Meta-analysis for Association of Interleukin 4 VNTR Polymorphism with Rheumatoid Arthritis Risk and Severity

Rheumatoid Arthritis (RA) is a chronic autoimmune disease characterized by severe joint pain. There are conflicting results for the association of Interleukin 4 (IL4) variable number tandem repeats (VNTR; rs8179190) polymorphism with RA. Therefore, we performed a meta-analysis of the available studies to investigate the association of IL4 VNTR polymorphism with RA risk and severity in the overall populations and Asian, Egyptian, European, and Turkish ethnicities by sub-group analyses. Eight studies involving 1993 RA patients and 1732 controls were included in this meta-analysis. We found increased RA risk for the susceptible R2R2 genotype and R2 allele under heterozygous, recessive, and allelic models in the Asian populations (p < 0.00001, p < 0.0001, p = 0.001). We observed a significant association between R2R2 genotype and R2 allele for RA protection in the Turkish population under heterozygous, recessive, and allelic models (p = 0.01, p = 0.004, p = 0.002). Disease severity-based analysis revealed significant association for R2R2 genotype and R2 allele with RA severity under homozygous, heterozygous, recessive, dominant, and allelic models(p = 0.0004, p = 0.03, p = 0.02, p = 0.003, p = 0.01), specifically in Asian populations (p = 0.009, p = 0.02, p = 0.003, p = 0.03, p = 0.01) and under heterozygous, dominant, and allelic genetic models in Egyptian (p = 0.0001, p < 0.0001, p < 0.0001) and European (p = 0.002, p = 0.0007, p = 0.0006) populations. In silico analysis suggested that the susceptible R2 allele changes the RNA secondary structure to a stable form by changing minimum free energy(Delta G) from - 115.20 to - 136.40 kcal/mol, which might lead to increased stability of IL-4 in RA patients. Overall, the meta-analysis suggests for the involvement of susceptible R2 allele with RA risk in the Asian populations, RA severity in the overall populations (specifically in Asian, Egyptian, & European populations), and RA protection in the Turkish population.

Automated summary

This study investigated the association of Interleukin 4 (IL4) variable number tandem repeats (VNTR) polymorphism with Rheumatoid Arthritis (RA) risk, severity, and protection through a meta-analysis. The results showed that the R2R2 genotype and R2 allele of IL4 VNTR were associated with increased RA risk in Asian populations and with RA protection in Turkish populations. Additionally, the R2R2 genotype and R2 allele were significantly associated with RA severity in different populations.