Associations between interleukin 1 polymorphisms and susceptibility to systemic lupus erythematosus: A meta-analysis

doi:10.1016/j.humimm.2013.09.002

Human Immunology

Volume 75, Issue 1, January 2014, Pages 105-112

https://doi.org/10.1016/j.humimm.2013.09.002 Get rights and content

Abstract

Objective

This study determined whether interleukin 1 (IL1) polymorphisms are associated with susceptibility to systemic lupus erythematosus (SLE).

Methods

A meta-analysis was conducted on the associations between the IL1A, IL1B, and IL1 receptor antagonist (IL1RN) polymorphisms and SLE.

Results

A total of 15 studies involving 1956 SLE cases and 2347 controls were included in the meta-analysis. The meta-analysis showed an association between SLE and the IL1A −889 T allele in the overall population and Europeans (OR = 0.858, 95% CI = 0.737–0.986, p = 0.032; OR = 0.827, 95% CI = 0.687–0.994, p = 0.043). Meta-analysis of the IL1RN polymorphism revealed an association with SLE in all study subjects (OR for IL1RN^∗2 = 1.539, 95% CI = 1.266–1.871, p = 1.5 × 10⁻²) and in Europeans and Asians (OR = 1.483, 95% CI = 1.187–1.852, p = 0.001; OR = 1.787, 95% CI = 1.167–2.736, p = 0.008). No associations were found between SLE and the IL1B −511 C/T, 3953 C/T, and IL1A +4845 G/T polymorphisms.

Conclusions

This meta-analysis suggests IL1A −889 C/T polymorphism is associated with susceptibility to SLE in Europeans, and that the IL1RN^∗2 allele is associated with susceptibility to SLE in Europeans and Asians.

Introduction

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease in which immune regulation is disrupted and which is characterized by intense inflammation and multiple organ damage. Furthermore, significant familial aggregation and convincing evidence of multiple genetic linkages demonstrate that the etiology of SLE is genetic in nature [1].

Interleukin 1 (IL1) initiates the recruitment of immune cells and inflammation [2]. Interleukin 1A (IL1A) and interleukin 1B (IL1B) are pro-inflammatory cytokines that bind to the IL-1 receptor, resulting in signal transduction. IL1RN is a competitive inhibitor that does not elicit intracellular signaling when bound to the same receptor [3]. IL1A, IL1B, and the IL-1 receptor antagonist (IL1RN) are three distinct and closely linked genes located in the 2q13 region [4]. The IL1A −889 C/T (rs1800587), IL1A +4845 G/T (rs17561), IL1B −511 C/T (rs16944), IL1B 3953 C/T (rs1143634) polymorphisms and the IL1RN variable number tandem repeat (VNTR) polymorphisms have been studied most frequently in SLE. IL1RN is a member of the IL-1 cytokine family; it inhibits the activity of IL1A and IL1B and modulates immune response [5]. The IL1RN has a VNTR polymorphism in intron 2. IL1RN^∗2 is associated with increased activity of IL1B, which plays a key role as a pro-inflammatory cytokine [6], [7].

IL-1 polymorphisms have been associated with autoimmune diseases such as rheumatoid arthritis (RA) [8] and ankylosing spondylitis [9]. IL-1 levels are associated with activity or susceptibility to autoimmune diseases [10]. IL-1 levels in SLE are significantly elevated and correlate with disease activity [11]. IL-1 production may be influenced by IL-1 polymorphisms [12], [13]. Thus, IL1A, IL1B, and IL1-RN are considered an attractive candidate genes of SLE based on its functional relevance [7], [14], [15]. A number of studies have examined the association between IL-1 polymorphisms and SLE [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], but the reported results are contradictory, possibly because of the low statistical powers of individual studies. Therefore, in order to overcome the limitations of individual studies, resolve inconsistencies, and reduce the likelihood that random errors are responsible for false-positive or false-negative associations [30], [31], [32], we performed a meta-analysis. In the present study, we used meta-analysis to explore whether the IL1A −889 C/T, IL1A +4945 G/T, IL1B −511 C/T, IL1B +3953 C/T polymorphisms and the IL1RN polymorphisms are associated with SLE susceptibility.

Section snippets

Identification of eligible studies and data extraction

A search was performed for studies that examined associations between IL1 polymorphisms and SLE. The literature was searched using the PUBMED and EMBASE databases to identify available articles in which IL-1 polymorphisms were analyzed in SLE patients (until May 2013). Combinations of keywords, such as “interleukin 1”, “IL1”, “polymorphism”, “systemic lupus erythematosus”, and “SLE” were entered as Medical Subject Heading (MeSH) components and as text words. References in identified studies

Studies included in the meta-analysis

One hundred twenty-five relevant studies that investigated the relation between IL1 polymorphisms and SLE were identified using PUBMED and EMBASE and by manual searching. Nineteen of these studies were selected for a full-text review based on title and abstract details [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29]. Five studies were excluded: three because of other IL1 polymorphisms [37], [38], two because of data not in HWE [39], [40], and one because it

Discussion

Although the multifactorial nature of SLE is well recognized, genetic factors are considered to be strong determinants of SLE. Thus, researchers have been encouraged to search for the genes responsible. IL-1 is a potent inflammatory cytokine and plays a key role in immune regulation [3]. Increased spontaneous release of IL-1 from SLE monotypes has been shown, and increased release of IL1A and IL1B has been correlated with autoantibodies [42]. IL1 levels were increased in the patient with active

Acknowledgment

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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Association of genetic variants of interleukin-1β gene -511T/C (rs16944) and +3954C/T (rs1143634) and serum levels of pentaxin (PTX3) and interleukin -1β (IL-1β) with disease activity of systemic lupus erythematosus patients
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These results were similar to that of other studies testing different races and ethinities (Umare et al., 2017; Parks et al., 2004; Wang et al., 2013; Nearmeen et al., 2019). In contrast, other studies (Huang et al., 2002; Song et al., 2014; Camargo et al., 2004) observed no association between IL-1 β polymorphism (rs16944) and SLE among their patients. Moreover, Muraki et al. (2004) found CC and TT genotypes of IL-1β gene -511CT polymorphisms to be less frequent in their Japanese SLE patients compared to controls.
This study aimed to assess the association of two genetic variants of interleukin-1β gene −511T/C (rs16944) and +3954C/T (rs1143634) and serum levels of pentaxin (PTX3) and interleukin -1β (IL-1β) with systemic lupus erythematosus (SLE) susceptibility and disease activity.
50 SLE patients and 50 apparently healthy subjects serving as control group were included in this study; they were subjected to full history and clinical examinations and lab investigations including assessment of serum levels of PTX3, IL-1B using ELISA technique. Genomic DNA for IL-1β polymorphism was extracted from the peripheral blood of patients and controls for identification of IL-1β polymorphisms (−511T/C (rs16944) and +3954C/T (rs1143634)) using Real-time PCR.
Serum levels of PTX3 and IL1β were significantly higher in cases (8.2 ng/mL & 45.9 pg/mL respectively) when compared to control group (5.4 ng/mL & 41 pg/mL respectively). Regarding rs16944; TT genotype and T allele showed significantly higher frequency in SLE when compared to the control group (p = 0.005, <0.001 respectively) with susceptibility to develop SLE (OR = 4.125, 3.245 respectively). PTX3 level was higher in rs1143634 CT + CC when compared to TT; rs16944 TC + TT when compared to CC. serum levels of IL1β increased gradually in rs1143634 TT, CT, CC respectively; and in rs16944 CC, TC, TT respectively with significant differences between genotypes. Linear regression analysis was conducted for prediction of higher SLEDAI, rs16944 (TC + TT), higher PTX3 and IL1β were significantly associated with higher SLE Disease Activity Index (SLEDAI) in univariate analysis, the multivariable analysis revealed that PTX3 and IL1β were independent predictors for higher SLEDAI.
Serum PTX3 and IL1β levels were significantly elevated in SLE patients when compared to controls and they were associated with high disease activity. TT genotype and T allele of rs16944 was associated with increased susceptibility to SLE development, higher disease activity and high PTX3 and IL-1β serum levels.
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Genetic studies so far conducted support the role of genes encoding IL-1F cytokines in conferring susceptibility to SLE. A recent meta-analysis confirms the association of IL1A − 889C/T polymorphism with susceptibility to SLE in Europeans, and the association of IL1RN*2 allele with susceptibility to SLE in Europeans and Asians [89]. As far as IL-18 is concerned, different polymorphisms all located in the promoter region confer susceptibility to the disease in Asians vs. Caucasian SLE patients [90].
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The causative role of IL-1β is well-established in autoinflammatory diseases, mainly due to gain-of-function mutations in genes encoding the IL-1β-maturing inflammasome. Exaggerated production of IL-1β and IL-18 correlates with disease and disease severity also in several autoimmune and chronic inflammatory and degenerative pathologies, although it is not clear whether they have a causative role or are only involved in the downstream disease symptoms.
A better understanding of the pathological role of IL-1 family cytokines in autoimmunity involves a deeper evaluation, in the pathological situations, of the possible anomalies in the feed-back anti-inflammatory mechanisms that in physiological reactions control and dump IL-1-mediated inflammation. Thus, we expect that IL-1 cytokines may be pathogenic only when, in addition to enhanced production, there is a concomitant failure of their control mechanisms.
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Moreover, IL1 gene SNPs have been associated with SLE susceptibility. In addition, expression level of IL-1 is also influenced greatly by these genetic components (Wang et al., 2013; Song et al., 2014; Mohammadoo-khorasani et al., 2016; Moossavi et al., 2018; Su et al., 2018). In line with these evidences, the present case-control study explored the association between five SNPs of IL-1 gene family (IL1A−889; rs1800587, IL1B−511; rs16944, IL1B+3962; rs1143634, IL1Rpsti 1970; rs2234650 and IL1RAmspa 11,100; rs315952) and SLE of Iraqi female patients.
Present case-control study explored the association between five single nucleotide polymorphisms (SNPs) of interleukin-1 (IL-1) gene family (IL1A₋₈₈₉; rs1800587, IL1B₋₅₁₁; rs16944, IL1B₊₃₉₆₂; rs1143634, IL1R_{psti 1970}; rs2234650 and IL1RA_{mspa 11,100}; rs315952) and SLE. A sample of 103 Iraqi female patients and 113 healthy matched females were investigated. Serological testing revealed that 91.1 and 88.9% of patients were seropositive for anti-nuclear and anti-double-stranded DNA antibodies, respectively, while none of the control females were seropositive. Serum level of C3 (54 vs. 108 mg/dL) and C4 (5 vs. 21 mg/dL) showed a significant decreased median in patients compared to control. Inspecting IL1 gene SNPs demonstrated a significant increased frequency of IL1A₋₈₈₉C allele in patients compared to control (72.8 vs.56.0%, odds ratio = 1.94, 95% confidence interval = 1.30–2.91), while T allele frequency was significantly decreased (27.2 vs.42.0%). For IL1B₋₅₁₁, IL1B₊₃₉₆₂, IL1R_{psti 1970} and IL1RA_{mspa 11,100} SNPs, allele and genotype frequencies showed no significant variation between patients and control. A significant two-locus linkage disequilibrium (LD) was recorded between IL1B₋₅₁₁ and IL1RA_{mspa 11}_,₁₀₀ SNPs in SLE patients only (log of likelihood odds ratio = 5.69, correlation coefficient = 0.241, LD coefficient = 0.517). Five-locus haplotype frequency estimation revealed that CCCTC and CCTCT haplotypes were positively associated with SLE risk. It is concluded that IL1A₋₈₈₉ SNP is associated with susceptibility to SLE, while, IL1B₋₅₁₁, IL1B₊₃₉₆₂, IL1R_{psti 1970} and IL1RA_{mspa 11,100} SNPs may have no influence on SLE risk. Specific allelic combinations (haplotypes) between the five SNPs may also have a susceptibility role in SLE.
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Parks et al. reported that -511T allele was significantly associated with disease susceptibility and TT genotype was inversely associated with proteinuria in SLE patients of African American ethnicity (Parks et al., 2004). Recently, two independent meta-analyses conducted by Song et al. (Song et al., 2014) and Wang et al. (Wang et al., 2013) using reports from Europeans and Asians reported that there was no association between -511C/T polymorphism and SLE susceptibility. However, they obtained inconsistent results for association of IL-1A and IL-1RN polymorphisms with risk of SLE.
To see the role of IL-1β gene polymorphisms to disease susceptibility in Indian SLE patients.
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IL-1β gene polymorphisms appear to confer susceptibility to the disease in Indian SLE patients.
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Moreover, due to the relatively small sample size, single study may be too underpowered to detect a possible small effect of the gene polymorphism on PCOS. By combining samples from different studies, meta-analysis has been applied widely to detect the relationship between a specific gene and diseases [27,28]. Therefore, we conducted this meta-analysis to explore the association between INS VNTR and PCOS.
The present meta-analysis aimed to investigate the association between insulin gene variable number of tandem repeats (INS VNTR) and polycystic ovary syndrome (PCOS). Systematic searches of electronic databases, reference lists of included articles, and the abstracts presented at related scientific societies meetings were performed. Statistical analyses were conducted using software Stata 11.0. The pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were applied. Publication bias was tested by Begg’s funnel plot and Egger’s regression test. A total of 9 studies including 1075 PCOS patients and 2878 controls were included in the meta-analysis. There were evidence of statistical significant association between INS VNTR and PCOS in allelic model (OR = 1.25, 95% CI = 1.08–1.43, P = 0.002) and dominant model (OR = 1.34, 95% CI = 1.11–1.63, P = 0.003) but not in additive model (OR = 1.38, 95% CI = 0.93–2.04, P = 0.11) and recessive model (OR = 1.26, 95% CI = 0.96–1.65, P = 0.09). No significant publication bias was shown by funnel plots and Egger’s regression tests. In conclusion, our meta-analysis suggests that the III allele of INS VNTR is associated with increased risk of PCOS.

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Associations between interleukin 1 polymorphisms and susceptibility to systemic lupus erythematosus: A meta-analysis

Abstract

Objective

Methods

Results

Conclusions

Introduction

Section snippets

Identification of eligible studies and data extraction

Studies included in the meta-analysis

Discussion

Acknowledgment

Int J Biochem Cell B

Genomics

Joint Bone Spine

Cytokine

Control Clin Trials

J Biol Chem

Systemic lupus erythematosus susceptibility loci defined by genome scan meta-analysis

Hum Genet

The IL-1 family and inflammatory diseases

Clin Exp Rheumatol

Purification, cloning, expression, and biological characterization of an interleukin-1 receptor antagonist protein

Nature

Polymorphism in human IL-1 receptor antagonist gene intron 2 is caused by variable numbers of an 86-bp tandem repeat

Hum Genet

Length variation within intron 2 of the human IL-1 receptor antagonist protein gene (IL1RN)

Nucleic Acids Res

Association between interleukin 1 polymorphisms and rheumatoid arthritis susceptibility: a meta-analysis

J Rheumatol

The role of interleukin-1 in disease

New Engl J Med

Cytokine production, serum levels and disease activity in systemic lupus erythematosus

Clin Exp Rheumatol

A TaqI polymorphism in the human interleukin-1 beta (IL-1 beta) gene correlates with IL-1 beta secretion in vitro

Eur J Clin Invest

Cloning and functional analysis of the allelic polymorphism in the transcription regulatory region of interleukin-1 alpha

Immunogenetics

A rare allele combination of the interleukin-1 gene complex is associated with high interleukin-1 beta plasma levels in healthy individuals

Eur Cytokine Netw

Interleukin-1 gene cluster and IL-1 receptor polymorphisms in Iranian patients with systemic lupus erythematosus

Rheumatol Int

Higher genetic susceptibility to inflammation in mild disease activity of systemic lupus erythematosus

Rheumatol Int

Association study of genetic variants of pro-inflammatory chemokine and cytokine genes in systemic lupus erythematosus

BMC Med Genet

Analysis of HLA DR, HLA DQ, C4A, FcgammaRIIa, FcgammaRIIIa, MBL, and IL-1Ra allelic variants in Caucasian systemic lupus erythematosus patients suggests an effect of the combined FcgammaRIIa R/R and IL-1Ra 2/2 genotypes on disease susceptibility

Arthritis Res Ther

Polymorphisms of IL-1 beta gene in Japanese patients with Sjogren’s syndrome and systemic lupus erythematosus

J Rheumatol

Systemic lupus erythematosus and genetic variation in the interleukin 1 gene cluster: a population based study in the southeastern United States

Ann Rheum Dis