Haplotype Synergism of MACIR Gene Polymorphisms Reveals a 'Flip-Flop' Phenomenon Driving Rheumatoid Arthritis Susceptibility in an Iraqi Population"

Abstract

Background: "Rheumatoid arthritis (RA) is a systemic autoimmune pathology driven by intricate genetic predispositions and chronic synovial inflammation. The macrophage immunometabolism regulator MACIR gene, also known as (C5orf30), has emerged as a key regulator of macrophage-mediated synovial inflammation. This study investigated the association of MACIR gene polymorphisms (rs26232 and rs26233) with RA susceptibility in an Iraqi cohort, focusing on genetic inheritance models and haplotype synergism.
Methods: A case-control study was conducted involving 90 participants (45 newly diagnosed RA patients and 45 healthy controls). Precise genotyping was performed using bidirectional PCR-Sanger sequencing. Genetic associations were evaluated across multiple inheritance models (co-dominant, dominant, and recessive). Linkage disequilibrium (LD) and haplotype frequencies were estimated to determine the combined allelic impact.
Multivariable logistic regression was utilized to calculate adjusted odds ratios (AOR), controlling for potential demographic confounding factors.
Results: High-resolution mapping revealed an exceptionally strong linkage disequilibrium between rs26232 and rs26233 (D' = 0.97, r2 = 0.85), identifying a stable "genetic block" in the Iraqi population. The T allele for both SNPs was identified as the primary risk variant (p < 0.001). Under the co-dominant model, the homozygous mutant TT genotype conferred a 6.93-fold increase in RA risk for rs26232 and a 10.74-fold increase for rs26233. Haplotype analysis confirmed that the T-T haplotype significantly amplified disease susceptibility (OR = 4.134, p < 0.001), while the C-G haplotype exhibited a robust protective effect (OR = 0.304).
Conclusion: Our findings establish the MACIR gene, TT genotype and T-T haplotype as potent genetic markers for RA in Iraq. The identification of the T allele as a risk factor-contrary to some Western studies-highlights a significant "flip-flop" phenomenon and underscores the necessity of population-specific genetic screening for personalized medicine in the Middle East.