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Egyptian Journal of Medical Human Genetics
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Genetic variations in PADI4 and CCR6: a comprehensive meta-analysis on rheumatoid arthritis susceptibility

Egyptian Journal of Medical Human Genetics volume 25, Article number: 108 (2024) Cite this article

Abstract

Background

Rheumatoid arthritis is a long-term autoimmune condition that causes damage and inflammation to the joints. Genetic factors, including polymorphisms in the PADI4 and CCR6 genes, contribute significantly to RA susceptibility.

Methods

To find research on RA, PADI4, CCR6, gene polymorphisms, and SNPs, we performed a meta-analysis using PubMed, Scopus, Medline, Google Scholar, and EMBASE. Inclusion criteria comprised case–control studies providing genotypic data and allele frequencies. Review Manager 5.4 was used to conduct statistical analysis and evaluate odds ratios with 95% confidence intervals.

Results

Heterogeneity analyses of CCR6 rs3093024 showed no significant associations across genetic models: allele (OR = 0.69, 95% CI [0.36–1.32]), homozygous (OR = 2.18, 95%CI [0.58–8.22]), heterozygous (OR = 0.60, 95% CI [0.31–1.16]), dominant (OR = 1.60, 95% CI [0.64–3.95]), and recessive (OR = 1.79, 95% CI [0.75–4.27]). Similarly, PADI4 rs1748033 and rs2240340 showed insignificant associations across all genetic models.

Conclusion

This meta-analysis identifies a substantial relationship between CCR6 rs3093024 and RA susceptibility in Asian populations. However, heterogeneity analyses indicate inconsistent associations for PADI4 rs1748033 and rs2240340 across different populations and genetic models, suggesting varied genetic influences. Further large-scale studies are required to confirm these results and investigate the complex genetic and environmental interactions underlying RA pathogenesis.

Introduction

Rheumatoid arthritis (RA) is like a relentless invader in the body, causing persistent inflammation that slowly chips away at the joints, leading to deformity, disability, and, in extreme cases, even threatening life itself [1]. As our global population ages, RA is on the rise. Given the considerable mortality and morbidity associated with RA, individuals affected by it often experience a diminished quality of life, placing a substantial economic burden on society [2]. It is an intricate condition influenced by genetic, environmental, and unpredictable factors. This widespread ailment is found across the globe, affecting approximately 0.5% to 2% of the inhabitants, with a higher occurrence observed in females, smokers, and individuals with a family history of the disease [3]. While there is currently no cure for rheumatoid arthritis, individuals grappling with this condition are compelled to rely on long-term medication to manage and alleviate their symptoms effectively [4]. The development of RA is believed to stem from a complex interplay of genetic, epigenetic, environmental, metabolic, immunological, and microbial factors. Extensive research has been conducted to explore the connections between genetic, epigenetic, metabolic, and microbiological variables concerning RA [5]. Earlier studies have uncovered that approximately 50–65% of the risk of emerging RA can be attributed to hereditary factors [6]. Over the last decade, genome-wide associations (GWAS) have identified approximately 150 susceptibility loci linked to the consequence of emerging RA [7]. In addition to the well-recognized human leukocyte antigen (HLA) locus, which is a recognized genetic risk aspect for RA, several other susceptibility genes and loci have been identified and illustrated [8]. Despite family studies indicating that human leukocyte antigen (HLA) alleles contribute to approximately 30% of genetic susceptibility, it is essential to note that non-HLA loci are also associated with RA [9].

Research has established a connection between single-nucleotide polymorphisms (SNPs) in the peptidyl arginine deiminase 4 (PADI4) gene and the chance of acquiring RA, extending beyond the influence of the HLA gene [10]. PADI4 is an enzyme that plays a crucial role in transforming arginine residues within proteins into citrulline through post-translational modifications of proteins [11]. Inside our bodies, the PADI4 gene plays a vital role by providing instructions for the PAD4 enzyme. This enzyme works after protein translation, converting arginine residues to citrulline. In the context of RA, important markers like ACPA antibodies and rheumatoid factor (RF) help in diagnosis. Notably, antibodies against PAD4, known as anti-PAD4 antibodies, target this enzyme and are linked to more challenging outcomes in the course of the disease [12]. Earlier studies have identified a correlation between SNPs in the PADI4 gene and an increased vulnerability to RA in Asian populations. However, findings among Caucasians have been inconsistent and inconclusive [13]. Numerous studies conducted in East Asian, German, and North American populations have consistently affirmed the correlation between SNPs in the PADI4 and the chance of developing RA [14,15,16]. In 2013, researchers conducted a thorough review combining studies from both Egyptian and Chinese populations. The findings from this analysis pointed to a notable association between certain variations in the PADI4 gene and an elevated risk of developing RA [17]. In Southeast Iran, a study on people with RA discovered that a particular genetic variant, PADI4 rs1748033, was linked to a greater risk of acquiring the condition [18]. PADI4 has an ACPA-positive SNP (rs2240340) located in intron 3 that was found to have the highest correlation with RA susceptibility [19]. We decided to delve deeper into the intronic SNP rs2240340 (PADI4) because it had already been extensively investigated in previous studies examining its connection to RA [20].

Recently, three separate genome-wide association studies (two involving Asian populations and one with European populations) have distinguished the chemokine (C–C motif) receptor 6 gene (CCR6) as a vulnerability locus for RA [21, 22]. Situated on chromosome 6 (6q27), the CCR6 gene is responsible for encoding a protein known as C–C chemokine receptor type 6, consisting of 374 amino acids. One of the genes demonstrating an assuring part in the development of RA is the CCR6 gene [23]. Immature dendritic cells and memory T-cells express this gene, which also takes a vital part in the maturation and differentiation of B-cells [24]. Kochi and team, using a comprehensive genome-wide approach, pinpointed a specific variation (rs3093024) in the CCR6 gene. This genetic tweak was found to be linked to the likelihood of developing RA, adding valuable insights to our understanding [25].

Methodology

Literature search

Electronic databases, including PubMed, Scopus, Medline, EMBASE, and academic search engines like Google Scholar, conducted an exhaustive literature search. The search criteria included RA, PADI4, CCR6, gene, polymorphism, SNPs, and genetic variations. The meta-analysis investigation involves a thorough assessment of relevant references to analyze data, considering predetermined inclusion and exclusion criteria. Only English-language articles were included in this survey.

Inclusion and exclusion criteria

The studies that may be included in the meta-analysis were selected based on the following inclusion criteria: The chosen studies required to focus on the relationship between the PADI4 and CCR6 genes and RA, have a case–control or probable study design, provide genotype and allele frequency for calculating the odds ratio (OR), and have reliable 95% confidence intervals (CIs) and p values. To assess the value of case–control analysis and interpret the findings of the meta-analysis, the Newcastle–Ottawa Scale (NOS) was utilized. Research that did not match the specified criteria or had inadequate data was not taken into account.

Data extraction

In compliance with the inclusion criteria, the investigators methodically gathered pertinent articles and standardized the data extraction process. A thorough review of the available publications was carried out to obtain information on allelic and genotypic frequencies of both case and control participants. When genotypic data was not supplied extensively, it was generated from existing data, like allelic frequencies. Studies that were unable to gather meaningful information from both groups were eliminated. The extracted data from each study includes the PUBMED ID, study design, publication year, first author name, sample size, ethnicity, Hardy–Weinberg equilibrium (HWE) score, language, and other relevant information.

Statistical analysis

The data was assessed using Review Manager 5.4 software, with a statistical consequence threshold of p < 0.05 for each genetic variant. These techniques and methods are essential for carrying out thorough meta-analyses of genetic connections, evaluating the clinical significance of genetic variations, and guaranteeing strong statistical power and impact testing in the context of extensive genetic discoveries. Using the Chi-square-based Q statistic test, which is determined by the I2 metric value, heterogeneity assumptions from earlier studies were investigated; a p value of less than 0.1 was shown to be considerable. The random effect model was utilized in earlier studies to assess the OR, accompanied by 95% CI. To assess the depth of the connection between gene polymorphism and RA, we created a forest plot illustrating the total OR along with 95% CI. A funnel plot was also used to examine possible publication bias in the meta-analysis [26].

Results

Following strict inclusion and exclusion criteria, the study choice and evaluation process is fully illustrated in Figs. 1 and 2. The studies' features were displayed, along with their NOS score, and comprehensive details on allelic frequency, genotype distribution, and HWE/Chi-square values for the selected polymorphisms were given (Tables 1, 2 and 3).

Fig. 1
figure 1

Selection of studies on CCR6 gene polymorphism and its association with RA

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Fig. 2
figure 2

Selection of studies on PADI4 gene polymorphism and its association with RA

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Table 1 The studies associating the CCR6 gene with RA
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Table 2 Studies on the association between the PADI4 (rs1748033) gene and RA
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Table 3 Studies on the association between the PADI4 (rs2240340) gene and RA
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The heterogeneity analysis of CCR6 (rs3093024) polymorphism shows an insignificant association between all the genetic models in allele (I2 = 98%) OR = 0.69 (95% CI [0.36–1.32]), p = 0.26; homozygous (I2 = 98%) OR = 2.18 (95% CI [0.58–8.22]), p = 0.25; heterozygous (I2 = 94%) OR = 0.60 (95% CI [0.31–1.16]), p = 0.13; dominant (I2 = 98%) OR = 1.60 (95% CI [0.64–3.95]), p = 0.31; and recessive (I2 = 97%) OR = 1.79 (95% CI [0.75–4.27]), p = 0.19, (i.e., p =  > 0.05).

The heterogeneity analysis of PADI4 (rs1748033) polymorphism shows an insignificant association between all the genetic models, in allele (I2 = 97%) OR = 0.62 (95% CI [0.36–1.08]), p = 0.09; homozygous (I2 = 81%) OR = 1.48 (95% CI [0.84–2.62]), p = 0.18; heterozygous (I2 = 84%) OR = 0.74 (95% CI [0.39–1.41]), p = 0.36; dominant (I2 = 98%) OR = 2.04 (95% CI [0.77–5.38]), p = 0.15; and recessive (I2 = 85%) OR = 1.32 (95% CI [0.75–2.33]), p = 0.33, (i.e., p =  > 0.05) (Fig. 3).

Fig. 3
figure 3

The Circos plot visualizes chromosomal interactions involving the rs3093024 SNP

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The heterogeneity analysis of PADI4 (rs2240340) polymorphism shows an insignificant association between all the genetic models, in allele (I2 = 95%) OR = 1.13 (95% CI [0.75–1.69]), p = 0.57; homozygous (I2 = 96%) OR = 1.12 (95% CI [0.47–2.64]), p = 0.80; heterozygous (I2 = 97%) OR = 1.16 (95% CI [0.49–2.79]), p = 0.73; dominant (I2 = 95%) OR = 1.15 (95% CI [0.65–2.05]), p = 0.63; and recessive (I2 = 98%) OR = 1.03 (95% CI [0.41–2.57]), p = 0.95, (i.e., p =  > 0.05). As seen in Figs. 4, 5 and 6, Begg's and Egger's tests were performed, and no evidence of publication bias was found in this study.

Fig. 4
figure 4

A forest plot illustrating the genetic model's relationship between RA and the CCR6 gene polymorphism

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Fig. 5
figure 5

Forest plot illustrating the genetic model's relationship between RA and the polymorphism of the PADI4 gene. rs1748033 in a and rs2240340 in b

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Fig. 6
figure 6

Funnel plot representing publication bias in the relationship between CCR6 and PADI4 gene polymorphisms and RA across genetic models: a rs3093024, b rs1748033, and c rs2240340

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Protein–protein interaction

The STRING database (version 11.0; https://string-db.org/) can predict functional proteins and PPIs associated with rheumatoid arthritis and gene polymorphisms of CCR6 and PADI4 with a PPI score of at least greater than or equal to 0.4. (Fig. 7).

Fig. 7
figure 7

The differentially expressed genes (DEGs) in the network of protein–protein interactions (PPI) among the chosen genes are linked to RA

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Discussion

Rheumatoid arthritis is an inflammatory condition characterized by joint damage and disability resulting from the destruction of synovial joints. About 60% of the risk for progressing RA is believed to be inherited, with the remaining 40% likely influenced by environmental and other factors [10]. The findings from this meta-analysis provide valuable insights into the genetic factors contributing to RA susceptibility. The correlation between PADI4 and CCR6 gene polymorphisms and RA risk underscores the intricate interplay between genetic and immunological factors in the pathogenesis of RA. On chromosome 6 (6q27), the CCR6 gene codes for a protein known as C–C chemokine receptor type 6, which consists of 374 amino acids [23]. The first involvement study of CCR6 rs3093024 with RA was performed on the Pakistani cohort, revealing a substantial correlation between this SNP and RA [27]. In the Iraqi population, the analysis of SNP rs3093024 within the CCR6 gene indicated that none of the alleles or genotypes were linked to susceptibility to RA disease [28]. In a study conducted in Japan, an association between CCR6 rs3093024 and RA, along with several autoimmune disorders, was observed [25]. A necessary step would be to conduct a multicentre cohort study in Asia aimed at elucidating the biological impact of CCR6, particularly concerning gender. This study revealed that the CCR6 polymorphism acted as a risk factor among females but exhibited a protective effect among males [29]. In a Taiwanese population, an important link was identified between the genotype of CCR6 (rs3093024) and susceptibility to RA [30].

PADI4, located on the 1p36 region, catalyzes the citrullination process, converting arginine to citrulline residues and producing citrullinated proteins. This leads to a reduced immune response, initiating the production of anti-CCP, a critical diagnostic marker widely located in the synovial fluids and tissues of patients with RA [31]. Findings from a study in Pakistan revealed a significant association, indicating that the rs1748033 and rs2240340 genotypes of the PADI4 gene are linked to an increased risk of RA [32]. The rs1748033 SNP in the PADI4 gene demonstrated an association with an elevated predisposition to rheumatoid arthritis in an Iranian population [33]. A strong association was observed between PADI-4 gene polymorphism and the occurrence of both RA and osteoarthritis (OA) in the Pakistani population [34]. The study demonstrates that there is no association between the intensities of anti-PAD4 antibodies and the prevalence of genotypes for both SNPs, rs2240340 and rs1748033, under diverse genetic models (dominant, codominant, over dominant, and recessive) [35]. Compelling evidence from a study suggests that polymorphisms in PADI4, specifically rs1748033, may influence the risk of RA in the Egyptian inhabitants [36]. A considerable relationship was discovered between the PADI4 rs1748033 variant and vulnerability to RA in the population of southeast Iran [18]. The study offered compelling evidence that PADI4 polymorphisms play a significant role in contributing to RA susceptibility, particularly in cases of anti-CCP positive RA severity in the Chinese Han population [37]. The study results imply that PADI4 polymorphisms do not have a vital part in the progress of RA within the Chinese Han population [38]. The PADI4 (rs2240340) polymorphisms were found not to be a risk factor for patients with RA in Algeria, as revealed by the study [39]. The study unveiled an involvement between the PADI4 (rs2240340) T allele and the T/T genotype with ACPA-positive RA in the population of Kazakhstan [40]. The study confirmed that polymorphisms connecting the PADI4 gene, the significant aspect of citrullination, also appeared in the Polish RA population [41]. Strong evidence was provided by the study that functional polymorphisms of PADI4 rs2240340 G/A may influence the risk of RA in the Chinese population [42]. A cohort in the Caucasian population found that there was no considerable link between the SNP rs2240340 and RA [43]. The chromosomal interactions with the rs3093024 SNP are represented by a Circos plot for visualizing the complete data by the 3DSNP tool in Fig. 3.

Conclusion

In conclusion, this study explored the genetic associations between RA susceptibility and polymorphisms in the PADI4 and CCR6 genes. The results contribute to a beneficial understanding of the intricate interaction between genetic and immunological factors in the pathogenesis of RA. The study identified a considerable association between the CCR6 polymorphism (rs3093024) and RA vulnerability in Asian populations, highlighting the possible role of this gene in the development of RA. However, heterogeneity analyses revealed insignificant associations in various genetic models, indicating the need for further investigation and replication studies to validate these findings. Regarding the PADI4 gene, specifically the polymorphisms rs1748033 and rs2240340, the heterogeneity analyses for PADI4 polymorphisms demonstrated inconsistent associations across different genetic models, suggesting diverse genetic influences in various populations. The study underscores the importance of considering genetic variations in both PADI4 and CCR6 genes when evaluating RA susceptibility. However, since RA is complex and influenced by genetic, environmental, and immunological factors, it warrants further research and replication studies on a large scale to validate the associations across various populations. It is essential to acknowledge the limitations of this meta-analysis, including the potential for publication bias and the heterogeneity observed in specific analyses. Even with these limitations, the study delivers a comprehensive summary of the current evidence on PADI4 and CCR6 gene polymorphisms in RA susceptibility, guiding future research directions in understanding the genetic basis of this complex autoimmune disease.

Availability of data and materials

Not applicable.

Abbreviations

RA:

Rheumatoid arthritis

ORs:

Odds ratios

CIs:

Confidence intervals

HLA:

Human leukocyte antigen

SNPs:

Single-nucleotide polymorphisms

PADI4 :

Peptidyl arginine deiminase 4

RF:

Rheumatoid factor

CCR6 :

Chemokine (C–C motif) receptor 6

NOS:

Newcastle–Ottawa Scale

HWE:

Hardy–Weinberg equilibrium

PPI:

Protein–protein interaction

ACPA:

Anti-citrullinated peptide antibody

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Acknowledgements

Thanks are due to the Chettinad Academy of Research and Education for their continuous support and encouragement.

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  1. Human Cytogenetics and Genomics Laboratory, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, Tamilnadu, 603103, India

    Jethendra Kumar Muruganantham, Sheena Mariyam Thomas, Iyshwarya Bhaskar Kalarani & Ramakrishnan Veerabathiran

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  1. Jethendra Kumar Muruganantham
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  2. Sheena Mariyam Thomas
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  3. Iyshwarya Bhaskar Kalarani
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  4. Ramakrishnan Veerabathiran
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JM, SMT, and IBK wrote the contents, edited the figures and tables of this manuscript.

RV designed the study, edited the contents of this manuscript, and approved the manuscript for submission. “All authors read and approved the final manuscript.”

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Correspondence to Ramakrishnan Veerabathiran.

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Muruganantham, J.K., Thomas, S.M., Kalarani, I.B. et al. Genetic variations in PADI4 and CCR6: a comprehensive meta-analysis on rheumatoid arthritis susceptibility. Egypt J Med Hum Genet 25, 108 (2024). https://doi.org/10.1186/s43042-024-00550-1

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