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(ΔG) 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.
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