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Pages 447-455 (October 2021)
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Vol. 17. Issue 8.
Pages 447-455 (October 2021)
Original Article
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The association between interleukin-6 promoter polymorphisms and rheumatoid arthritis by ethnicity: A meta-analysis of 33 studies
Asociación entre los polimorfismos del promotor de la interleucina-6 y la artritis reumatoide analizado por etnicidad: un metaanálisis de 33 estudios
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Blanca T. Pacheco-Sotoa,1, Leonardo M. Porchiab,1, William C. Lara-Vazqueza, Enrique Torres-Rasgadoa, Ricardo Perez-Fuentesa,b, M. Elba Gonzalez-Mejiaa,
Corresponding author
elba.gonzalezmejia@gmail.com

Corresponding author.
a Facultad de Medicina, Benemérita Universidad Autónoma de Puebla, 13 Sur 2901 Col. Volcanes, C.P. 72420 Puebla, Pue, Mexico
b Laboratorio de Investigación en Fisiopatologia de Enfermedades Crónicas, Centro de Investigación Biomédica de Oriente, Instituto Mexicano del Seguro Social, Delegación Puebla, Km 4.5 Carretera Federal Atlixco-Metepec, C.P. 42730 Atlixco, Puebla, Mexico
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Figures (1)
Tables (4)
Table 1. Characteristics of included studies.
Table 2. The association between IL-6 promoter polymorphism and the risk of developing Rheumatoid Arthritis.
Table 3. The association of the −174 G>C polymorphism on the development of Rheumatoid Arthritis, stratified by ethnicity.
Table 4. The association of the −572 G>C polymorphism on the development of Rheumatoid Arthritis, stratified by ethnicity.
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Additional material (2)
Abstract
Objective

We performed a meta-analysis to determine the effect Interleukin-6 (IL-6) promoter polymorphism (−174 G>C, −572 G>C, and −597 G>A) have on the development rheumatoid arthritis (RA) by ethnicity.

Material and methods

PubMed, EBSCO, LILACS, and Scopus databases were searched for studies exploring the association between any IL6 polymorphisms and RA until November 2018. Genotype distributions were extracted and, depending on the level heterogeneity, determined by the ψ2-based Q test and the Inconsistency Index (I2), fixed-effects or random-effects models were used to calculate pooled odds ratios (ORs) with 95% confidence intervals (95%CIs) for the heterozygous, homozygous, dominant, recessive, and allelic genetic models.

Results

From 708 identified publications, 33 were used in this analysis. For the −174 polymorphism, Asians (ORheterozygous=7.57, 95%CI: 2.28–25.14, ORhomozygous=5.84, 95%CI: 2.06–16.56, ORdominant=7.21, 95%CI: 2.30–22.63, ORrecessive=5.04, 95%CI: 1.78–14.28, ORallelic=6.60, 95%CI: 2.26–19.28, p<.05) and Middle East countries (ORheterozygous=2.30, 95%CI: 1.10–4.81, ORdominant=2.27, 95%CI: 1.22–4.22, ORallelic=2.29, 95%CI: 1.24–4.23, p<.05) were associated with a significant risk of developing RA. Whereas, for Latinos, the C-allele was associated with a benefit (ORhomozygous=0.26, 95%CI: .08–.82, ORrecessive=.25, 95%CI: .08–.80, p<.05). For the −572 polymorphism, Asians demonstrated a significant association for the homozygous and recessive genetic models (8 studies, ORhomozygous=1.56, 95%CI: 1.16–2.09, ORrecessive=1.63, 95%CI: 1.08–2.45, p<.05). For the −597 polymorphism, no association was observed.

Conclusions

Here, the −174 G>C polymorphism increased the risk of developing RA in Asians and Middle East populations. Interestingly, for Latinos, the polymorphism was associated with a benefit. For the −572 polymorphism, only the Asian population showed an increased risk of developing RA for the CC genotype.

Keywords:
Interleukin-6
Rheumatoid arthritis
Single nucleotide polymorphism
Meta-analysis
Ethnicity
Resumen
Objetivos

Realizamos un meta-análisis para determinar el efecto de los polimorfismos del promotor de interleucina-6 (IL-6) (-174 G>C, -572 G>C, y -597 G>A) sobre el desarrollo de artritis reumatoide (RA) analizado por etnicidad.

Materiales y métodos

En las bases de datos PubMed, EBSCO, LILACS y Scopus se buscaron estudios con la asociación entre polimorfismo de IL-6 y RA publicados hasta noviembre 2018. se obtuvieron las distribuciones de genotipo y de acuerdo al nivel de heterogeneidad el efecto fijo o aleatorio fueron utilizados para calcular los Odds Ratio (OR) con intervalos de confianza del 95% para los modelos genéticos heterocigoto, homocigoto, dominante, recesivo y alélico.

Resultados

De 708 estudios identificados, 33 fueron utilizados para este análisis. Para el polimorfismo -174, los países Asiáticos (ORheterocigoto=7,57, 95%CI: 2,28–25,14, ORhomocigoto=5,84, 95%CI: 2,06-16,56, ORdominante=7,21, 95%CI: 2,30-22,63, ORrecesivo=5,04, 95%CI: 1,78-14,28, ORalélico=6,60, 95%CI: 2,26-19,28, p<0,05) y del Medio Oriente (ORheterocigoto=2,30, 95%CI: 1,10-4,81, ORdominante=2,27, 95%CI: 1,22-4,22, ORalélico=2,29, 95%CI: 1,24-4,23, p<0,05) están asociados con el riesgo de desarrollar RA significativamente. Mientras que, para los Latinos, el alelo-C está asociado con un beneficio (ORhomocigoto=0,26, 95%CI: 0,08-0,82, ORrecesivo=0,25, 95%CI: 0,08-0,80, p<0,05). Para el polimorfismo -572, los Asiáticos están asociados significativamente con los modelos genéticos homocigoto y recesivo (8 estudios, ORhomocigoto=1,56, 95%CI: 1,16-2,09, ORrecesivo=1,63, 95%CI: 1,08-2,45, p<0,05). Para el polimorfismo -597, no se observó asociación.

Conclusiones

El polimorfismo -174 G>C aumenta el riesgo de desarrollar RA en población Asiática y Medio Oriente. Curiosamente, para los Latinos el polimorfismo está asociado con un beneficio. Para el polimorfismo -572, solo la población Asiática demuestra una aumento en el riesgo de desarrollar RA con el genotipo CC.

Palabras clave:
Interleucina-6
Artritis reumatoide
Polimorfismo de un solo nucleótido
Metaanálisis
Etnicidad
Full Text
Introduction

The world prevalence of rheumatoid arthritis (RA) ranges between 0.5% and 1.0% of the adult population, in which women are four times more likely to develop the disease.1 RA is a chronic autoimmune disease, characterized by the inflammation of the synovium.2 RA can lead to destruction of the patient's joints and prolong/untreated RA can result in multiple organ manifestations, leading to severe disability and even mortality.3 Since RA is a multi-faceted disease, the exact etiology remains elusive. Evidence supports IL-6 as a factor in RA development, such as elevated IL-6 levels are found in RA patients’ serum and synovial fluid4,5; moreover, tocilizumab ameliorates disease activity and radiological progression.6 For a complete explanation of IL-6's role in RA, please see the review by Srirangan and Choy.7

IL-6 is a pro-inflammatory cytokine, released from many types of cells and is a mediator of the acute phase response.7 To date, many polymorphisms of the IL6 gene have been identified; however, the promoter polymorphisms have been shown to affect RA development.8–12 Three polymorphisms, −174 G>C (rs1800795), −572 G>C (rs1800796), and −597G>A (rs1800797) have been shown to augment or decrease IL-6 serum levels.13,14 Previous meta-analyses have shown that for the Asian population, the −174 G>C polymorphism increases the risk of developing RA15–17; however, for the −572 G>C and −597 G>A polymorphism, the results remain inconclusive. Moreover, with previous meta-analyses, there is an incomplete analysis with respect to Latin America and Middle East countries. Since the latest meta-analyses in 2016 for the −174 polymorphism, which included 13 to 15 studies, there have been 6 additional studies.9,18–23 Moreover, it is possible that between 7 and 10 studies were not included with these meta-analyses. Here, we preformed this meta-analysis to elucidate the effect the IL6 promoter polymorphisms have on the development of RA by ethnicity.

MethodsSearch strategy

PubMed, SCOPUS, EBSCO and LILACS databases were searched for all studies that investigated for any IL6 polymorphisms and RA. The following keywords/index terms and any of their derivations were used: “Interleukin 6 or IL-6 or IFNB2”, “rheumatoid”, and “variant or SNP or polymorphism or genotype”. The search was performed without any language restrictions for publications published until December 15, 2018. Afterwards, the complied publications references were hand searched.

Inclusion and exclusion criteria

Two authors independently determined if each study was to be included. If a disagreement occurred about a publication, a third author analyzed the publication in question. Initially, the titles and abstract were examined to determine if the article focused on RA and IL-6. Afterwards, the publications were thoroughly examined for the IL6 polymorphisms and the genotype distribution. For inclusion, the studies must have met the following criteria: (1) case-controls studies; (2) examined for any IL6 polymorphisms; (3) focused on human subjects; (4) RA-confirmed patients using either the American College of Rheumatology or the European League Against Rheumatism24 criteria; and (5) contained information about genotype frequencies. Studies were excluded if they were: (1) not a case-control study; (2) information was used in a previous publication; or (3) meta-analysis, reviews, or editorial articles.

Bias analysis and data extraction

Two authors independently assessed the quality of the studies using the Newcastle–Ottawa Quality Assessment Scale.25 The following aspects of each study were appraised: selection of cases and controls, comparability, and outcome or exposure. For the analysis, the possible quality scores ranged from 0 to 9 (see Supplement information). Studies that scored6 were considered as a high-quality study. The following data was collected from each study: first author's name, year of publication, geographical location, diagnosis criteria of RA, technique used to detect the polymorphism, source of controls, and genotype distribution for cases and controls. Before a study was to be excluded for missing information, we attempted to contact the corresponding author by email at least three times.

Statistical analysis

For each study, the Hardy–Weinberg Equilibrium (HWE) was determined by the ψ2-test for the controls and was considered in agreement when the p-value was>0.05. The crude odds ratios (ORs) and 95% Confidence Intervals (95% CI) were used to assess the strength of the association between the IL6 polymorphisms and the risk of RA. The pooled crude ORs were calculated for allelic (2 vs. 1), dominant (12+22 vs. 11), recessive (22 vs. 12+11), heterozygous (12 vs. 11), and homozygous (22 vs. 11) genetic models, where for the −174 polymorphism 1=G (Wild-type) and 2=C (mutant), for the −572 polymorphism 1=G (Wild-type) and 2=C (mutant), and for the −597 polymorphism 1=G (Wild-type) and 2=A (mutant). Heterogeneity was determined using the ψ2-based Q-test and its degree was assessed by the Inconsistency Index (I2). If there was not significant heterogeneity (ψ2-based Q-test p-value0.10 and I2<50%), the fixed-effects model was used (Mantel–Haenszel method), or if there was significant heterogeneity (ψ2-based Q-test p-value<0.10 and I250%), the random-effects model was used (DerSimonian and Laird method) to calculate the pooled OR and 95%CI. Sensitivity analysis, removing one study and recalculation of the pooled OR, was conducted to verify the stability of the results. Begg's funnel plot, Begg–Mazumdar's test, and Egger's linear regression test were used to assess for publication bias. For geographic sub-analysis, initially, the studies were categories based on their country into Northern Africa, Sub-Saharan Africa, Latin America and the Caribbean, Northern America, Central Asia, Eastern Asia, South-eastern Asia, Southern Asia, Western Asia, Eastern Europe, Northern Europe, Southern Europe, Western Europe, or Oceania, according to United Nations M49 standard.26 Afterwards, the regions were group into Eastern Europe, Western Europe (Northern, Southern, and Western Europe), Latin America, Asian (Eastern and South-eastern Asia), and Middle East (Northern Africa, Southern and Western Asia). The Middle East category was based on the criteria that most countries identify as Arab and/or Muslim.27 All statistical analyses were conducted by using Comprehensive Meta-analysis v2 (Biostat, Inc., Englewood, New Jersey, USA). Unless noted otherwise, p-values <0.05 (two-sided) were considered statistically significant.

ResultsSelection of eligible studies

After duplicate removal, our literature search resulted in the recovery of 708 publications that focused on the association between the IL6 polymorphisms and patients with arthritis (Fig. 1). To note, 7 of the hand search articles were identified by the reference list, but the titles were originally in Chinese. After reviewing titles and abstract, 79 publications were considered for full-article examination. Of these publications, 24 were not case-control studies, 10 lacked sufficient data for analysis, 5 focused on the wrong pathology, and 7 were duplicate studies. Therefore, this meta-analysis contains 33 publications, which were divided between the −174 polymorphism (29 studies: cases=5920 and controls=6246), the −572 polymorphism (13 studies: cases=1973 and controls=1963), and the −597 polymorphism (6 studies: cases=1278 and controls=1524). The characteristics of the studies are presented in Table 1. 27.3% of the studies are from Asians countries: China,10,11,17,28–31 Taiwan,32 Japan.33 18.2% are from Eastern European countries: Russia,20,23 Czech Republic,34 Macedonia,35 Poland.18,36 24.2% are from Western European countries: Germany,37 Netherlands,12 Spain,38–40 Sweden41 and UK.42,43 21.2% are from the Middle East: Egypt,9,14,19 Iraq,22 India,15,44 and Turkey.8 Lastly, 3 studies are from Latin America.21,45,46 All the studies used the American College of Rheumatology criteria for RA diagnosis. For only the Pavkova et al. and the Lo et al. studies, the data was represented as allelic frequencies.32,34 Using the Newcastle-Ottawa scale, none of the studies were determined to contain significant study bias, but the Guseva et al. study9 and the Marinou et al. study9 could possible contain potential study bias. For the controls with respect to HWE, 5 studies for the −174 polymorphism,8,17,29,37,45 1 study for the −572 polymorphism,9 and 4 studies for the −597 polymorphism8,17,37,38 were determined to be not in agreement.

Fig. 1.

Flow chart for literature review of studies to be included in the meta-analysis.

(0.4MB).
Table 1.

Characteristics of included studies.

Study  Country (region)  RA criteria  Groupa  −174 G>Cb  −572 G>Cb  −597 G>Ab  NOSd 
Ad’hiah 2018Iraq(Middle East)ACRCases  –/–/–  1/3/47  –/–/–  8
Control  –/–/–  0/0/45  –/–/– 
Amr 2016Egypt(Middle East)ACRCases  44/46/9  26/64/9  –/–/–  7
Control  75/23/1  36/58/5 *  –/–/– 
Arman 2012Turkey(Middle East)ACRCases  95/62/21  143/31/4  97/59/22  8
Control  144/80/23 *  194/52/1  133/86/28 * 
Dahlqvist 2002Sweden(Western Europe)N/SCases  83/121/51  –/–/–  –/–/–  7
Control  57/103/38  –/–/–  –/–/– 
Dar 2017India(Middle East)N/SCases  20/8/6  –/–/–  –/–/–  7
Control  64/16/0  –/–/–  –/–/– 
de Souza 2014Brazil(Latin America)ACRCases  49/14/1  –/–/–  –/–/–  8
Control  29/12/7 *  –/–/–  –/–/– 
Emonts 2011Netherlands(Western Europe)ACRCases  146/133/56  –/–/–  –/–/–  7
Control  146/231/82  –/–/–  –/–/– 
Gaber 2103Egypt(Middle East)ACRCases  24/11/2  –/–/–  –/–/–  7
Control  9/1/0  –/–/–  –/–/– 
Gomes-Silva 2018Brazil(Latin America)ACRCases  68/50/2  –/–/–  –/–/–  8
Control  72/43/5  –/–/–  –/–/– 
Guseva 2016Russia(Eastern Europe)ACRCases  40/62/20  –/–/–  –/–/–  8
Control  85/162/54  –/–/–  –/–/– 
Guseva 2018Russia(Eastern Europe)N/SCases  97/22/1  –/–/–  –/–/–  6
Control  165/3/0  –/–/–  –/–/– 
Huang 2007China(Asia)ACRCases  97/22/1  4/15/101  –/–/–  8
Control  165/3/0  13/50/105  –/–/– 
Julia 2007Spain(Western Europe)ACRCases  –/–/–  –/–/–  115/112/31  8
Control  –/–/–  –/–/–  87/66/28 * 
Kobayashi 2009Japan(Asia)ACRCases  137/0/0  10/45/82  –/–/–  8
Control  108/0/0  8/40/60  –/–/– 
Li 2009China(Asia)ACRCases  48/11/1  52/6/2  –/–/–  8
Control  82/2/0  52/25/7  –/–/– 
Li 2014aChina(Asia)ACRCases  247/7/2  23/125/108  249/5/2  8
Control  329/1/1 *  41/152/138  330/0/1 * 
Li 2014bChina(Asia)ACRCases  613/124/15  –/–/–  –/–/–  8
Control  786/10/2 *  –/–/–  –/–/– 
Liu 2013China(Asia)N/SCases  –/–/–  12/36/39  –/–/–  8
Control  –/–/–  16/34/15  –/–/– 
Lo 2008cTaiwan(Asia)ACRCases  –/–/–  199: 87/311  –/–/–  8
Control  –/–/–  130: 33/227  –/–/– 
Lu 2009China(Asia)ACRCases  120/27/1  5/18/125  –/–/–  8
Control  118/2/0  9/36/75  –/–/– 
Marinou 2007UK(Western Europe)ACRCases  282/482/166  –/–/–  –/–/–  6
Control  154/226/80  –/–/–  –/–/– 
Palomino-Morales 2009Spain(Western Europe)ACRCases  127/144/40  –/–/–  –/–/–  8
Control  103/94/29  –/–/–  –/–/– 
Panoulas 2009UK(Western Europe)ACRCases  135/176/72  –/–/–  –/–/–  7
Control  148/211/63  –/–/–  –/–/– 
Pascual 2000Spain(Western Europe)ACRCases  75/72/16  –/–/–  –/–/–  7
Control  73/66/18  –/–/–  –/–/– 
Pavkova 2014cCzech Republic(Eastern Europe)ACRCases  144: 159/129  –/–/–  –/–/–  8
Control  200: 232/168  –/–/–  –/–/– 
Pawlik 2005Poland(Eastern Europe)ACRCases  26/53/19  –/–/–  –/–/–  8
Control  25/58/22  –/–/–  –/–/– 
Raafat Hamed 2018Egypt(Middle East)ACRCases  15/8/2  –/–/–  –/–/–  7
Control  25/0/0  –/–/–  –/–/– 
Schotte 2015Germany(Western Europe)ACRCases  17/24/9  46/4/0  17/24/9  7
Control  30/36/25 *  85/6/0  30/36/25 * 
Shafia 2014India(Middle East)ACRCases  122/27/1  –/–/–  –/–/–  8
Control  167/30/3  –/–/–  –/–/– 
Trajkov 2009Macedonia(Western Europe)ACRCases  38/30/16  –/–/–  38/33/13  7
Control  144/132/25  –/–/–  153/123/25 
Wielinska 2018Poland(Eastern Europe)ACRCases  40/65/25  –/–/–  –/–/–  7
Control  37/53/22  –/–/–  –/–/– 
You 2013China(Asia)ACRCases  431/21/0  38/191/222  418/31/3  8
Control  357/16/0  39/166/168  359/14/0 
Zavaleta-Muñiz 2013Mexico(Latin America)ACRCases  106/30/1  74/58/5  –/–/–  8
Control  80/20/2  62/37/3  –/–/– 

Abbreviations: ACR: American College of Rheumatology; N/S: not specified; NOS: New Castle-Ottawa Scale.

a

For the controls. HWE was calculated using ψ2-test. p<0.05 is not in agreement with HWE and indicated with an *.

b

The ratios are given as Wild type, heterozgotes, and homozygote mutant. For the −174 polymorphism, the G-allele is considered the Wild-type and C-allele as the mutant. For the −572 polymorphism, the G-allele is considered the Wild-type and C-allele as the mutant. For the −597 polymorphism, the G-allele is considered the Wild-type and A-allele as the mutant.

c

For the Lo 2008 study and the Pavkova 2014 study, the genotype distribution is represented as total number: Wild-type allelic frequency/mutant allelic frequency.

d

Score was calculated using Newcastle-Ottawa Quality Assessment Scale. A score <6 indicates high bias and indicated with an *.

The −174 polymorphism is associated with RA development

The ORs and 95%CIs were calculated for each study for all 5 genetic models (all Forest plots are available as supplement information). Using the selected studies, for the −174 polymorphism, there was significant heterogeneity for all the genetic models; therefore, the random-effects model was utilized (Table 2). When the studies were pooled together, the heterozygous (OR: 1.47, 95%CI: 1.13–1.91, p=0.004), dominant (OR: 1.50, 95%CI: 1.15–1.96, p=0.003), and allelic (OR: 1.38, 95%CI: 1.13–1.68, p=0.001) genetic models demonstrated a significant association. Removing one study did not change the association for any of the genetic models.

Table 2.

The association between IL-6 promoter polymorphism and the risk of developing Rheumatoid Arthritis.

      HeterogeneitybAssociationcPublication Biasd
Genetic model  Analysis  Na  Qp-value  I2 (%)  Model  OR  95% CI  p-Value  Begg  Egger 
-174 G>C
Heterozygous  Overall  27  <0.01  82  Random  1.47  1.13–1.91  0.004*  Tau=0.39, p<0.01*  Bias=2.78, p<0.01* 
Homozygous  Overall  26  <0.01  47  Random  1.13  0.88–1.44  0.337  Tau=0.12, p=0.39  Bias=0.67, p=0.14 
Dominant  Overall  27  <0.01  84  Random  1.50  1.15–1.96  0.003*  Tau=0.31, p=0.02*  Bias=2.87, p<0.01* 
Recessive  Overall  26  0.03  38  Random  1.12  0.92–1.37  0.270  Tau=0.09, p=0.49  Bias=0.49, p=0.23 
Allelic  Overall  28  <0.01  85  Random  1.38  1.13–1.68  0.001*  Tau=0.35, p<0.01*  Bias=2.73, p<0.01* 
-572 G>C
Heterozygous  Overall  11  0.17  29  Fixed  1.09  0.88–1.35  0.420  Tau=-0.09, p=0.70  Bias=-0.94, p=0.39 
Homozygous  Overall  11  0.21  24  Fixed  1.60  1.21–2.12  0.001*  Tau=-0.13, p=0.59  Bias=0.21, p=0.80 
Dominant  Overall  12  0.04  46  Random  1.21  0.90–1.63  0.208  Tau=0.09, p=0.68  Bias=-0.11, p=0.92 
Recessive  Overall  11  <0.01  68  Random  1.61  1.11–2.33  0.012*  Tau=-0.09, p=0.70  Bias=0.56, p=0.59 
Allelic  Overall  13  <0.01  79  Random  1.18  0.90–1.54  0.246  Tau=0.03, p=0.90  Bias=-0.46, p=0.75 
-597 G>A
Heterozygous  Overall  0.28  21  Fixed  1.20  0.96–1.51  0.115  Tau=0.47, p=0.19  Bias=1.91, p=0.09 
Homozygous  Overall  0.25  24  Fixed  1.10  0.79–1.55  0.575  Tau=0.33, p=0.34  Bias=1.13, p=0.32 
Dominant  Overall  0.15  38  Fixed  1.19  0.97–1.48  0.100  Tau=0.47, p=0.19  Bias=2.21, p=0.09 
Recessive  Overall  0.14  40  Fixed  1.03  0.75–1.42  0.854  Tau=0.33, p=0.34  Bias=1.21, p=0.35 
Allelic  Overall  0.02  61  Random  1.21  0.90–1.61  0.205  Tau=0.47, p=0.19  Bias=2.68, p=0.10 

Abbreviations: OR: Odds ratio; 95%CI: 95% confidence interval; and I2: Inconsistency Index.

a

N=number of studies included in analysis.

b

Depending on the level of heterogeneity, either Random Effects model or Fixed Effects model was used.

c

The pooled effect was calculated using Comprehensive Meta-analysis software v2.

d

Publication bias was assessed by Egger's bias test (Egger) and Begg and Mazumdar's correlation test (Begg).

*

p-Value<0.05 (two-tailed) were considered significant.

Publication bias was assessed by examining the funnel plot. The funnel plots demonstrated no significant asymmetry and the shape of the funnel plots suggested no evidence of publication bias (see Supplement information), even though some over-dispersion can be seen. No correlation was determined by the Begg-Mazumdar's test or bias by Egger's test for the homozygous and recessive genetic models (Table 2); however, there was the presence of publication bias for the heterozygous, dominant, and allelic genetic models (Begg–Mazumdar's test: p<0.01, Egger's test: p<0.01).

When the cohort was stratified by geographic region, for the Asian population, the −174 polymorphism did demonstrate a strong association for all the genetic models (Table 3). For Middle East countries, the −174 polymorphism showed an association for the heterozygous (OR: 2.30, 95%CI: 1.10–4.81, p=0.028), dominant (OR: 2.27, 95%CI: 1.22–4.22, p=0.010), and allelic (OR: 2.29, 95%CI: 1.24–4.23, p=0.008) genetic models. Interestingly, for Latin America, the −174 polymorphism demonstrated a protective benefit for the homozygous (OR: 0.26, 95%CI: 0.08–0.82, p=0.022) and recessive (OR: 0.25, 95%CI: 0.08–0.80, p=0.019) genetic models.

Table 3.

The association of the −174 G>C polymorphism on the development of Rheumatoid Arthritis, stratified by ethnicity.

      HeterogeneitybAssociationc
Genetic model  Analysis  Na  Qp-value  I2 (%)  Model  OR  95% CI  p-Value 
Asian
  Heterozygous  <0.01  86  Random  7.57  2.28–25.14  0.001* 
  Homozygous  0.91  Fixed  5.84  2.06–16.56  0.001* 
  Dominant  <0.01  87  Random  7.21  2.30–22.63  0.001* 
  Recessive  0.92  Fixed  5.04  1.78–14.28  0.002* 
  Allelic  <0.01  86  Random  6.60  2.26–19.28  0.001* 
Middle East
  Heterozygous  0.02  66  Random  2.30  1.10–4.81  0.028* 
  Homozygous  0.05  56  Random  3.42  0.94–12.42  0.062 
  Dominant  <0.01  72  Random  2.27  1.22–4.22  0.010* 
  Recessive  0.09  48  Random  2.69  0.83–8.66  0.098 
  Allelic  <0.01  79  Random  2.29  1.24–4.23  0.008* 
East Europe
  Heterozygous  0.93  Fixed  0.91  0.72–1.14  0.393 
  Homozygous  0.18  36  Fixed  1.09  0.81–1.49  0.562 
  Dominant  0.85  Fixed  0.94  0.75–1.17  0.581 
  Recessive  0.14  43  Fixed  1.15  0.88–1.51  0.307 
  Allelic  0.56  Fixed  1.03  0.90–1.18  0.650 
West Europe
  Heterozygous  0.01  63  Random  0.96  0.76–1.20  0.689 
  Homozygous  0.40  Fixed  0.99  0.82–1.18  0.876 
  Dominant  0.03  58  Random  0.95  0.77–1.16  0.606 
  Recessive  0.66  Fixed  1.03  0.87–1.21  0.759 
  Allelic  0.14  37  Fixed  0.99  0.90–1.08  0.732 
Latin
  Heterozygous  0.55  Fixed  1.09  0.75–1.57  0.664 
  Homozygous  0.48  Fixed  0.26  0.08–0.82  0.022* 
  Dominant  0.17  43  Fixed  0.94  0.66–0.35  0.750 
  Recessive  0.55  Fixed  0.25  0.08–0.80  0.019* 
  Allelic  <0.05  67  Random  0.77  0.44–1.34  0.353 

Abbreviations: OR: Odds ratio; 95%CI: 95% confidence interval; and I2: Inconsistency Index.

a

N=number of studies included in analysis.

b

Depending on the level of heterogeneity, either Random Effects (RE) model or Fixed Effects (FE) model was used.

c

The pooled effect was calculated using Comprehensive Meta-analysis software v2.

*

p-Value<0.05 (two-tailed) were considered significant.

The −572 polymorphism is associated with RA development

For the −572 polymorphism, the homozygous and heterozygous genetic models did not present with a significant level of heterogeneity and were analyzed using fixed-effects, whereas the rest of the genetic models were analyzed with random-effects. Only the homozygous (OR: 1.60, 95%CI: 1.21–2.12, p=0.001) and recessive (OR: 1.61, 95%CI: 1.11–2.33, p=0.012) genetic models demonstrated a positive association between the polymorphism and the risk of developing RA (Table 2). Removing the Li et al. study9 resulted in a significant positive association for the dominant genetic model (OR: 1.32, 95%CI: 1.08–1.63, p=0.008), none of the other studies had any effect. For the remaining genetic model, the results were resilient to any change from removing one study. No publication bias was determined by examining the Funnel plot, Egger's bias test, or by Begg–Mazumdar's correlation test.

When stratified by geographic region, it appears that the association was due to the inclusion of studies from the Asian population (Table 4). For the Asian population alone, there was an association between the −572 polymorphism and the development of RA for the homozygous (OR: 1.56, 95%CI: 1.16–2.09, p=0.004) and recessive genetic models (OR: 1.63, 95%CI: 1.08–2.45, p=0.020). No association was observed for the Middle East region.

Table 4.

The association of the −572 G>C polymorphism on the development of Rheumatoid Arthritis, stratified by ethnicity.

      HeterogeneitybAssociationc
Genetic model  Analysis  Na  Q p-value  I2 (%)  Model  OR  95% CI  p-Value 
Asian
  Heterozygous  0.09  46  Random  0.97  0.63–1.49  0.883 
  Homozygous  0.10  43  Fixed  1.56  1.16–2.09  0.004* 
  Dominant  <0.01  66  Random  1.23  0.74–2.05  0.416 
  Recessive  <0.01  78  Random  1.63  1.08–2.45  0.020* 
  Allelic  <0.01  86  Random  1.20  0.82–1.74  0.351 
Middle East
  Heterozygous  0.12  60  Random  1.08  0.58–2.01  0.806 
  Homozygous  0.39  Fixed  2.42  0.89–6.61  0.084 
  Dominant  0.27  24  Fixed  1.10  0.76–1.60  0.604 
  Recessive  0.11  54  Fixed  1.73  0.67–4.48  0.260 
  Allelic  0.15  46  Fixed  1.15  0.85–1.54  0.367 

Abbreviations: OR: Odds ratio; 95%CI: 95% confidence interval; and I2: Inconsistency Index.

a

N=number of studies included in analysis.

b

Depending on the level of heterogeneity, either Random Effects (RE) model or Fixed Effects (FE) model was used.

c

The pooled effect was calculated using Comprehensive Meta-analysis software v2.

*

p-Value<0.05 (two-tailed) were considered significant.

No association between the −597 polymorphism and RA development

For the −597 polymorphism, all the genetic models were analyzed with the fixed-effects model, except the allelic genetic model. When the studies were pooled together, there was no effect for any of the genetic models (Table 2). However, removing the Arman et al. study,8 a positive association for the heterozygous (OR: 1.33, 95%CI: 1.01–1.74, p=0.040) and dominant (OR: 1.30, 95%CI: 1.01–1.68, p=0.040) genetic models was observed. No publication bias was determined by examining the Funnel plot, Egger's bias test, or by Begg–Mazumdar's correlation test. No sub-analysis could be performed for the −597 polymorphism, due to the few studies.

Discussion

Some studies have shown that IL-6 serum levels are associated with the development of RA14; moreover, it has been postulated that the IL6 −174, −572, and −597 polymorphisms are associated with RA development. Here, we show that the −597 polymorphism does not promote RA development; however, the −174 and the −572 polymorphisms do indeed increase the risk of developing RA, especially in Asian and Middle East countries. Unexpectedly, the −174 polymorphism showed a protective effect for Latin American countries.

Previous meta-analyses have shown that the −174 polymorphism does augment the risk of developing RA, especially for Asian populations and not others.15–17,47 Our results also confirm this; however, we also found an effect for the −174 polymorphism with countries that are from the Middle East. When the genotype distributions were examined, it appeared that these Middle East and Asian populations had the lowest minor allele frequencies (10% and 1%, respectively), which were different from European populations (∼40%). Since the GG genotype is associated with higher serum IL-6 and incremental decreases in serum IL-6 were associated with each additional C-allele,48 this would suggest that a large portion of the Europe population would have lower IL-6 serum levels. However, serum IL-6 are also affected by many confounding factors. Serum IL-6 was shown to be affected by age, circadian rhythm, and stress as well as overweight or obesity patients present with elevated serum IL-6 when compared to normal weight subjects.49–52 Lastly, it is demonstrated that diets with phytoestrogens decrease serum IL-6,53 whereas, diet with increase carbohydrates or monounsaturated fat augment serum IL-6.54,55 Therefore lifestyle, diet, or other factors could significantly affect serum IL-6 level and mitigate the −174 polymorphism's effect associated with RA development.

There are many studies that show differences in the IL-6 serum levels is ethnic dependent. In African Americans, the production of IL-6 was higher compared to Cuban Americans.47 Whereas, in Hispanics, especially Mexicans, IL-6 production was demonstrated to be lower than other ethnicities.51 However, promoter polymorphisms have shown to increase the production of IL-6,14 but the prevalence of these polymorphisms varying significantly from region to region. For example, Gao et al. reported the prevalence of −174 polymorphism was less frequent in Asian Indian, Afro-Caribbean, Afro-American, and Asians.13

Here, we show that, for Latinos, the homozygous mutant of the −174 polymorphism was associated with a protective effect. The mechanism for this result remains elusive. Even though the −174 polymorphism was shown to increase IL-6 production, with a lower basal level, it is possible that the increases are insufficient to augment the risk of developing RA. Moreover, the quality of life and lifestyle in Latin American, which has not fully adopted the Western lifestyle, these confounding factors can mitigate the effect elevated IL-6 causes in developing RA. In support of this, it has been shown that the type of diet affects the production of IL-6 from muscle cells, which indirectly affects immune cell penetration of muscle tissue, promoting prolong IL-6 release.56 Diets, in which more carbohydrates are consumed, does mitigate the secondary IL-6 peak, caused by immune cells, after moderate exercise.57 Moreover, the more active the subject's lifestyle, the lower IL-6 production.58,59 In Latin American countries, it is possible that the lifestyle and quality of life does mitigate the effect the −174 polymorphism has on the development of RA in Latin American. This does posit that some factors such as lifestyle or diet in the presence of elevated IL-6 levels does sensitize a subject to an anti-inflammatory state, leading to the increased release of IL-6 and the development of RA; however, more studies are required to elucidated if the protective effect against RA development is connected to these confounding factors. In a review by Saavedra Ramirez et al., they eloquently explain the enigma of IL-6 in disease pathogenesis and present the possible switch between pro- and anti-inflammatory functions of IL-6.60

Three previous meta-analyses did examine for any associations between the −572 and −597 polymorphisms with RA development-one conducted in 2012, which used 2 and 1 studies, respectively, one in 2014, which used 6 and 2 studies, respectively, and one in 2019 that used 6 studies for the −572 polymorphism.17,47,61 Since then, numerous studies have examined the association and, in our study using 6 studies, we found no association between the −597 polymorphism and the development of RA. However, removing the Arman et al. study did indicate that an association could exist. Therefore, more research is required to deduce the association between RA and the −597 polymorphism.

For the −572 polymorphism, using 13 studies, we found that the homozygous mutant does increase the risk of developing RA; however, this result appears to be due the Asian population. This is in disagreement with the Li et al. meta-analysis17; however, we would say our study is in agreement with the Dar et al. meta-analysis,15 but their result was based-off of the Huang et al. study, which is included here. Recently, in 2019, a systematic review by Zhang et al., which solely focused on the −572 polymorphism, did determined that the polymorphism is associated with the risk of RA, specially the GG genotype.62 We believe that their study presents with similar results, but our study appears to be more inclusive. Here, we have 13 studies, whereas Zhang et al. only used 6 studies, of which all were included in our study, suggesting a possibility of publication/selection bias. Indeed, when we compared the results, we found that for their dominant model (our study's recessive model), the result did not concur, which highly suggests the presence of selection bias. Nevertheless, as we postulated, any effect observed was due to the Asian population and Zhang et al. confirmed our observation.62 However, it must be noted that Zhang et al.’s Asian population consisted of 3 studies, whereas our Asian population consisted of 8 studies. This would suggest that our results are more stable than Zhang et al. It could be expected that the Middle East region should have presented with an association; however, with the few studies included here, we could not determine this result.62

With our meta-analysis, some models presented with significant heterogeneity. We believe the cause could be due to the cases and controls, which were not matched by sex (majority of cases were women), age, or type of RA. In a previous study by Donn et al., in juvenile idiopathic arthritis, there was a significant difference in the ratio between systemic onset and enthesitis-related,63 thus indicating that the type of RA could be affected differently. Another cause could be the subject's ethnicity. Even though we performed an ethnic sub-analysis, genetic differences within a country can vary significantly, as indicated in China,64,65 Mexico,66 Brazil,67,68 and India.69 The diagnostic criteria used to identify or categorize RA could also act as a source of heterogeneity.

This study has a few limitations. First, as mentioned above, due to the large genetic variation within a country, more studies are required to determine specific effects, such as the protective benefit our results indicated for Latin Americans. Second, our results can only focus on overall risk of developing RA, and stage-specific effects (low, moderate, high or remission) cannot be determined. Third, we calculated crude ORs that were not adjusted.

Here, we show that the −174 polymorphism increased the risk of developing RA for Asians and Middle East populations; interestingly, there was a protective effect for Latinos. As for the −572 polymorphism, only the Asian population was associated with an increased risk of developing RA. No affect was observed for the −597 polymorphism.

Conflicts of interests

The authors declare that they have no conflicts of interests to report.

Acknowledgements

We would like to express their gratitude to Mtro. Ricardo Villegas Tovar, Coordinator of Scientific Production and International Visibility, Benemérita Universidad Autónoma de Puebla. Moreover, we would like to thank Dr. Solbritt Rantapää Dahlqvist, Dr. Irina Anatolyevna Guseva, Dr. Anthony G Wilson, and Dr. Heiko Schotte for their prompt replies to our emails and the sharing of the data to allow a more conclusive analysis between IL6 promoter polymorphisms and the development of RA. This study was supported by grants from the Vicerrectoría de Investigación of Benemérita Universidad Autónoma de Puebla (10051909-VIEP2018 to MEGM and 100170644-VIEP2018 to RPF. 100493499-VIEP2018 to ETR).

Appendix A
Supplementary data

The following are the supplementary data to this article:

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Both authors contributed equally.

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