Association between IL1B polymorphisms and the risk of rheumatoid arthritis

https://doi.org/10.1016/j.intimp.2020.106401Get rights and content

Highlights

  • Genetic variants in IL1B were associated with RA susceptibility.

  • Rs16944 and rs2853550 contributed to increase RA risk in Chinese Han population.

  • Our findings provided new targets for RA risk assessment and prevention.

Abstract

Rheumatoid arthritis (RA) is a chronic, inflammatory synovitis dominated systemic disease with unknown etiology. The purpose of this study was to determine the relationship between IL1B polymorphisms and RA risk in a Chinese Han population. Four single-nucleotide polymorphisms (SNPs) of IL1B, rs2853550, rs1143643, rs3136558 and rs16944 were genotyped in 508 RA cases and 494 healthy controls using the Agena MassARRAY method. A genetic model analysis was performed to evaluate the relationships between the variants and RA risk. Haplotype analysis was used to evaluate the potential relationship between the genetic block and RA risk. We determined that rs1143643 was linked to a reduced risk of RA based on the results of the co-dominant model (OR = 0.67, 95%CI: 0.50–0.89, p = 0.006) and the dominant model (OR = 0.73, 95%CI = 0.56–0.96, p = 0.025). On the other hand, rs16944 was associated with an increased risk of RA in the co-dominant model (OR = 1.71, 95%CI = 1.53–1.97, p = 0.029) and the recessive model (OR = 1.41, 95%CI = 1.05–1.88, p = 0.021). Among individuals older than 50 years, we observed that rs2853550 was associated with an increased risk of RA, and that rs1143643 decreased RA risk. Furthermore, rs1143643 was associated with a decreased RA risk in female patients. However, rs16944 increased RA risk in both the co-dominant and the additive models in different age subgroups. In addition, rs16944-GA increased RA risk in males in the co-dominance model and rs16944-AA increased RA risk in females in the additive model. These results suggested that rs2853550, rs1143643, and rs16944 in the IL1B gene are associated with RA risk.

Introduction

Rheumatoid arthritis (RA) is a common autoimmune disease in the clinic that is characterized by chronic synovitis, articular cartilage and bone destruction, joint deformity and loss of function. RA can cause painful stiffness and has a prolonged disease period. Movement impairment caused by arthritis can lead to physical and mental exhaustion, but there is no reliable treatment. RA incidence is approximately 1% in the total population; the incidence in females is significantly higher than that in males [1], [2]. The incidence of RA is considered to be the result of the combined action of genetic factors and environmental factors, but the specific mechanism remains unclear. Studies have shown that approximately 60% of RA risk is due to genetic factors [3]. Thus, we attempted to define genetic abnormalities associated with RA, as these may lead to more effective treatment strategies and a better understanding of risk prediction.

Early biomarkers can be found through genetic research, which can not only predict the occurrence of RA but also prevent the occurrence of inflammation, and ultimately achieve the goal of improving the quality of life of patients. Single nucleotide polymorphisms (SNPs) are a third-generation molecular marker. There are two main functions of SNPs: first, SNPs directly lead to changes in gene transcription level, translation level or protein function, thus leading to a disease or phenotype. Second, an SNP can be a genetic marker closely related to a disease or phenotype. Previous studies have shown that members of the interleukin cytokine family play a significant role in RA, such as IL-1 [4], IL-6 [5], IL-9 [6] and other factors.

The IL1B gene encodes the pro-inflammatory cytokine interleukin-1 (IL-1), a member of the IL-1 family that plays an important role in a variety of cell types, such as blood monocytes, macrophages, and cells of the central nervous system [7]. IL1B has been found to mediate chronic inflammatory responses in many diseases, such as neurodegenerative disease, Parkinson's disease [8], amyotrophic lateral sclerosis [9], essential tremor [10], Alzheimer’s disease [11] and inflammatory diseases [12]. Studies have shown that IL-1 blockers improve arthritis in mouse models and that IL-1 blockers have been confirmed in clinical trials to relieve rheumatoid arthritis in humans [13]. In vitro and in vivo trials have also shown that IL-1 beta significantly affects cartilage destruction and bone resorption [14], [15], [16]. Studies on IL1B gene polymorphisms have been carried out worldwide, but there are few studies of the correlation between the IL1B polymorphisms and the susceptibility to RA in China.

In this study, we investigated four SNPs, rs2853550, rs1143643, rs3136558 and rs16944, of the IL1B gene. We observed the relationship of these SNPs with RA susceptibility in Chinese Han population. Our research might provide more vital evidence for further elucidating the pathogenesis of RA.

Section snippets

Study subjects

We randomly recruited 508 RA patients and 494 unrelated healthy controls at 630 Rheumatic Hospital in Xi'an and conducted the study. After pathological diagnosis by a physician, all patients were confirmed as having RA. The control group was healthy subjects matched in age and sex without any inflammatory bone and/or joint diseases or other conditions. The subjects were ethnic Han Chinese who were genetically unrelated.

SNP genotyping

Based on the USCS database and previous studies, we selected four

Results

The mean age was 59.00 ± 9.83 years in the patients and 51.16 ± 11.49 years in the controls (Table 1). In this study, the age distribution was matched between the case group and the control group (p > 0.05). To evaluate the function of the selected SNPs, we used HaploReg4.1 to annotate the functions of SNPs in IL-1B to reveal the potential associations between these SNPs and RA risk. The results showed that these SNPs were involved in the regulation of promoter/enhancer histone markers, DNase,

Discussion

The purpose of this research was to explore the correlations of IL-1B gene polymorphisms with RA susceptibility. Our findings suggested that polymorphisms of rs2853550, rs1143643 and rs16944 of IL-1B might be significantly correlated with RA susceptibility.

Cytokines play a key role in intercellular communication, immunity and inflammation as cellular signaling molecules. IL-1β is a major inflammatory immune response inducer and combines with the same cell surface receptors, leading to an

Conclusions

In summary, our findings showed a relationship between IL-1B polymorphisms and the increased risk of RA in a Chinese Northwest Han male population, which might provide a potential theoretical basis for the study of RA.

Ethics approval and consent to participate

This study has been approved by the Ethics Committee of Xi'an 630 Rheumatology Hospital. All procedures performed in this study conform to the ethical standards of the Institutional Research Board and the ethical standards of the Helsinki Declaration and its subsequent amendments. All participants were informed of the research procedures and purpose by the researchers and voluntarily signed informed consent.

Funding

This work was supported by the National Natural Science Foundation of China [8196029].

CRediT authorship contribution statement

Hao Rong: Data curation, Formal analysis, Writing - original draft. Xue He: Investigation, Methodology. Li Wang: Project administration. Mei Bai: Resources. Tianbo Jin: Software, Supervision. Yuhe Wang: Writing - review & editing. Wei Yang: Writing - review & editing. Yongjun He: Validation. Dongya Yuan: Conceptualization.

Declaration of Competing Interest

All authors state that they have no conflicts of interest.

Acknowledgments

We thank all participants who agreed to provide blood samples and the hospital staff who cooperated with our study.

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