Skip to main content

An intron SNP rs2069837 in IL-6 is associated with osteonecrosis of the femoral head development



Genetic polymorphisms play a crucial role in the development of osteonecrosis of the femoral head (ONFH). This study mainly explored the association of IL-6 variants and ONFH susceptibility among the Chinese Han population.


Two variants (rs2069837, and rs13306435) in the IL-6 gene were identified and genotyped from 566 patients with ONFH and 566 healthy controls. The associations between IL-6 polymorphisms and ONFH susceptibility were assessed using odds ratio (OR) and 95% confidence interval (95% CI) via logistic regression. The potential function of these two variants was predicted by the HaploReg online database.


The results of the overall analysis revealed that IL-6 rs2069837 was correlated with decreased risk of ONFH among the Chinese Han population (p < 0.05). In stratified analysis, rs2069837 also reduced the susceptibility to ONFH in older people (> 51 years), males, nonsmokers, and nondrinkers (p < 0.05). However, no associations between rs13306435 and ONFH susceptibility were observed (p > 0.05).


To sum up, we suggested that rs2069837 G>A polymorphism in the IL-6 gene was significantly associated with a decreased risk of ONFH among the Chinese Hans. These findings underscored the crucial role of IL-6 rs2069837 in the occurrence of ONFH.

Peer Review reports


Osteonecrosis of the femoral head (ONFH) refers to the death of some osteocytes or the necrosis of some marrow elements caused by venous congestion, impairment or interruption of arterial blood, and subsequent repair, which in turn causes the necrosis of bone tissues [1]. The number of ONFH patients is increasing worldwide year by year [2]. The incidence of ONFH was 2.91 cases per 100,000 person-years in the Japanese population [3]. In Korea, the estimated yearly prevalence increased from 20.53/100,000 in 2002 to 37.96/100,000 in 2006, and the average number of new cases annually has been estimated at 14,103 [4]. Based on Chinese population data from 2010, there are approximately 8.12 million cases of ONFH among Chinese people aged 15 years and over [5]. And it poses a severe financial burden for both individuals and healthcare systems. However, the pathophysiology of ONFH has not been elucidated.

There is a wide spectrum of aetiological risk factors in ONFH including alcohol use, glucocorticoid use, and genetic factors [6, 7]. Up to now, the role of genetic polymorphisms in the development of ONFH has been widely reported. For example, Zhao et al. found that NOS3 variants were associated with the occurrence of ONFH [8]. A meta-analysis by Song et al. showed that eNOS polymorphism was correlated with idiopathic and secondary ONFH in Caucasians and Asians [9]. In addition, increasing studies have documented that candidate gene polymorphisms (e.g. RANK, OPG, RTEN, TNF-α) can affect the susceptibility to ONFH [10,11,12].

Interleukin-6 (IL-6) is a major pro-inflammatory cytokine that participants in the pathophysiological process of many diseases [13, 14]. Meanwhile, the function of IL-6 in bone disease has been extensively studied. Ding et al. reported that IL-6 was decreased in older adults, and it could serve as a predictor of bone loss and resorption [15]. IL-6 stimulated osteoclastogenesis by increasing RANKL gene expression by osteoblasts [16]. Yamaguchi et al. have shown that ischemic osteonecrosis may increased IL-6 levels in the synovial fluid [17]. In addition, IL-6 was found to be involved in the pathogenesis of rheumatoid arthritis and osteoarthritis [18, 19]. These findings suggest that IL-6 played a crucial role in the occurrence of bone disease. The association of IL-6 rs2069837, and rs13306435 polymorphisms with the risk of rheumatoid arthritis and lumbar disc disease were assessed [20, 21], but not studies on ONFH.

In the present study, we aimed to investigate the effect of IL-6 rs2069837 and rs13306435 polymorphisms on ONFH susceptibility among Chinese Hans.

Materials and methods

Study subjects

In this case–control study, we recruited 566 patients with ONFH and 566 healthy controls. ONFH patients were diagnosed by examining osteonecrosis in anteroposterior and frog view X-rays of both hips and/or magnetic resonance imaging. All patients were selected randomly from The Second Affiliated Hospital of Xi’an Jiaotong University. The patients without other direct trauma, cardiovascular diseases, rheumatoid arthritis, ankylosing spondylitis, hip joint-involving diseases (like hip dysplasia), diabetes mellitus, renal dysfunction, cancer, corticosteroids, alcohol use, and familial hereditary diseases were included. The healthy control group enrolled from the same hospital during the same period. The healthy controls were included if individuals met the following criteria: (1) No hip pain; (2) Anteroposterior and frog-leg lateral pelvic radiographs did not show any lesions; (3) Subjects without a long term of alcohol use and steroid use.

This study was approved by the Ethics Committee of the hospital and followed the Declaration of Helsinki. The informed consent of all subjects was obtained before the experiment.

SNP selection and genotyping

Based on previous studies [20, 21], 1000 Genomes Chinese Han Beijing population and dbSNP database ( with a minor allele frequency (MAF) > 0.01, and Hardy–Weinberg equilibrium (HWE) > 0.05, we selected rs2069837 and rs13306435 in IL-6 gene for genotyping. Genomic DNA was extracted from peripheral blood samples using the GoldMag DNA Extraction Kit (GoldMag Co. Ltd, Xi’an, China). The concentration and purity of DNA were assessed using the NanDrop 2000 (Thermo Scientific, USA).

The primer sequence of rs2069837 and rs13306435 was presented in Additional file 1: Table S1. PCR reactions were performed in a buffer containing 1 μl DNA, 0.5 μl PCR Buffer, 0.4 μl MgCl2, 0.1 μl dNTP Mix, 1.0 μl primer mix, and 0.2 μl Taq ligase in a final reaction volume of 5 μl. The reaction mixture was heated to 94 °C for 15 min for denaturation. Then, the sample was subjected to 45 cycles of 94 °C 20 s, annealing at 56 °C 30 s and extension at 72 °C 60 s, followed by a final extension step at 72 °C for 3 min. The PCR product was used to genotype using the Agena MassArray platform (Agena Bioscience, San Diego, CA, USA) [21, 22]. Then, the raw data was analyzed and managed using the Agena Typer 4.0 software.

Statistical analysis

The demographic characteristics (age and sex) were assessed in the case and control groups using the student t-test and χ2 test. Hardy–Weinberg equilibrium (HWE) of each SNP among controls was evaluated using the χ2 test. The correlation between IL-6 polymorphisms (rs2069837, rs13306435) and ONFH susceptibility was examined using odds ratio (OR) and 95% confidence interval (CI) by logistic regression by plink 1.9 software ( The functional annotation of each SNP was predicted by the HaploReg v4.1 database ( We used String database and Cytoscape software to generate protein–protein interaction networks. Then, Gene Ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) on mRNAs were performed to explore their functions using Cluster Profiler in R package. The ggplot2 in R package was used to draw the GO and KEGG analysis results. A p value < 0.05 was considered statistically significant.


Characteristics of study participants

In this study, we enrolled 566 patients with an average age of 51.34 ± 14.51 years and 566 healthy controls with an average age of 51.10 ± 13.93 years, respectively. There was no significant difference in terms of age (p = 0.503) and sex (p = 0.858) between the case and control group (Table 1). There were 223 cases of stage III/IV and 77 cases of stage I/II.

Table 1 Characteristics of ONFH patients and controls

In addition, the basic information of IL-6 polymorphisms was presented in Table 2. Rs2069837 is an intronic polymorphism, and rs13306435 is a missense polymorphism. Furthermore, these two SNPs were consistent with HWE (p > 0.05). The functional role of rs2069837 and rs13306435 are associated with regulation of promoter histone marks, enhancer histone marks, DNAse, proteins bound and motifs changed.

Table 2 Basic information of SNPs in IL-6 gene

Associations between rs2069837, rs13306435 and ONFH susceptibility

The results of Table 3 revealed that rs2069837 decreased the susceptibility to ONFH in the allele (OR = 0.76, 95% CI = 0.62–0.93, p = 0.009), heterozygote (OR = 0.75, 95% CI = 0.58–0.96, p = 0.023), dominant (OR = 0.73, 95% CI = 0.57–0.93, p = 0.011), and additive (OR = 0.76, 95% CI = 0.62–0.93, p = 0.009) models. In stratified analysis (Table 4), rs2069837 was also correlated with a lower-risk of ONFH in males, non-smokers and individuals aged > 51 years old in the allele, heterozygote, dominant, and additive models (p < 0.05). Additionally, rs2069837 only reduced the risk of ONFH in non-drinkers in the heterozygote and dominant models (p < 0.05). However, the associations between rs13306435 and ONFH susceptibility were not observed in the overall analysis and stratified analysis (p > 0.05, data no shown). Besides, we also evaluated the associations between IL-6 polymorphisms and ONFH susceptibility stratified by stage. However, no significant association was found (Additional file 1: Table S2).

Table 3 Associations between IL-6 polymorphisms and ONFH susceptibility
Table 4 Relationship between IL-rs2069837 and ONFH susceptibility in different subgroups

FPRP analysis

The statistical power and FPRP were calculated for all positive results. As was shown in Table 5, all of the significant findings for rs2069837 polymorphism remained noteworthy at the prior probability level of 0.25 and FPRP threshold of 0.2.

Table 5 False positive report probability of the association rs2069837 and ONFH susceptibility in subgroups

GO and KEGG analysis

Using String database and Cytoscape software, a protein–protein interaction network for IL-6 gene (Fig. 1A). The GO enrichment analysis showed that IL-6 was mainly enriched in cytokine receptor binding and growth factor receptor binding (Fig. 1B). The results of KEGG pathway analysis revealed that IL-6 is mainly involved in the Jak-STAT signaling pathway and rheumatoid arthritis (Fig. 1C).

Fig. 1
figure 1

The potential function of IL-6. A Protein–protein interaction network of IL-6; B GO analysis of IL-6; C KEGG pathway analysis of IL-6


In this case–control study, IL-6 rs2069837 and rs13306435 were genotyped to investigate the susceptibility to ONFH risk in the Chinese Han population. We only found that rs2069837 in the IL-6 gene was correlated with a decreased susceptibility to ONFH in the Chinese population. Some studies reported that age, gender, smoking and drinking exert the crucial role in the etiology of ONFH [3, 23]. Given that age, gender, smoking and drinking are the risk factor for ONFH, stratification analysis by sex (males and females), age (> 51 years and ≤ 51 years), smoking (yes and no) and drinking (yes and no) were performed to estimate the effect of these factor on the association between these variants and ONFH risk. The stratified results showed that IL-6 rs2069837 reduced the risk of ONFH among males, nonsmokers, nondrinkers, and individuals with age > 51 years. These data demonstrated that rs2069837 G>A polymorphism might have a beneficial effect on the development of ONFH.

The IL-6 gene is located on chromosome 7p15.3, containing six exons and five introns [24]. IL-6 encodes a cytokine protein, which functions in inflammation, maintains immune homeostasis and plays an important role in bone metabolism [25]. Xie et al. have reported that IL-6 level increased during osteogenic differentiation in bone marrow-derived mesenchymal stem cells (BM-MSCs) and was positively correlated with the osteogenic potential of BM-MSCs [26]. A previous study showed that significant upregulation of IL-6 levels was observed in osteoporotic BMMCs compared with normal controls, suggesting IL-6 as a promising target for osteoporosis therapy [27]. And another study has indicated that IL-6 classic signaling is essential for the bone healing process [28]. These lines of evidence have demonstrated that IL-6 gene played a crucial role in bone-related disease.

The rs2069837 polymorphism, located in the intron of IL-6 gene, was identified as an important susceptibility variant of many diseases. Previous study has demonstrated that rs2069837 elevated papillary thyroid cancer risk among Chinese [29]. Some research also found a significant association of rs2069837 with an increased risk of cervical cancer in Eastern Chinese women [30, 31]. Renauer et al. have indicated that rs2069837 was correlated with increased risk of Takayasu’s arteritis in Turkey and North America people [32]. In addition, Chen et al. found that rs2069837 variant increased the susceptibility to rheumatoid arthritis among young people and males [21]. However, we found that rs2069837 is associated with a lower risk of ONFH among the Chinese Hans. The reason for these inconsistent results may be associated with factors such as type of disease, region, ethnicity, and sample size. Furthermore, rs2069837 might be associated with the regulation of promoter histone marks, enhancer histone marks, DNAse, proteins bound and motifs changed, suggesting its potential function in ONFH. Rs2069837 in IL-6 might increase disease susceptibility by suppression of the anti-inflammatory gene GPNMB, but a direct effect from rs2069837 on IL-6 expression was not detect [33]. The specific mechanisms of rs2069837 on ONFH occurrence require further investigation.

Rs13306435 was located in exon 5 of IL-6gene. The T>A variation of rs13306435 changed an amino acid from Asp to Glu. The T allele of rs13306435 had been reported previously to be associated with increased expression and plasma levels of IL-6 [34]. Reportedly, Americans present the highest allele frequency of IL6 rs13306435 (A = 0.078) among all ethnic groups (Global A = 0.020, the 1000 Genomes Project, Phase 3) [35]. IL-6 rs13306435 was associated with hematological toxicity in leukemic patients [36], baseline peritoneal transport property [37]. However, no associations between rs13306435 and ONFH susceptibility were observed in the overall analysis and stratified analysis. The contribution of rs13306435 to ONFH risk need to further investigate in larger-scale prospective studies.

Although interesting results were found between rs2069837 variant and ONFH susceptibility, there were some limitations in this study. First of all, only two polymorphisms in IL-6 gene were studied, more polymorphisms are needed to investigate. Second, all participants were Han Chinese, so we need more different ethnic populations to confirm our findings. Third, IL-6 levels in plasma/serum or synovial fluid of ONFH patients and the association of IL-6 SNPs and the mNRA expression were not be detected. In further studies, multiple SNPs in IL-6 should be selected and genotyped to investigate the contribution of IL-6 polymorphisms to ONFH risk, and further studies for functional effect of SNPs on IL-6 expression are desired.


To sum up, we suggested that rs2069837 G>A polymorphism in IL-6 gene was significantly associated with a decreased risk of ONFH among the Chinese Hans. These findings underscored the crucial role of IL-6 rs2069837 in the occurrence of ONFH.

Availability of data and materials

The datasets generated during the current study are available in the [zenodo] repository, accession number: 5372106 (


  1. 1.

    Séguin C, Kassis J, Busque L, Bestawros A, Theodoropoulos J, Alonso ML, Harvey EJ. Non-traumatic necrosis of bone (osteonecrosis) is associated with endothelial cell activation but not thrombophilia. Rheumatology (Oxford). 2008;47(8):1151–5.

    Article  Google Scholar 

  2. 2.

    Chughtai M, Piuzzi NS, Khlopas A, Jones LC, Goodman SB, Mont MA. An evidence-based guide to the treatment of osteonecrosis of the femoral head. Bone Jt J. 2017;99-b(10):1267–79.

    CAS  Article  Google Scholar 

  3. 3.

    Ikeuchi K, Hasegawa Y, Seki T, Takegami Y, Amano T, Ishiguro N. Epidemiology of nontraumatic osteonecrosis of the femoral head in Japan. Mod Rheumatol. 2015;25(2):278–81.

    Article  Google Scholar 

  4. 4.

    Kang JS, Park S, Song JH, Jung YY, Cho MR, Rhyu KH. Prevalence of osteonecrosis of the femoral head: a nationwide epidemiologic analysis in Korea. J Arthroplasty. 2009;24(8):1178–83.

    Article  Google Scholar 

  5. 5.

    Zhao DW, Yu M, Hu K, Wang W, Yang L, Wang BJ, Gao XH, Guo YM, Xu YQ, Wei YS, et al. Prevalence of nontraumatic osteonecrosis of the femoral head and its associated risk factors in the Chinese Population: results from a nationally representative survey. Chin Med J. 2015;128(21):2843–50.

    CAS  Article  Google Scholar 

  6. 6.

    Mont MA, Cherian JJ, Sierra RJ, Jones LC, Lieberman JR. Nontraumatic osteonecrosis of the femoral head: where do we stand today? A 10-year update. J Bone Jt Surg Am. 2015;97(19):1604–27.

    Article  Google Scholar 

  7. 7.

    Chen WM, Liu YF, Lin MW, Chen IC, Lin PY, Lin GL, Jou YS, Lin YT, Fann CS, Wu JY, et al. Autosomal dominant avascular necrosis of femoral head in two Taiwanese pedigrees and linkage to chromosome 12q13. Am J Hum Genet. 2004;75(2):310–7.

    CAS  Article  Google Scholar 

  8. 8.

    Zhao X, Yang F, Sun L, Zhang A. Association between NOS3 polymorphisms and osteonecrosis of the femoral head. Artif Cells Nanomed Biotechnol. 2019;47(1):1423–7.

    CAS  Article  Google Scholar 

  9. 9.

    Song GG, Lee YH. Association of eNOS polymorphisms with susceptibility to osteonecrosis of the femur head: a meta-analysis. Z Rheumatol. 2017;76(3):267–73.

    CAS  Article  Google Scholar 

  10. 10.

    Chen B, Du Z, Dong X, Li Z, Wang Q, Chen G, Zhang G, Song Y. Association of variant interactions in RANK, RANKL, OPG, TRAF6, and NFATC1 genes with the development of osteonecrosis of the femoral head. DNA Cell Biol. 2019;38(7):734–46.

    CAS  Article  Google Scholar 

  11. 11.

    An F, Zhang L, Gao H, Wang J, Liu C, Tian Y, Ma C, Zhao J, Wang K, Wang J. Variants in RETN gene are associated with steroid-induced osteonecrosis of the femoral head risk among Han Chinese people. J Orthop Surg Res. 2020;15(1):96.

    Article  Google Scholar 

  12. 12.

    Peng Y, Liu Y, Huang D, Huang W, Shao Z. Association of TNF-α-308(G/A) and -238(G/A) polymorphisms with non-traumatic osteonecrosis of the femoral head risks: a meta-analysis. Int Orthop. 2018;42(7):1711–21.

    Article  Google Scholar 

  13. 13.

    Akbari M, Hassan-Zadeh V. IL-6 signalling pathways and the development of type 2 diabetes. Inflammopharmacology. 2018;26(3):685–98.

    CAS  Article  Google Scholar 

  14. 14.

    Araki M. Blockade of IL-6 signaling in neuromyelitis optica. Neurochemistry Int. 2019;130:104315.

    CAS  Article  Google Scholar 

  15. 15.

    Ding C, Parameswaran V, Udayan R, Burgess J, Jones G. Circulating levels of inflammatory markers predict change in bone mineral density and resorption in older adults: a longitudinal study. J Clin Endocrinol Metab. 2008;93(5):1952–8.

    CAS  Article  Google Scholar 

  16. 16.

    Duplomb L, Baud’huin M, Charrier C, Berreur M, Trichet V, Blanchard F, Heymann D. Interleukin-6 inhibits receptor activator of nuclear factor kappaB ligand-induced osteoclastogenesis by diverting cells into the macrophage lineage: key role of Serine727 phosphorylation of signal transducer and activator of transcription 3. Endocrinology. 2008;149(7):3688–97.

    CAS  Article  Google Scholar 

  17. 17.

    Yamaguchi R, Kamiya N, Adapala NS, Drissi H, Kim HK. HIF-1-dependent IL-6 activation in articular chondrocytes initiating synovitis in femoral head ischemic osteonecrosis. J Bone Jt Surg Am. 2016;98(13):1122–31.

    Article  Google Scholar 

  18. 18.

    Laavola M, Leppänen T, Hämäläinen M, Vuolteenaho K, Moilanen T, Nieminen R, Moilanen E. IL-6 in osteoarthritis: effects of pine stilbenoids. Molecules (Basel, Switzerland). 2018;24(1):109.

    Article  Google Scholar 

  19. 19.

    Pandolfi F, Franza L, Carusi V, Altamura S, Andriollo G, Nucera E. Interleukin-6 in rheumatoid arthritis. Int J Mol Sci. 2020;21(15):5238.

    Article  Google Scholar 

  20. 20.

    Guan Y, Wang S, Wang J, Meng D, Wu H, Wei Q, Jiang H. Gene polymorphisms and expression levels of interleukin-6 and interleukin-10 in lumbar disc disease: a meta-analysis and immunohistochemical study. J Orthop Surg Res. 2020;15(1):54.

    Article  Google Scholar 

  21. 21.

    Chen J, Zhang A, Yang Y, Si Y, Hao D. Assessment of interleukin 6 gene polymorphisms with rheumatoid arthritis. Gene. 2021;765:145070.

    CAS  Article  Google Scholar 

  22. 22.

    Ellis JA, Ong B. The MassARRAY(®) system for targeted SNP genotyping. Methods Mol Biol (Clifton, NJ). 2017;1492:77–94.

    CAS  Article  Google Scholar 

  23. 23.

    Xie XH, Wang XL, Yang HL, Zhao DW, Qin L. Steroid-associated osteonecrosis: epidemiology, pathophysiology, animal model, prevention, and potential treatments (an overview). J Orthop Transl. 2015;3(2):58–70.

    Google Scholar 

  24. 24.

    Duan HX, Chen YY, Shi JZ, Ren NN, Li XJ. Association of IL-6 -174G>C (rs1800795) polymorphism with cervical cancer susceptibility. Biosci Rep. 2018;38(5):BSR20181071.

    Article  Google Scholar 

  25. 25.

    Lorenzo JA. The role of interleukin-6 in bone. J Endocr Soc. 2020;4(10):bvaa112.

    Article  Google Scholar 

  26. 26.

    Xie Z, Tang S, Ye G, Wang P, Li J, Liu W, Li M, Wang S, Wu X, Cen S, et al. Interleukin-6/interleukin-6 receptor complex promotes osteogenic differentiation of bone marrow-derived mesenchymal stem cells. Stem Cell Res Ther. 2018;9(1):13.

    CAS  Article  Google Scholar 

  27. 27.

    Li X, Zhou ZY, Zhang YY, Yang HL. IL-6 contributes to the defective osteogenesis of bone marrow stromal cells from the vertebral body of the glucocorticoid-induced osteoporotic mouse. PLoS ONE. 2016;11(4):e0154677.

    Article  Google Scholar 

  28. 28.

    Prystaz K, Kaiser K, Kovtun A, Haffner-Luntzer M, Fischer V, Rapp AE, Liedert A, Strauss G, Waetzig GH, Rose-John S, et al. Distinct effects of IL-6 classic and trans-signaling in bone fracture healing. Am J Pathol. 2018;188(2):474–90.

    CAS  Article  Google Scholar 

  29. 29.

    Li H, Dai H, Li H, Li B, Shao Y. Polymorphisms of the highly expressed IL-6 gene in the papillary thyroid cancer susceptibility among Chinese. Curr Mol Med. 2019;19(6):443–51.

    CAS  Article  Google Scholar 

  30. 30.

    Shi TY, Zhu ML, He J, Wang MY, Li QX, Zhou XY, Sun MH, Shao ZM, Yu KD, Cheng X, et al. Polymorphisms of the Interleukin 6 gene contribute to cervical cancer susceptibility in Eastern Chinese women. Hum Genet. 2013;132(3):301–12.

    CAS  Article  Google Scholar 

  31. 31.

    Pu X, Gu Z, Wang X. Polymorphisms of the interleukin 6 gene and additional gene–gene interaction contribute to cervical cancer susceptibility in Eastern Chinese women. Arch Gynecol Obstet. 2016;294(6):1305–10.

    CAS  Article  Google Scholar 

  32. 32.

    Renauer PA, Saruhan-Direskeneli G, Coit P, Adler A, Aksu K, Keser G, Alibaz-Oner F, Aydin SZ, Kamali S, Inanc M, et al. Identification of susceptibility loci in IL6, RPS9/LILRB3, and an intergenic locus on chromosome 21q22 in takayasu arteritis in a genome-wide association study. Arthritis Rheumatol (Hoboken, NJ). 2015;67(5):1361–8.

    CAS  Article  Google Scholar 

  33. 33.

    Kong X, Sawalha AH. Takayasu arteritis risk locus in IL6 represses the anti-inflammatory gene GPNMB through chromatin looping and recruiting MEF2-HDAC complex. Ann Rheum Dis. 2019;78(10):1388–97.

    CAS  Article  Google Scholar 

  34. 34.

    Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin JS, Humphries S, Woo P. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Investig. 1998;102(7):1369–76.

    CAS  Article  Google Scholar 

  35. 35.

    Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, Korbel JO, Marchini JL, McCarthy S, McVean GA, Abecasis GR. A global reference for human genetic variation. Nature. 2015;526(7571):68–74.

    Article  Google Scholar 

  36. 36.

    Kim H, You S, Park Y, Choi JY, Ma Y, Hong KT, Koh KN, Yun S, Lee KH, Shin HY, et al. Interplay between IL6 and CRIM1 in thiopurine intolerance due to hematological toxicity in leukemic patients with wild-type NUDT15 and TPMT. Sci Rep. 2021;11(1):9676.

    CAS  Article  Google Scholar 

  37. 37.

    Ding L, Shao X, Cao L, Fang W, Yan H, Huang J, Gu A, Yu Z, Qi C, Chang X, et al. Possible role of IL-6 and TIE2 gene polymorphisms in predicting the initial high transport status in patients with peritoneal dialysis: an observational study. BMJ Open. 2016;6(10):e012967.

    Article  Google Scholar 

Download references


The authors thank all the participants in this study.


This study was supported by National Natural Science Foundation of China (No. 81772411).

Author information




RL designed this study protocol; RW drafted the manuscript and performed the DNA extraction and genotyping; RL performed the data analysis; RL conceived and supervised the study. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Ruiyu Liu.

Ethics declarations

Ethics approval and consent to participate

The protocol for this study was approved by the Ethics Committee of the Second Affiliated Hospital of Xi’an Jiaotong University and was in line with the Helsinki declaration. And the participant’s Informed consent was received.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Additional file 1:

Supplemental tables.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wang, R., Li, R. & Liu, R. An intron SNP rs2069837 in IL-6 is associated with osteonecrosis of the femoral head development. BMC Med Genomics 15, 5 (2022).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI:


  • ONFH
  • IL-6
  • Susceptibility
  • Polymorphism