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. 2021 Feb 17;35:25. doi: 10.47176/mjiri.35.25

Relationship between common interleukin 1-beta gene polymorphisms and the risk of gestational disorders: An updated meta-analysis

Mahdiyeh Harati-Sadegh 1, Saman Sargazi 2,*, Hamed Taheri 2,3, Narges Arbabi 4, Ramin Saravani 2,5,*, Shekoufeh Mirinejad 2
PMCID: PMC8214042  PMID: 34169037

Abstract

Background: To quantitatively estimate the relationship between IL‐1β -511C>T, −31T>C, and +3954C>T polymorphisms and risk of gestational disorders.

Methods: In this meta-analysis, eligible publications were searched in Web of Knowledge, MEDLINE, PubMed, Scopus, and Google Scholar databases (updated April 2020), using appropriate or relevant keywords. Case-control population-based reports were included if provided with genotypic frequencies of both studied groups. Statistical analyses were performed using the MetaGenyo web tool software, where a P value less than 0.05 indicated a significant association. For the assessment of between-study variations, heterogeneity analysis was applied with the I2 statistics.

Results: A total of thirteen studies were included. We observed a significant association between IL‐1β−31T>C polymorphism and reduced risk of gestational disorders under codominant CT vs. CC [OR= 0.74, CI (0.59-0.92)], and dominant CT+TT vs. CC [OR= 0.74, CI (0.60-0.91)] contrasted genetic models. The stratified analysis considering the disease type showed that the 511C>T variant, under the recessive CC vs. CT+TT model, enhanced the risk of preterm birth by 1.29 fold.

Conclusion: Our results failed to support an association between two IL‐1β polymorphisms, 511C>T and +3954C>T, with the overall risk of gestational disorders. In contrast, the 31T>C variant reduced the incidence of such diseases. Further studies are encouraged to get more precise estimates of effect sizes.

Keywords: Cytokine, Interleukin, Polymorphism, Pregnancy, Meta-analysis

↑ What is “already known” in this topic:

Gestational disorders are a heterogeneous group of conditions affecting pregnant women with unknown etiology. Regulation of inflammatory responses seems to be etiologically crucial in the pathogenesis of gestational diseases. Previous studies have shown the correlation between IL‐1β gene polymorphisms and the risk of gestational disorders; still, the results showed inconsistency.

→ What this article adds:

In this study, we observed a significant association between IL‐1β−31T>C polymorphism and reduced risk of gestational disorders under CT vs. CC and CT+TT vs. CC genetic contrasted models. Our results failed to support an association between the other two IL‐1β polymorphisms, 511C>T and +3954C>T, with the overall risk of gestational disorders.

Introduction

Gestational disorders are a heterogeneous group of conditions affecting pregnant women with unknown etiology (1, 2). Notwithstanding, many of these disorders are caused by insufficient oxygen transfer and/or nutrients from mother to the fetus (3, 4). Pregnancy itself is marked by increased expression of inflammatory mediators, such as chemokines, cytokines, and pattern recognition receptors, which is often occurred during gestation (5, 6). During gestation, the balance between multiple cytokines is profoundly altered. This might trigger the production of inflammatory cytokines, which are mainly involved in adverse pregnancy outcomes (7). Through innate immune response, an organism reacts to possible perturbations in organ function, playing a substantial role in preterm birth (PTB), preeclampsia, recurrent spontaneous abortion (RSA), etc. (7, 8). Moreover, high levels of inflammatory mediators were detected in placentae affected by gestational diabetes, causing defective placentation (9). That is to say, several types of gestational disorders share a mutual phenotype of variability in inflammatory responses.

Cytokines are immunomodulatory proteins that are primarily involved in many aspects of pregnancy (10). As a multifunctional cytokine, interleukin 1 (IL1) is produced by villous syncytiotrophoblast of the human placenta during early pregnancy (11, 12).

Several genetic variants of the IL‐1 gene contribute to altered IL‐1 expression, causing impaired embryogenesis and abortion (13). In this regard, single-nucleotide polymorphisms (SNPs) located within coding or noncoding-regions of the IL‐1β gene are well-studied. One well-studied variant is rs16944, a C-to-T substitution variant that resided in the promoter region of the IL-1β gene. The other IL-1β variant, rs1143634 (in the +3954 locus), is associated with an elevated cytokine production as a four-fold higher amount of IL-1β was observed in homozygous carriers of the T allele compared with the CC genotype carriers (14). Besides, rs1143627 is a TATA box polymorphism (genotype T/C) in the -31 locus of the IL-1β gene (15). These SNPs are high-risk candidates, and investigating their effects will provide new information in developing novel treatment strategies for subjects with etiologically different conditions.

Regulation of inflammatory responses seems to be etiologically crucial in the pathogenesis of gestational disorders. Previous studies have established a link between IL‐1β gene polymorphisms and the risk of gestational disorders (16-18). However, the results showed inconsistency. In this comprehensive study, we sought to explore a more accurate estimation of the relationship between three common IL‐1β polymorphisms and susceptibility to gestational disorders.

Methods

Study selection

In this meta-analysis, we searched Web of Knowledge, MEDLINE, PubMed, Scopus, and Google Scholar databases for relevant reports (the last search on April 2020) and statistically combined the results of previous case-control studies. Keywords in the searches included "rs1143627 or IL-1β -31T or rs16944 or IL-1β -511T or rs1143634 or IL-1β -3954 C/T" and "gestation or gestational or pregnancy or labor or miscarriage or abortion or preterm or preterm or preeclampsia or preeclampsia" and "polymorphism or mutation or variant or SNP or single-nucleotide polymorphism." Also, additional eligible studies were identified by the use of hand searching of retrieved articles.

High-quality case-control population-based reports were included if provided with genotypic frequencies of both studied groups. Cohort studies, review articles, conference abstracts, publication in other languages, low-quality studies, and duplicated data were excluded. If more than one different case-controls were reported in the same article, they were treated as independent studies.

Data extraction

Information including the first author's name, publication date, country, ethnicity, number of subjects in the studied groups, genotyping method, and the genotypic distribution of IL-1β polymorphisms (-31T, -511, and -3954) in cases and controls were recorded from each publication. Data extraction was done independently by two authors (S.S. and M.H.S.) from all eligible publications. In case of disagreement, a third reviewer (N.A.) settled the discrepancy.

Risk of bias

The quality assessment (QA) was performed according to the Newcastle-Ottawa Scale (NOS) as described previously (19), and scores are presented in Tables 1-3. Studies with a score ≤ 6 were regarded as "low-quality," whereas those scored > 6 were considered "high-quality."

Table 1. Main characteristics of the studies included in the meta-analysis for IL‐1β −511C>T .

Study (year) Genotyping method Disease Country Ethnicity Case Control Cases Controls PHWE PHWE* Score
IL‐1β −511C>T CC CT TT C T CC CT TT C T
Hefler et al. (2002) PCR-RFLP RSA Austria Caucasian 130 67 29 90 11 148 112 20 38 9 78 56 0.17 0.52 5
Wang et al. (2002) PCR-RFLP RSA USA Caucasian 131 72 65 49 17 179 83 21 32 19 74 70 0.35 0.53 5
Linjawi et al. (2005) PCR-RFLP RSA UK Caucasian 206 224 69 117 20 255 157 85 110 29 280 168 0.48 0.57 6
Sata et al. (2009) RT PCR PTB Japan Asian 73 341 26 27 20 79 67 86 162 93 334 348 0.36 0.45 8
Ma et al. (2011) PCR-RFLP RSA China Asian 162 156 38 84 40 160 164 46 84 26 176 136 0.24 0.45 7
Agrawal et al. (2012) PCR-RFLP RSA India Asian 200 300 13 86 101 112 288 15 126 159 156 411 0.11 0.51 7
Schmid et al. (2012) PCR and pyrosequencing PTB Austria Caucasian 100 100 37 47 16 121 79 43 39 18 125 75 0.09 0.37 6
Yilmaz et al. (2012) PCR-RFLP PTB Turkey Caucasian 100 101 41 52 7 134 66 35 36 30 106 96 0.004 0.05 6
Kim et al. (2014) PCR-RFLP RSA Korea Asian 385 232 96 190 99 382 388 39 120 73 198 266 0.38 0.45 7
Wang et al. (2014) PCR-RFLP PE China Asian 232 447 52 98 82 202 262 125 214 108 464 430 0.38 0.45 7
Awasthi et al. (2015) PCR-RFLP PTB India Asian 559 559 199 223 137 621 497 166 266 127 598 520 0.30 0.45 7
Langmia et al. (2016) Mass ARRAY PTB Malaysia Asian 92 391 22 49 21 93 91 104 203 84 411 371 0.42 0.45 7
Pereyra et al. (2016) RT PCR PTB Uruguay Hispanic 142 100 44 81 17 169 115 23 61 16 107 93 0.02 0.14 7
Nasr et al. (2017) PCR-RFLP PE Egypt Arab 80 80 17 32 31 66 94 24 40 16 88 72 0.93 0.93 6
Rahmani et al. (2018) PCR-RFLP RSA Iran Caucasian 100 100 35 43 22 113 87 40 42 18 122 78 0.24 0.45 7
Wang et al. (2019) PCR-RFLP RSA China Asian 598 603 149 294 155 592 604 110 275 218 495 711 0.16 0.45 8
Majcher et al. (2019) Taqman GDM Poland Caucasian 204 207 93 93 18 279 129 86 95 26 267 147 0.98 0.98 7
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RSA: Recurrent spontaneous abortion; PE: Preeclampsia; PTB: Pre term birth; GDM: Gestational diabetes mellitus; UK: United Kingdom; USA: United States; RT PCR: Real-time PCR. PHWE: The P-value of chi-square test for Hardy-Weinberg in controls; PHWE*: PHWE corrected for multiple testing by FDR method.

Table 3. Main characteristics of the studies included in the meta-analysis for IL‐1β +3954C>T .

Study (year) Genotyping method Disease Country Ethnicity Case Control Cases Controls PHWE PHWE* Score
IL‐1β, +3954C>T CC CT TT C T CC CT TT C T
Reid et al. (2001) PCR-RFLP PE UK Caucasian 17 40 11 6 0 28 6 26 14 0 66 14 0.18 0.37 6
Ma et al. (2011) PCR-RFLP RSA China Asian 162 156 124 38 0 286 38 130 26 0 286 26 0.26 0.38 7
Mohajertehran et al. (2012) PCR-RFLP PE Iran Asian 54 50 28 20 6 76 32 28 20 2 76 24 0.49 0.59 6
Galvao et al. (2016) RT PCR PE Brazil Hispanic 168 449 5 58 105 68 268 181 87 181 449 449 0 0 7
Langmia et al. (2016) MassArray PTB Malaysia Asian 94 398 83 11 0 177 11 346 52 0 744 52 0.16 0.38 7
Tavakkol Afshari et al. (2016) PCR-RFLP PE Iran Arab 153 150 80 57 16 217 89 84 60 6 228 72 0.24 0.38 7
Wang et al. (2019) PCR-RFLP RSA China Asian 598 603 482 111 5 1075 121 474 121 8 1069 137 0.93 0.93 8
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RSA: Recurrent spontaneous abortion; PE: Preeclampsia; PTB: Preterm birth; UK: United Kingdom; RT PCR: Real-time PCR. PHWE: The P-value of chi- test for Hardy-Weinberg Equilibrium (HWE) in controls; PHWE*: PHWE corrected for multiple testing by FDR method.

Statistical analysis

Data were analyzed using the MetaGenyoweb tool (20) and Stata v.12 software. The Mantel-Haenszel method was used to pool Odds Ratios (ORs) with 95 % confidence intervals (CIs) for estimation of the strengths of association under the allelic and different genetic contrasted models (21). Subgroup analysis was performed by disease type, ethnicity, and score of each study. For each study, deviations from Hardy–Weinberg equilibrium (HWE in the controls) were checked using the Chi-square test. Heterogeneity analysis was applied with the I2 statistics (>50% as heterogeneity) to assess variations between studies. When appropriate, the fixed-effect model (in the absence of between-study variation) or the random effect model (in the presence of between-study variation) was applied to pool the data from individual studies. Publication bias was estimated using Egger's tests. Analysis of sensitivity was also performed to assess the robustness of summary ORs.

Results

Study characteristics

Upon performing a comprehensive literature search, 22 reports of genetic association studies were identified regarding three IL‐1β polymorphisms and the risk of gestational disorders (16-18, 22-39) containing 7574 subjects (for IL‐1β -511), 2452 subjects (for IL‐1β -31), and 3092 subjects (for IL-1β -3954). Eleven of these studies were performed on Asians, and eight studies were on Caucasians. Figure 1 shows the PRISMA diagram of the searching procedure. The characteristics of all included studies are summarized in Tables 1, 2, and 3.

Fig. 1.

Fig. 1

Flow diagram of the study selection procedure

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Table 2. Main characteristics of the studies included in the meta-analysis for IL‐1β −31T>C .

Study (year) Genotyping method Disease Country Ethnicity Case Control Cases Controls PHWE PHWE* Score
IL‐1β−31T>C CC CT TT C T CC CT TT C T
Wang et al. (2002) PCR-RFLP RSA USA Caucasian 127 72 19 47 61 85 155 19 33 20 71 73 0.48 0.87 5
Sata et al. (2009) RT PCR PTB Japan Asian 73 341 17 30 26 64 82 91 166 84 348 334 0.63 0.89 8
Ma et al. (2011) PCR-RFLP RSA China Asian 162 156 56 78 28 190 134 40 80 36 160 152 0.74 0.89 7
Wang et al. (2014) PCR-RFLP PE China Asian 232 447 90 90 52 270 194 117 210 120 444 450 0.20 0.61 7
Langmia et al. (2016) MassArray PTB Malaysia Asian 93 389 26 47 20 99 87 98 199 92 395 383 0.64 0.89 7
Nasr et al. (2017) PCR-RFLP PE Egypt Arab 80 80 28 28 24 84 76 20 40 20 80 80 1.00 1.00 6
Rahmani et al. (2018) PCR-RFLP RSA Iran Caucasian 100 100 37 44 19 118 82 38 42 20 118 82 0.19 0.61 7
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RSA: Recurrent spontaneous abortion; PE: Preeclampsia; PTB: Preterm birth; USA: United States; RT PCR: Real-time PCR. PHWE: The P-value of chi- test for Hardy-Weinberg Equilibrium (HWE) in controls; PHWE*: PHWE corrected for multiple testing by FDR method.

Eight studies rated low-quality and therefore excluded. Finally, a total of 13 studies were included in the meta-analysis.

Meta-analysis results of IL1-β -511C>T polymorphism

Eleven studies with a total of 2747 women with gestational disorders and 3436 controls were included to examine the correlation of IL1-β -511C>T polymorphism and gestational disorders risk. The Meta-analysis identified no significant link between the overall risk of gestational disorders and the SNP under different genetic models (Table 4). Subgroup analysis indicated an increased PTB risk under the recessive (OR 1.29, 95% CI 1.06-1.58, p= 0.01; CC vs. CT+TT) genetic model. Besides, stratified analysis by ethnicity revealed that this polymorphism conferred a protective effect against susceptibility to gestational disorders under the heterozygous codominant model in Asians (OR 0.85, 95% CI 0.72-0.99, p= 0.036; CT vs. TT) (Table 5).

Table 4. The pooled ORs and 95% CIs for the association between IL1-β polymorphisms and overall risk of gestational disorders .

Association test Heterogeneity Egger's test

Polymorphism 		No Genetic model OR (95% CI) p Model p I2 (%) p
IL‐1β −511C>T 11 C vs. T 1.07 (0.91-1.26) 0.39 Random 0.0001 70.44% 0.0002
11 CT vs. TT 0.90 (0.78-1.04) 0.14 Fixed 0.32 31.32% 0.15
11 CC vs. TT 1.15 (0.85-1.58) 0.39 Random 0.00 68.03% 0.0005
11 CT+CC vs. TT 1.00 (0.80-1.25) 0.98 Random 0.03 57.88% 0.008
11 CC vs. CT+TT 1.18 (0.95-1.46) 0.12 Random 0.0004 56.10% 0.011
IL‐1β −31T>C 5 T vs. C 0.89 (0.71-1.11) 0.31 Random 0.04 60.10% 0.12
5 CT vs. CC 0.74 (0.59-0.92) 0.01 Fixed 0.30 17.30% 0.01
5 TT vs. CC 0.80 (0.54-1.20) 0.28 Random 0.08 51.94% 0.23
5 CT+TT vs. CC 0.74 (0.60-0.91) 0.01 Fixed 0.13 44.41% 0.02
5 TT vs. CT+CC 0.92 (0.73-1.15) 0.47 Fixed 0.16 39.31% 0.64
IL- β +3954C>T 5 T vs. C 1.44 (0.75-2.77) 0.27 Random 0.0001 93.35% 0.88
5 CT vs. CC 1.79 (0.82-3.91) 0.14 Random 0.0001 90.95% 0.17
3 TT vs. CC 3.37 (0.46-24.88) 0.23 Random 0.0001 91.53% 0.72
5 CT+TT vs. CC 1.82 (0.84-3.95) 0.13 Random 0.0001 91.18% 0.16
3 TT vs. CT+CC 1.83 (0.86-3.90) 0.12 Random 0.07 63.05% 0.54
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P<0.05 is considered as statistically significant (bolded P-value).

Table 5. Stratified analysis of IL1-β polymorphisms and gestational disorders susceptibility by type and ethnicity .

No OR
(95%CI) 		P I2(%) OR
(95%CI) 		P I2(%) OR
(95%CI) 		P I2(%) OR
(95%CI) 		P I2(%) OR
(95%CI) 		P I2(%)
−511C>T C vs. T CT vs. TT CC vs. TT CT+CC vs. TT CC vs. CT+TT
Type
PTB 4 1.09
(0.97-1.27) 		0.16 0 0.84
(0.66-1.06) 		0.15 0 1.15
(0.90-1.48) 		0.26 0 0.95
(0.77-1.19) 		0.68 0 1.29
(1.06-1.58) 		0.01 6.35
RSA 5 1.12
(0.84-1.52) 		0.44 78.05 1.04
(0.84-1.30) 		0.7 15.88 1.26
(0.68-2.35) 		0.46 76.02 1.10
(0.76-1.59) 		0.62 62.80 1.24
(0.80-1.93) 		0.33 68.27
Ethnicity
Asian 7 1.00
(0.84-1.20) 		0.96 70.28 0.85
(0.72-0.99) 		0.036 32.64 0.99
(0.69-1.42) 		0.96 68.68 0.90
(0.71-1.13) 		0.36 56.69 1.11
(0.85-1.45) 		0.42 60.39
Caucasian 3 0.80
(0.50-1.26) 		0.33 78.75 1.26
(0.83-1.93) 		0.27 0 1.56
(0.67-3.61) 		0.3 73.51 1.40
(0.75-2.59) 		0.28 58.91 1.29
(0.75-2.34) 		0.36 69.79
−31T>C T vs. C CT vs. CC TT vs. CC CT+TT vs. CC TT vs. CT+CC
Type
PTB 2 1.08
(0.85-1.37) 		0.55 59.71 0.92
(0.61-1.39) 		0.70 0 1.15
(0.72-1.83) 		0.57 53.67 0.99
(0.68-1.46) 		0.98 0 1.23
(0.65-2.31) 		0.53 63.56
RSA 2 0.83
(0.65-1.06) 		0.14 24.62 0.83
(0.56-1.23) 		0.36 11.18 0.70
(0.43-1.14) 		0.15 17.29 0.79
(0.55-1.15) 		0.22 33.59 0.78
(0.51-1.20) 		0.26 0
Ethnicity
Asian 4 0.87
(0.67-1.14) 		0.32 67.87 0.70
(0.55-0.89) 		0.003 6.10 0.78
(0.48-1.25) 		0.30 61.71 0.70
(0.56-0.88) 		0.002 46.60 0.94
(0.65-1.35) 		0.74 54.45
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P<0.05 is considered as statistically significant (bolded P-value).

Meta-analysis results of IL1-β -31T>C polymorphism

By pooling the results of5 studies, including 660 cases and 1433 healthy women, we found a noteworthy link between IL‐1β −31T>C polymorphism and reduced the risk of gestational disorders under heterozygous codominant (OR 0.74, 95% CI 0.59-0.92, p= 0.01; CT vs. CC) and dominant (OR 0.74, 95% CI 0.60-0.91, p= 0.01; CT+TT vs. CC) models (Table 4). Stratified analysis by ethnicity revealed a significant decrease in the risk of gestational disorders under codominant (OR 0.70, 95% CI 0.55-0.89, p= 0.003; CT vs. CC) and dominant (OR 0.70, 95% CI 0.56-0.88, p= 0.002; CT+TT vs. CC) contrasted models. In this regard, no remarkable association was noticed in Caucasian women (Table 5). Figure 2 shows the forest plot for the association between the IL-1β -31T>C polymorphism and overall risk of gestational disorders under the codominant heterozygous CT vs. CC contrasted model.

Fig. 2.

Fig. 2

Forest plot describing the meta-analysis for the association between the IL-1β -31T>C polymorphism and overall risk of gestational disorders under the codominant CT vs. CC contrasted model.

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Meta-analysis results of IL1-β +3954C>T polymorphism

An overall analysis of 5 studies for IL1-β +3954C>T polymorphisms, including 1175 cases and 1756 controls, revealed no significant association between the SNP and risk of gestational disorders (Table 4). Unfortunately, we could not carry out the subgroup analysis for this variant due to low genotypic frequencies.

Heterogeneity and publication bias

The Egger's test showed significant publication bias regarding −511C>T and −31T>C polymorphisms in some studied models (Table 4). Except for the codominant model of −511C>T and recessive model of +3954C>T polymorphisms, high degrees of heterogeneity was found between studies under the assessed genetic models of both SNPs (p<0.05). As regards -31 polymorphism, heterogeneity was observed between studies under the allelic model (p=0.04).

Sensitivity analysis

To examine the effect of each study on summary ORs, a sensitivity analysis was carried out by deleting each study one by one in all inheritance modes. We found that ORs were not statistically influenced, which proved the accuracy of pooled results. Figure 3 shows the sensitivity analysis describing the correlation between the IL-1β -31T>C polymorphism and the risk of gestational disorders under the codominant CT vs. CC genetic model.

Fig. 3.

Fig. 3

Sensitivity analysis was carried out to test the effect of the each dataset on the summary ORs between the IL-1β -31T>C polymorphism and risk of gestational disorders under the codominant CT vs. CC genetic model.

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Discussion

Immune imbalance leads to unsuccessful pregnancy (40). Aberrant function and expression of cytokines have a potential role in different pregnancy complications (41). The incidence of these complications is significantly higher in developing countries (42).

It has been well documented that polymorphisms could alter cytokine production levels and the strength of cytokine responses (43). The IL-1α and IL-1β, most-studied interleukins in pregnancy disorders, are proinflammatory cytokines that bind to the IL-1 receptor to rapidly initiate signal transduction and apply biological effects (44). The expression of the IL-1 cytokine family by the placenta in normotensive pregnancies highlights the role of this cytokine in pregnancy (45). A wealth of studies have reported the increased level of IL-1β in plasma of women with pregnancy disorders (29). Previous studies have examined the effect of IL1-β gene polymorphisms on gestational disorders. However, the reports for the association between -511C>T, −31T>C, and +3954C>T polymorphisms, as common IL1β SNPs, and various gestational disorders have shown inconsistent results in different populations. A meta-analysis of available data presents the precise estimation of the effects of the polymorphisms. Previous meta-analyses showed that IL1β polymorphisms affect the risk of various clinical conditions and cancers (46-48). However, to this date, no meta-analysis study has reported a precise correlation between IL1β polymorphisms and the risk of gestational disorders. Hence, in the current study, we combined data from the 13 genetic association studies regarding -511C>T, −31T>C, and +3954C>T polymorphisms and the risk of gestational disorders.

Pooled results from our meta-analysis revealed that IL‐1β −31T>C polymorphism reduces the risk of gestational disorders under codominant CT vs. CC and dominant CT+TT vs. CC genetic models. Besides, in the overall analysis, no noteworthy association was noticed between -511C>T and +3954C>T polymorphisms and the incidence of gestational disorders. By performing the stratified analysis by disease type, our findings showed that -511C>T variant decreased the risk of PTB under the recessive genetic model. Moreover, +3954C>T did not influence the risk of gestational disorders under the assessed genetic models. For counting the potential distracting effect of population admixture, we carried out subgroup analysis by ethnicity. We found the protective effect of -511C>T and −31T>C polymorphisms against the risk of gestational disorders in Asians.

Awasthi and colleagues carried out a meta-analysis to examine the correlation between IL1β-511C/T polymorphism and the risk of PTB (30). By including four studies (consist of 832 cases and 1101 controls) in the analysis, they failed to find a link between this SNP and vulnerability to PTB under the studied genetic models. Likewise, in the present up-dated meta-analysis, we pooled the results of 11 studies, including 2747 women with gestational disorders and 3436 healthy women, and found the same results. The first meta-analysis describing the correlation between IL1β polymorphisms and risk of RSA was performed by Bombell and Mcguire in 2008 (49). By pooling the findings of three case-control studies, they failed to find a noteworthy link between -511C/T and RSA risk, although an association between -31T allele with RSA was detected by pooling trial results of two studies. Another meta-analysis by Agrawal et al. in 2012 revealed similar results for the lack of association between -511C/T and RSA susceptibility (three studies included) (27). In a recent meta-analysis, Zhang et al. pooled five studies (1052 patients and 915 controls). They observed a significant correlation between the -511C/T polymorphism and RSA incidence under the recessive genetic model (50). In our work, however, we found an enhanced risk of PTB under the recessive CC vs. CT+TT inheritance mode.

IL1 gene polymorphisms served significant roles in the development of gestational disorders. However, the findings of the former meta-analysis were controversial because of the limited sample size. Therefore, updated results can help to get more reliable details of gestational disorders' pathogenesis and find biomarkers for predicting their risk. Our meta-analysis had several limitations. First, gestational disorders are multifactorial, and gene variants cannot be considered the only underlying etiology. Second, we merely examined the role of the polymorphisms while their functional consequences were not evaluated. Third, we did not consider gene-environment interactions and haplotypes due to the unavailability of individual data in retrieved publications. Finally, heterogeneity was observed between studies, which might be due to the varied study designs, application of different genotyping methods, and ethnicity differences.

Conclusion

In conclusion, our results failed to support an association between two IL‐1β polymorphisms, 511C>T and +3954C>T, with the overall risk of gestational disorders. In contrast, the 31T>C variant reduced the incidence of such diseases. Further studies are encouraged to get more precise estimates of effect sizes.

Acknowledgment

The authors wish to thank Dr. Alireza Ansari Moghadam for his contribution to data analyses.

Conflict of Interests

The authors declare that they have no competing interests.

Cite this article as: Harati-Sadegh M, Sargazi S, Taheri H, Arbabi N, Saravani R, Mirinejad Sh. Relationship between common interleukin 1-beta gene polymorphisms and the risk of gestational disorders: An updated meta-analysis. Med J Islam Repub Iran. 2021 (17 Feb);35:25. https://doi.org/10.47176/mjiri.35.25

Footnotes

Conflicts of Interest: None declared

Funding:None

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