Abstract

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.

© 2021 The Author(s). Published by S. Karger AG, Basel

Introduction

With the widespread, clinical use of hormone drugs, the reports of steroid-induced osteonecrosis of the femoral head (ONFH) at home and abroad are gradually increasing. Steroid-induced ONFH is a serious concomitant hormone widely recognized in clinical practice disease, high disability rate, and seriously affects the physical and mental health of patients. In China, long-term or high-dose corticosteroids are the most common cause of nontraumatic femoral head necrosis [1]. The pathogenesis is currently unclear, and studies have shown that the genome changes in epigenetics are closely related to its occurrence and development, including genetic polymorphism and methylation changes.

Neuroimmune diseases and rheumatic diseases often need to be treated with glucocorticoids. Glucocorticoids can cause adverse reactions such as edema, high sodium and low potassium, high blood sugar, centripetal obesity, and infection. Steroid-induced ONFH is the most common one of the severe adverse reactions. Abnormal glucocorticoid metabolism, transporter receptor and target, lipid metabolism disorder, coagulation and fibrinolysis dysfunction, inflammatory response, and osteoporosis are the important pathogenesis of steroid-induced ONFH. Glucocorticoids act on osteoblasts, osteoclasts, and osteocytes, reducing fluid in the interstitial tubules of bone, blood supply and strength of bone, and causing damage [2]. However, not all glucocorticoids are used for treatment. All patients had femoral head necrosis, suggesting that there may be other risk factors or individual differences in the occurrence of steroid-induced ONFH. Current research has shown that the pathogenesis and genes of the disease single-nucleotide polymorphisms (SNPs) are related to gene mutations. Steroid-induced ONFH may be a polygenic disease, such as lipid metabolism-related genes (ApoA and ApoB), drug metabolizing enzymes (CYP), drug transporters (ABCB1and ABCG2), and drug target molecules (NR3C1). [3-5] For example, MMP-8, MMP-9, MMP-14, and TIMP4 [6-9] have been confirmed to be associated with steroid-induced ONFH risk.

MiRNAs are regulatory short-stranded non-coding RNAs found in eukaryotes [9]. MiRNAs have been shown to participate in many biological and pathological processes, as well as tissue development [10]. The primary targeted pathways of miRNA with differential expression are mostly related to osteogenic differentiation, bone metabolism, and vascular pathways. SNPs in miRNAs-encoding genes may alter the expression or function of their host miRNAs and are thus associated with cancer-related risks [11, 12]. MIR3142HG, also known as the MIR146A host gene, is reported that MIR3142HG can produce miR-146a [13]. MiR-146a is located on chromosome 5Q34 and inhibits tumor necrosis factor receptor-associated factor 6 and interleukin-1 receptor-associated kinase 1 by targeting. It can reduce the production of tumor necrosis factor-α, interleukin-1β, interleukin-6, and other cytokines in the nuclear protein factor κB pathway, achieve the negative feedback regulation of innate immunity, and participate in inflammation, immune response regulation, cell proliferation and apoptosis, and other pathophysiological processes. Therefore, miR-146a is closely related to the pathological process of tissue necrosis.

To our knowledge, the contact between MIR3142HG polymorphism and the risk of steroid-induced ONFH has not been studied previously. Therefore, we designed a study to evaluate the MIR3142HG gene polymorphism at the allele, genotype, and haplotype interface for the development of the steroid-induced ONFH in the population of Northern China.

Materials and Methods Study Participants

From 2018 to 2020, a total of 924 subjects participated in this study including 199 consecutive recruited steroid-induced ONFH and 725 healthy controls at the Second Affiliated Hospital of Inner Mongolia Medical University. The control is based on the physical examination enrollment group, without steroid-induced ONFH or other related diseases. This study was approved by the Hospital Ethics Committee. Informed consent of all participants was collected.

All patients were diagnosed with hormonal femoral head necrosis in accordance with the relevant standards established by the International Bone Circulation Research Association. Inclusion criteria for the case group were long-term use of steroids, more than 16 mg per day, or high-dose steroid impulsive treatment appears after more than 1 week. The patient presented with relevant clinical manifestations, such as hip pain, lower limb muscle atrophy, claudication, etc. [6]. All outcome measures were confirmed as femur head necrosis by MRI X-ray bone scan or MRI. None of the patients had a history of alcohol consumption, chronic metabolic history, tumor history, hip trauma history, or infection history. The patient had complete clinical data and no history of other treatments. Our exclusion criteria are patients who did not strictly meet the diagnostic criteria for hormonal cerebral hemorrhage and the diagnostic criteria for traumatic cerebral hemorrhage compared to other hip diseases and those with weekly alcohol intake of more than 400 mL patients. The healthy control group is defined according to the following criteria: no symptoms of hip-joint disease and no history of thromboembolism. People with severe chronic diseases and other significant family genetic diseases will be excluded.

Genotyping Assay

In our study, blood samples of steroid-induced ONFH patients and normal control group were collected to analyze the difference of miR3142HG SNP in the blood of steroid-induced ONFH patients and normal control group and its correlation with clinical data, so as to study the application of miR3142HG in the diagnosis of steroid-induced ONFH. rs1582417, rs2431689, rs7727115, and rs17057846 in the MIR3142HG gene were further selected. Blood samples were taken in EDTA tubes and centrifuged at 2,000 rpm for 10 min. Blood samples are stored at −80°C for future experiments. Genomic DNA was extracted from whole blood of steroid-induced ONFH patients and healthy controls, using the GoldMag-Mini Purification Kit (GoldMag Co. Ltd., Xian City, China). In this experiment, MassARRAY flight mass spectrometer was mainly used for genotyping detection, including PCR amplification, SAP purification, single base extension, resin purification, and chip mass spectrometry. The genotyping of 4 SNPs (rs1582417, rs2431689, rs7727115, and rs17057846) was put into practice on the Agena MassARRAY platform (San Diego, CA, USA). And data management and analysis were performed using the Sequenom TYPER software.

Statistical Analyses

Results were presented as the mean ± standard deviation. All data were statistically analyzed using SPSS19.0. An exact test was used to assess the variation in each SNP genotype frequency from the Hardy-Weinberg equilibrium in the control participants before analysis. The difference in age between the 2 groups was analyzed by T test or T ′test, and the functional analysis of SNP on SONFH susceptibility was performed by logistic regression analysis. We used the χ2 test/Fisher’s exact tests to compare the allelic and genotypic frequencies of cases and controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were determined using logistic regression analysis with adjustments for age and gender. Associations between the genotype polymorphisms and the risk of steroid-induced ONFH were evaluated under different genetic models using PLINK version 1.07 software. Finally, linkage disequilibrium among polymorphic sites was assessed with Haploview software package (version 4.2). p values <0.05 were considered statistically significant.

Results

A total of 924 people participated in this study of 199 patients (83 female, 116 male) and 725 healthy controls (301 female, 424 male). The mean ages were 42.21 ± 12.890 years for the cases and 41.15 ± 11.854 years for the controls. The information of the steroid-induced ONFH patients and healthy participants were shown in Table 1. There was no gender match between the patients and healthy participants in this study, and we will adjust this factor in the subsequent analysis.

Table 1.

Characteristics of the participants

Four SNPs (rs1582417, rs2431689, rs7727115, and rs17057846) of MIR3142HG gene were selected for this case-control study. The basic information about all the SNPs, including alleles, minor allele frequency, OR, 95% CI, and Hardy-Weinberg equilibrium results are presented in Table 2. It was found that rs1582417 (OR = 1.29, 95% CI = 1.03–1.61, p = 0.028) was related to an increased risk of steroid-induced ONFH. On the other hand, rs7727115 (OR = 0.74, 95% CI = 0.57–0.95, p = 0.017) was related to a reduced risk of steroid-induced ONFH.

Table 2.

Basic information of candidate SNPs of MIR3142HG gene in this study

Subsequently, genetic models were used to compare the relationship between SNP genotypes and steroid-induced ONFH risk. As illustrated in Table 3, rs1582417 in the MIR3142HG gene showed an increased risk of steroid-induced ONFH in the dominant model (OR = 1.46, 95% CI: 1.04–2.04, p = 0.027). At the same time, rs1582417 showed a negative effect on steroid-induced ONFH under the log-additive model (OR = 1.29, 95% CI: 1.03–1.62, p = 0.027). Moreover, rs7727115 was found to be associated with a reduced risk of steroid-induced ONFH under the log-additive model (OR = 0.73, 95% CI: 0.57–0.94, p = 0.016), codominant model (OR = 0.50, 95% CI: 0.26–0.96, p = 0.037), and dominant model (OR = 0.71, 95% CI: 0.52–0.98, p = 0.035).

Table 3.

Genotypic model analysis of relationship between SNPs and steroid-induced ONFH

Stratified analysis by age, hip lesions classification, and gender was performed. The results show that in the male group, the MIR3142HG rs1582417 GA-AA genotype was significantly associated with increased risk of steroid-induced ONFH in the dominant model (OR = 2.13, 95% CI: 1.35–3.37, p = 0.001) and in the codominant model (GA:OR = 2.10, 95% CI: 1.30–3.40, p = 0.003; AA:OR = 2.24, 95% CI: 1.20–4.16, p = 0.012) and in the log-additive model (OR = 1.56, 95% CI: 1.16–2.09, p = 0.003). In the female group, the MIR3142HG rs17057846 AA genotype accelerated the risk of steroid-induced ONFH in the codominant model (OR = 3.57, 95% CI: 1.30–9.80, p = 0.013) and in the recessive model (OR = 3.37, 95% CI: 1.25–9.06, p = 0.016). We observed that rs17057846 shows association with unilateral and bilateral lesion of the hip joint in the codominant model (OR = 2.41, 95% CI: 1.14–5.09, p = 0.021) and in the dominant model (OR = 2.11, 95% CI: 1.05–4.26, p = 0.037) (Table 4). In the age (older than 42), rs1582417 GA and AA genotype in the MIR3142HG gene are danger factors, increasing the risk of steroid-induced ONFH in the codominant model (OR = 1.74, 95% CI: 1.00–3.00, p = 0.048; OR = 2.31, 95% CI: 1.17–4.58, p = 0.016) and log-additive model (OR = 1.54, 95% CI: 1.11–2.15, p = 0.011). In addition, in the age (older than 42), rs7727115 TG genotype in the MIR3142HG gene are protect factors, reducing the risk of steroid-induced ONFH under the codominant model (OR = 0.54, 95% CI: 0.33–0.90, p = 0.019) and dominant model TG-GG (OR = 0.52, 95% CI: 0.32–0.85, p = 0.009) and log-additive model (OR = 0.61, 95% CI: 0.42–0.90, p = 0.012).

Table 4.

Analysis of the relationship between MIR3142HG gene polymorphism and steroid-induced ONFH subgroups

Considering the effect on lipid metabolism level in patients, we found that the HDL-C and ApoA1 levels of the AA genotype carriers in rs2431689 were higher than the GG genotype carriers, and the ApoB ratio of the GG genotype carriers in rs17057846 was significantly lower than that of the AA genes. For genotype carriers, TC level AA genotype is significantly lower than GG genotype carrier (Table 5).

Table 5.

The association of genotypes in MIR3142HG genes with the clinical phenotypes

In haplotype model analysis, one linkage disequilibrium block was detected in the MIR3142HG SNPs (rs2431689, rs7727115, rs17057846; Fig. 1; Table 6). The “GGG” sequence was associated with an increased risk of steroid-induced ONFH (OR = 1.33, 95% CI: 1.04–1.70, p = 0.021; adjusted OR = 01.40, 95% CI: 1.08–1.81, p = 0.010).

Table 6.

The haplotype frequencies of MIR3142HG polymorphisms and their association with the risk of steroid-induced ONFH

Fig. 1.

LD analysis of the SNPs on MIR3142HG. Red squares display statistically significant associations between a pair of SNPs, as measured by D’; darker shades of red indicate higher D’. LD, linkage disequilibrium; SNP, single-nucleotide polymorphism.

Discussion

Despite the introduction of many new treatment methods, and the rapid development of surgical techniques, the therapeutic effect of osteonecrosis has not improved significantly. Because many patients have reached the early stage of diagnosis, the final hip replacement is an inevitable choice. Therefore, researching the underlying mechanism of femoral head necrosis and development, and searching for more accurate biomarkers, is crucial for clinicians to formulate precise treatment strategies.

We assessed the relationship between the 4 SNPs in MIR3142HG and steroid-induced ONFH susceptibility in Han Chinese. The frequencies of 4 allelic SNPs of MIR3142HG genotype and haplotype in cases and control group were compared and further stratified. Among them, the rs1582417 polymorphism is associated with increased risk of steroid-induced ONFH, while the rs7727115 mutation is associated with reduced risk. For all we know, this is the first case-control study to examine the relationship between MIR3142HG gene polymorphism and the risk of steroid-induced ONFH. This research provides evidence for the biological significance of genetic variation in miRNA-coding genes, suggesting that it may affect the pathogenesis of steroid-induced ONFH.

MiRNA is highly conservative in evolution and its expression is tissue-specific. MiRNA has the following characteristics: highly conserved; the order of time and space; and some miRNAs are tissue-specific. Studies have shown that miRNAs play a crucial role in different physiological and pathological processes via regulating gene expression post-transcriptionally; that is, it specifically binds to the untranslated region (3′-UTR) at the 3′-end of the mRNA of the target gene through base complementary pairing, inhibits the translation process of the mRNA, or directly mediates the degradation of the mRNA, so as to achieve the purpose of regulating the expression of the target gene [14-16]. Recently, more and more miRNAs have been studied in orthopedic diseases. Increasing evidence also indicates that miRNAs can directly play a role in the pathogenesis of many orthopedic diseases, regulating bone development and bone regeneration, such as disc degeneration, osteoarthritis, osteoporosis, and osteosarcoma [17-20]. In recent years, miRNAs have gradually become a research hotspot in the field of non-coding RNA, and some miRNAs have been proved to be closely related to the pathogenesis of steroid-induced ONFH [21, 22].

MiR-146a is abnormal in lung cancer, breast cancer, colorectal cancer, glioma, and other cancers [23-26]. MiR-146a may participate in ONFH and other physiological processes such as inflammation [27]. The study showed that MIR3142HG knockdown observably decreased the release of IL-8 and CCL2, and partially reduced the release of interleukin-6 in control fibroblasts, suggesting that the decreased expression of MIR3142HG might be the reason for the decreased inflammatory reaction of IPF fibroblasts stimulated by IL-1 [28]. It was found that MIR3142HG regulates the inflammatory response, and it is proved that the reduction of the inflammatory response of IPF fibroblasts is related to the decreased expression of MIR3142HG/miR-146a [28]. Yuan et al. [29] designed a study to compare miRNA expression profiles in 9 ONFH patients and 6 femoral neck fractures. It was confirmed that the expression of miR-146a was up-regulated in ONFH. So, we doped out that MIR3142HG polymorphism might affect the expression or function of miR-146a during the steroid-induced ONFH process. At present, the mechanism of MIR3142HG in steroid-induced ONFH has not been reported and remains to be studied.

We suggest that the induction of age-related steroid-induced ONFH may have relevance with rs1582417 and rs7727115 polymorphism in MIR3142HG. Further studies through gender stratification found that rs1582417 polymorphism increases steroid-induced ONFH susceptibility, suggesting that the polymorphism risk association may be gender-related. We found that the HDL-C and ApoA1 levels of the AA genotype carriers in rs2431689 were higher than the GG genotype carriers, and the ApoB ratio of the GG genotype carriers in rs17057846 was well below that of the AA genes. For genotype carriers, TC level AA genotype is significantly lower than GG genotype carrier. These results further illustrate the correlation between rs2431689, rs17057846, HDL-C levels, ApoA1 levels, ApoB levels, metabolic disorders, and osteonecrosis. At present, few functional studies have been reported. Understanding the function of miRNAs is crucial, which will provide new ideas for future treatment.

Some important findings were revealed in our study, but in interpreting these results, some limitations of this study should be considered. First, the sample size of hormonal femoral head necrosis is too small and lacks representativeness, while the large sample study takes time and effort; second, the relationship between genetic polymorphisms of different regions and races and the incidence of hormonal femoral head necrosis is inconsistent, and further analysis is needed to reduce the variation within the interval and reduce the impact of the sampling error; again, the combination of large sample size etiology and SNP analysis has become the direction of future research on steroid-related femoral head necrosis, but the credibility of the experimental results needs to be further improved, such as application of statistical methods such as multivariate analysis of variance and avoidance of confounding factors in case-control intervals.

Conclusions

In a word, this is the first evidence that 2 polymorphisms (rs1582417 and rs7727115) in MIR3142HG might contribute to the susceptibility to steroid-induced ONFH in the Chinese Han population. However, it is not clear whether these changes in MIR3142HG are consistent with the onset of ONFH, or simply reflect the terminal stage of the disease.

Acknowledgments

We thank the patients who participated in this study and the participants in the control group. We would also like to thank all those who contributed to the collection of samples and analysis of data for this study.

Statement of Ethics

This study was approved by the Hospital of Inner Mongolia Medical University Ethics Committee (Serial no.: YKD2016138). Written informed consent of all participants was collected.

Conflict of Interest Statement

The authors declare that they have no competing interests.

Funding Sources

This work was supported by the National Natural Science Foundation of China (No. 81160228, No. 81260284, No. 81660378, and No. 81860401).

Author Contributions

Jianzhong Wang and Huiqiang Wu conceived and designed the experiments, Huiqiang Wu, Tiantian Wang, Menghu Sun, Tingting Liu, and Feimeng An performed the experiments, and Tiantian Wang and Qiumei Dong analyzed the data. Jianzhong Wang and Tiantian Wang drafted the work or revised it critically for important content.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.

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Qiumei Dong, abcd20200717@163.com

Jianzhong Wang, wangjianzhongwj@163.com

Article / Publication Details

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Received: June 06, 2021
Accepted: September 09, 2021
Published online: November 17, 2021

Number of Print Pages: 9
Number of Figures: 1
Number of Tables: 6

ISSN: 1662-4246 (Print)
eISSN: 1662-8063 (Online)

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