0.005). In the MIR17HG SNP (rs75267932), patients with different genotypes had different levels of triglyceride (TG). The MIR155HG SNPs (rs77699734, rs1893650, and rs34904192) showed differences in triglyceride (TG), high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C) levels in patients with different genotypes. CONCLUSION: Our results confirm that MIR17HG and MIR155HG gene mutations are associated with steroid-induced ONFH susceptibility in the population of northern China, providing new evidence for the early detection and prevention of ONFH.

Association between Genetic Polymorphisms of MIR3142HG and the Risk of Steroid-Induced Osteonecrosis of the Femoral Head in the Population of Northern China.

BACKGROUND: Steroid-induced osteonecrosis of the femoral head (ONFH) is aseptic necrosis of the femoral head caused by glucocorticoid use. Once necrotic femoral head necrosis occurs, it irreversibly affects the quality of life seriously. Studies have shown that the susceptibility to steroid-induced ONFH is likely to be related to the variation of miRNA-coding genes. Therefore, this study aimed was to investigate the effect of MIR3142HG on steroid-induced ONFH. METHODS: Agena MassARRAY was used to genotype MIR3142HG gene rs1582417, rs2431689, rs7727155, and rs17057846 in 199 patients and 725 healthy people. A genetic model and haplotype analysis were used to evaluate the relationship between the MIR3142HG polymorphism and the risk of steroid-induced ONFH. The odds ratio and 95% confidence intervals were obtained through logistic regression to assess the influence of gene polymorphisms on the occurrence of steroid-induced ONFH. RESULTS: The consequences show that rs7727115 is a protective factor, it could reduce the risk of steroid-induced ONFH, and rs1582417 could increase the risk of steroid-induced ONFH. In the genetic model, rs1582417 was associated with increased risk of alcohol-induced ONFH in dominant model and log-additive model. rs7727115 showed a decreased risk in codominant model, dominant model, and log-additive model. In addition, rs2431689 is related to HDL-C (p = 0.012) and ApoA1 (p = 0.010) levels, and rs17057846 (p = 0.024) is related to ApoB levels. Thelinkage analysis indicated 3 single-nucleotide polymorphisms (rs2431689, rs7727115, and rs17057846) in MIR3142HG with significant chain imbalance. In addition, haplotype "GGG" of MIR3142HG was found out and is harmful for steroid-induced ONFH. CONCLUSION: Our results first confirm that the genetic polymorphism of MIR3142HG is associated with steroid-induced ONFH susceptibility in Chinese Han population.

Association between LINC-PINT and LINC00599 gene polymorphism and the risk of steroid-induced osteonecrosis of the femoral head in the population of northern China.

BACKGROUND: Steroid-induced osteonecrosis of the femoral head (ONFH) is a complex disease affected by genetics. LncRNA LINC-PINT and LINC00599 have been proved to be associated with susceptibility to a variety of diseases, however it is not clear whether they are related to steroid-induced ONFH. Therefore, this study was aimed at investigating the correlation between the polymorphisms of LINC-PINT and LINC00599 genes and steroid-induced ONFH in the population of northern China. METHODS: A case-control study including 199 patients and 725 controls was designed. The Agena MassARRAY platform was used for the detection of single nucleotide polymorphisms (SNPs) in LINC-PINT and LINC00599 genes. Chi-square test and logistic regression were used to evaluate the association between the above SNPs and steroid-induced ONFH in allelic and genetic models. Besides, one-way ANOVA was used to study the relationship between these SNPs and partial lipid levels. RESULTS: In the LINC00599 gene, two sites are related to steroid-induced ONFH. Among them, rs2272026 increased the risk of the disease in co-dominant (heterozygous) and dominant models. And rs1962430 is a risk factor for this disease in the allelic, co-dominance (heterozygous), dominant and additive model. whereas in women with steroid-induced ONFH, three sites in the LINC-PINT gene are related to the disease. Thereinto, rs157916 reduces the risk of the disease in allelic, co-dominant (homozygous), recessive and additive models. Rs16873842 is related to the reduced risk of the disease in allele, dominant and additive models. And rs7781295 is a protective factor for steroid-induced ONFH in the allelic and additive model. CONCLUSION: Our study suggests that the polymorphisms of LINC-PINT and LINC00599 genes are related to the susceptibility of steroid-induced ONFH in Chinese Han population.

DNA methylation in the OPG/RANK/RANKL pathway is associated with steroid-induced osteonecrosis of the femoral head.

BACKGROUND: Dysregulation of the OPG/RANK/RANKL signalling pathway is a key step in the occurrence of steroid-induced osteonecrosis of the femoral head (ONFH). This study aims to understand the degree of methylation of the OPG, RANK, and RANKL genes in steroid-related ONFH. METHODS: A case-control study was designed, including 50 patients (25 males and 25 females) and 50 matched controls. The European Molecular Biology Open Software Suite (EMBOSS) was used to predict the existence and location of CpG islands in the OPG, RANK, and RANKL genes. The Agena MassARRAY platform was used to detect the methylation status of the above genes in the blood of subjects. The relationship between the methylation level of CpG sites in each gene and steroid-related ONFH was analysed by the chi-square test, logistic regression analysis, and other statistical methods. RESULTS: In the CpG islands of the OPG, RANK, and RANKL genes in patients with steroid-related ONFH, several CpG sites with high methylation rates and high methylation levels were found. Some hypermethylated CpG sites increase the risk of steroid-related ONFH. In addition, a few hypermethylated CpG sites have predictive value for the early diagnosis of steroid-related ONFH. CONCLUSION: Methylation of certain sites in the OPG/RANK/RANKL signalling pathway increases the risk of steroid-related ONFH. Some hypermethylated CpG sites may be used as early prediction and diagnostic targets for steroid-related ONFH.

OPG/RANKL/RANK gene methylation among alcohol-induced femoral head necrosis in northern Chinese men.

BACKGROUND AND PURPOSE: Alcohol-induced osteonecrosis of the femoral head (ONFH) is a complex and heterogeneous disease. Genetic factors and epigenetic modifications are one of the pathogenesis of the disease. However, the influence of epigenetic factors on the disease has not been systematically studied. Our research aims to determine the methylation changes of alcohol-induced ONFH. METHODS: An analytical cross-sectional study of a Chinese male population (50 alcohol-induced ONFH patients and 50 controls). The EpiTYPER of the Sequenom MassARRAY platform was used to detect the DNA methylation status of 132 cytosine-phosphate-guanine (CpG) sites in the OPG/RANKL/RANK gene promoter region. RESULTS: In the whole study group, the chi-square test was used to analyze the methylation rate between the two groups, and six CpG sites were found to be different, among which OPG1_CpG_2, OPG3_CpG_4, RANK1_CpG_6, RANK3_CpG_10, RANKL2_CpG_21, and RANKL2_CpG_46 in the case group were higher than those in the control group, while OPG4_CpG_2 was lower than that in the control group. The results showed that in patients with alcohol-induced ONFH, 146 CpG sites were examined for differences in methylation levels compared with healthy controls, 32 of which were not detected, and 23 of the remaining 114 sites showed differences in methylation levels compared with alcohol-induced ONFH patients. Receiver operator characteristic (ROC) curve analysis demonstrated the methylation levels of OPG/RANKL/RANK could efficiently predict the existence of alcohol-induced ONFH. CONCLUSION: Our study of Chinese men suggests that several CpG sites in the OPG/RANKL/RANK gene in peripheral blood leukocytes of patients with alcohol-induced ONFH are in an abnormal methylation state (hypermethylation tended to be more frequent).

Variants in RETN gene are associated with steroid-induced osteonecrosis of the femoral head risk among Han Chinese people.

BACKGROUND: Gene polymorphism has an important influence on RETN gene expression level, and the increased level of resistin encoded in RETN will lead to metabolic disorder, especially lipid metabolism. Moreover, steroid-induced osteonecrosis of the femoral head (steroid-induced ONFH) is closely related to lipid metabolism level, so this study is intended to explore the relationship of RETN polymorphisms with susceptibility to steroid-induced ONFH in the Chinese Han population. METHODS: In this case-control study, eight single-nucleotide polymorphisms (SNPs) of RETN were genotyped by the Agena MassARRAY system in 199 steroid-induced ONFH patients and 200 healthy controls. The relationship between RETN polymorphisms and steroid-induced ONFH risk was assessed using genetic models and haplotype analyses. Odds ratio (OR) and 95% confidence intervals (CIs) were obtained by logistic regression adjusted for age. RESULTS: We found significant differences in the distribution of HDL-C, TG/HDL-C, and LDL-C/HDL-C between the patients and the control group (p < 0.05). In allele model and genotype model analysis, rs34861192, rs3219175, rs3745368, and rs1477341 could reduce the risk of steroid-induced ONFH. Further stratified analysis showed that rs3745367 was related to the clinical stage of patients, and rs1477341 was significantly correlated with an increased TG level and a decreased TC/HDL-C level. The linkage analysis showed that two SNPs (rs34861192 and rs3219175) in RETN even significant linkage disequilibrium. CONCLUSIONS: Our results provide the firstly evidence that RETN gene polymorphisms were associated with a reduced risk of steroid-induced ONFH in Chinese Han population.

Significant association between RETN genetic polymorphisms and alcohol-induced osteonecrosis of femoral head.

BACKGROUND: Alcohol-induced osteonecrosis of femoral head (ONFH) is a complex disease and genetic factors are one of the causes. The purpose of this study is to investigate the effects of RETN (resistin; OMIM: 605565) and LDLR (low density lipoprotein receptor; OMIM: 606945) polymorphisms on the risk of alcohol-induced ONFH in Chinese Han population. METHODS: A case-control study including 201 patients and 201 controls was designed. Seven single nucleotide polymorphisms (SNPs) in RETN gene and four SNPs in LDLR gene were genotyped using Agena MassARRAY platform. In allele model and genetic model, chi-square test and logistic regression were used to study the associations between these SNPs and ONFH susceptibility. In addition, the relationships between these SNPs, clinical phenotypes, and blood lipid level with one-way analysis of variance were analyzed. RESULTS: In the allele model, rs7408174 and rs3745369 in RETN were associated with increased risk of alcohol-induced ONFH, whereas rs34861192 and rs3219175 in RETN showed reduced risk of alcohol-induced ONFH. In the genetic model, rs7408174 was associated with increased risk of alcohol-induced ONFH in dominant model and log-additive model. Rs3745369 showed an increased risk in codominant model, recessive model, and log-additive model. Rs34861192 showed a decreased risk in codominant model, dominant model, and log-additive model, and rs3219175 showed a decreased risk in dominant model and log-additive model. The rs3745368 in RETN was associated with the clinical stage of the disease. CONCLUSION: These results suggest that RETN genetic polymorphisms are associated with the susceptibility of alcohol-induced ONFH in Chinese Han population.

MMP2 and MMP10 Polymorphisms Are Related to Steroid-Induced Osteonecrosis of the Femoral Head among Chinese Han Population.

BACKGROUND: Steroid-induced osteonecrosis of the femoral head is a relatively serious condition which seriously reduces patient quality of life. However, the pathogenesis of steroid-induced ONFH is still unclear. In recent years, more scholars have found that the pathogenesis of steroid-induced ONFH is related to susceptibility factors such as MMPs/TIMPs system. The main purpose of this study is to investigate the correlation between MMP2 and MMP10 gene polymorphisms and steroid-induced ONFH in Chinese Han population. METHODS: Six SNPs in MMP2 and two SNPs in MMP10 were genotyped using Agena MassARRAY RS1000 system from 286 patients of steroid-induced ONFH and in 309 healthy controls. The association between MMP2 and MMP10 polymorphisms and steroid-induced ONFH risk were estimated by the Chi-squared test, genetic model analysis, haplotype analysis, and stratification analysis. The relative risk was estimated by odd ratios (ORs) and 95% confidence intervals (CIs). RESULT: We found that the minor TG allele of rs470154 in MMP10 was associated with an increased risk of steroid-induced ONFH (OR = 1.45, 95% CI, 1.03 - 2.05, p = 0.032). In the genetic model analysis, we found that rs2241146 in MMP2 gene and rs470154 in MMP10 gene showed a statistically significant association with increased risk of steroid-induced ONFH. The six SNPs (rs470154, rs243866, rs243864, rs865094, rs11646643, and rs2241146) showed a statistically significant association with different clinical phenotypes. CONCLUSION: Our results verify that genetic polymorphisms of MMP2 and MMP10 contribute to steroid-induced ONFH susceptibility in the population of Chinese Han population, and our study provides new insights into the role that MMP2 and MMP10 plays in the mechanism of ONFH.

MMP20 Single-Nucleotide Polymorphisms Correlate with Susceptibility to Alcohol-Induced Osteonecrosis of the Femoral Head in Chinese Males.

BACKGROUND Alcohol-induced osteonecrosis of the femoral head (ONFH) is caused by the interaction of genetic and environmental factors. Genetic variations of matrix metalloproteinase (MMP) system are associated with ONFH development and progression. In this study, we aimed to evaluate the relationships between MMP20 gene polymorphisms and the risk of alcohol-induced ONFH in Chinese Han males. MATERIAL AND METHODS In this case-control study, genotypes of 14 selected SNPs in the MMP20 gene were assayed using MassARRAY in 299 male cases with alcohol-induced ONFH and in 197 healthy males. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the influence of gene polymorphism on occurrence of alcohol-induced ONFH by allelic model analysis, genotype model analysis and haplotype analysis. RESULTS After allelic model analysis, the minimum alleles of rs10895322, rs1784424, rs3781788, and rs1573954 correlated with an increased risk of alcohol-induced ONFH (P<0.05). Genetic model analysis revealed significant associations of 9 SNPs with alcohol-induced ONFH occurrence even after adjustment for age (P<0.05): 2 protective SNPs (rs1711423 and rs1784418) and 7 high-risk SNPs (rs10895322, rs1784424, rs3781788, rs7126560, rs1573954, rs1711399, and rs2292730). Moreover, 8 SNPs showed a statistically significant association with different clinical phenotypes (P<0.05). Beyond that, haplotype "CGGTTCCA" in MMP20 was discovered to correlate with a 1.63-fold increased risk of alcohol-induced ONFH (OR: 1.63, 95% CI: 1.15-2.30, P=0.0058). CONCLUSIONS Our data sheds new light on the associations of MMP20 gene polymorphisms with alcohol-induced ONFH predisposition in Chinese Han males.

Association of OPG gene polymorphisms with the risk of knee osteoarthritis among Chinese people.

BACKGROUND: Osteoarthritis (OA) is usually recognized to have a genetic factor, and in our study, we performed a case-control study to analyze the association between 14 single nucleotide polymorphisms (SNPs) in OPG and the risk of knee OA in a Chinese Han population. METHODS: Fourteen OPG SNPs were assayed using MassARRAY in 393 patients clinically and radiographically diagnosed with knee OA and in 500 controls. Allelic and genotypic frequencies were compared between the groups. Logistic regression adjusting for age and gender was used to estimate risk associations between specific genotypes and knee OA by computing odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: We found that the minor alleles of six SNPs in OPG were associated with an increased or decreased risk of knee OA in the allelic model analysis. In the genetic model analysis, we found that rs1905786, rs1032128, rs3134058, rs11573828, rs11573849, rs3134056, and rs1564861 were associated with an increased or decreased risk of knee OA before adjusted by sex and age. And after adjustment, three SNPs (rs1485286, rs1905786, and rs1032128) were identified to have a negative effect on knee OA. CONCLUSION: Our results verify that genetic variants of OPG contribute to knee OA susceptibility in the population of northern China. These genetic associations may identify individuals at a particularly high risk of developing knee OA.

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

BACKGROUND: In 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. METHODS: This 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. RESULTS: We 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. 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.

Impact of IL1R1 and IL1R2 gene polymorphisms on risk of osteonecrosis of the femoral head from a case-control study.

AIM: Osteonecrosis of the femoral head (ONFH) refers to bony changes caused by osteocyte death under the effects of complicated factors, which is caused by genetic factors and certain risk factors. Our study aimed to explore whether IL1R1/IL1R2 polymorphisms influenced ONFH risk in the Chinese Han population. METHODS: We selected 286 patients and 441 controls, with 11 single-nucleotide polymorphisms in IL1R1 and IL1R2 gene were successfully genotyped, and evaluated the associations using the chi-squared test, Fisher's exact test, T test, and genetic model analyses. Odds ratios and 95% confidence intervals (CIs) were calculated using unconditional logistic regression. RESULTS: In the allele model, rs11674595 in IL1R2 was associated with increasing the risk of ONFH, the rs10490571 and rs3917225 in IL1R1 gene were associated with an increased risk of ONFH, respectively. In the genetic model, the rs11674595 in IL1R2 gene was associated with an increased risk of ONFH in the codominant model, dominant model, and log-additive model, respectively. The rs10490571 and rs3917225 in IL1R1 gene conferred an increased risk of ONFH in the codominant model, dominant model, and log-additive model, respectively. We found none of the haplotypes in the IL1R2 gene was significantly associated with theONFH risk. CONCLUSION: Our findings have demonstrated that the rs11674595 (IL1R2), rs10490571, and rs3917225 (IL1R1) were significantly associated with increasing the ONFH risk in the Chinese Han population.

MMP9 polymorphism is associated with susceptibility to non-traumatic osteonecrosis of femoral head in a Chinese Han population.

Non-traumatic osteonecrosis of femoral head (ONFH) is an orthopedic refractory disease with escalating morbidity in Chinese Han population. In our case-control study, we examined eight previously identified MMP9 single-nucleotide polymorphisms (SNPs) in 585 non-traumatic ONFH patients and 507 healthy individuals from northern China to determine whether these SNPs associated with the risk of developing non-traumatic ONFH. Genetic model and haplotype analyses were used to evaluate the association between SNPs and non-traumatic ONFH. MMP9 rs2274755 (OR, 0.740; 95% CI, 0.578-0.949; p = 0.017) was associated with a reduced risk of non-traumatic ONFH. After adjusting for age and gender, the logistic regression results showed that rs2274755 associated with a lower risk of non-traumatic ONFH in the dominant (OR=0.71, 95% CI: 0.54-0.94, p=0.016), overdominant (OR=0.73, 95% CI: 0.55-0.96, p=0.026) and log-additive (OR=0.74740; 95% CI, 0.578-0.949; p=0.017) models. In addition, the "TGC" haplotype of rs2274755 was associated with a 0.79-fold decrease in risk while the "CTC" haplotype associated with a 0.65-fold decrease risk of the non-traumatic ONFH. These results provide evidence that the MMP9 SNP at the rs2274755 locus is associated with a decreased risk of non-traumatic ONFH in a Chinese Han population.

MMP8 polymorphism is associated with susceptibility to osteonecrosis of the femoral head in a Chinese Han population.

Osteonecrosis of the femoral head (ONFH) is an orthopedic refractory disease that adversely affects quality of life. Matrix metalloproteinase-8 (MMP-8) produced by the bone marrow has been implicated in the degradation of collagen during bone development. We assessed whether MMP8 polymorphisms are associated with ONFH. In a case-control study, using χ2 tests and genetic model analyses, we genotyped 5 MMP8 single-nucleotide polymorphisms (SNPs) in 585 ONFH patients and 507 healthy control subjects in a Chinese Han population. The MMP8 rs11225394 SNP was associated with an increased risk of ONFH in an allele model (OR=1.34; 95% CI, 1.003-1.786, P=0.047). In addition, rs11225394 was associated with an increased risk of ONFH in a dominant model (OR =1.39, 95% CI, 1.02-1.89, P=0.036), over-dominant model (OR=1.39, 95% CI, 1.02-1.89, P=0.038), and log-additive model (OR =1.36, 95% CI, 1.01-1.84, P=0.039). After adjusting for age and gender, rs11225394 was associated with ONFH in a dominant (OR =1.44, 95% CI, 1.05-1.96, P=0.023), over-dominant (OR =1.44, 95% CI, 1.05-1.98, P=0.022), and log-additive model (OR =1.40, 95% CI, 1.04-1.90, P=0.027). These results provide the first evidence that MMP8 SNP at the rs11225394 locus is associated with the increased risk of ONFH in Chinese Han population.