ICOS Gene Polymorphism and Serum Soluble ICOS Level as Genetic and Serological Correlates of Disease susceptibility in Iraqi Patient with Systemic Lupus Erythematosus

Abstract

Background: Systemic lupus erythematosus (SLE) is multifactorial disease arising from breakdown of peripheral immune tolerance, culminating in pathogenic autoantibody production and immune-complex mediate tissue injury. Inducible T-cell Co-Stimulator (ICOS, CD28), a CD28-family co-stimulatory receptor expressed predominantly on activated and follicular helper T (Tfh) cells is central to T-cell B-cell collaboration within germinal centers and has been implicated in the excessive humoral immunity characteristic of SLE. Whether genetic variation at the ICOS locus translates into altered circulating ICOS protein and, in turn, into susceptibility to and severity of SLE remains incompletely defined, particularly in middle-eastern population.
Methods/Objectives: This case-control study aimed to quantify serum soluble ICOS by ELISA and to charcharis ICOS exon-5 single nucleotide polymorphism (rs78281070, rs10172036, rs10183087) by sanger sequencing in Iraqi SLE patient and matched healthy control, and to evaluate the relationship between genotype, serum sICOS concentration and clinical/serological indices of disease.
Result/Discussion: Serum sICOS was markedly elevated in patient relative to control (202.8 ± 10.4 vs 88.9 ± 1.8 pg/mL; P = 0.0001) and discriminated the two groups with high accuracy (AUC=0.92). sICOS correlated inversely with anti-dsDNA, Consistent with a state of net T-cell co-stimulator hyperactivation with impaired counter-regulation. Although individual SNP genotype and allele frequencies did not differ significantly between groups, haplotypes analysis identified a risk associated ATT Haplotype (OR = 2.47, P = 0.047) and protective AGT haplotype (OR = 0.23, P = 0.015), with disease-restricted deviation from Hardy-Wennberg equilibrium at two loci, suggesting that ICOS locus haplotype architecture, rather than any single variant, shapes the serological.
Study Limitation: due to high the high cost associated with sanger sequencing, Genotyping of the ICOS gene polymorphism was restricted to a subset of 40 participant (20 SLE patient and 20 healthy controls
Conclusion: Serum sICOS behaves as a robust, disease-intrinsic biomarker of IOCS/ICOS-L pathway hyperactivation in SLE and show excellent discriminative capacity, while ICOS haplotype architecture offers a plausible though preliminary, genetic substrate for this phenotype. Together, this finding positions the ICOS gene and its soluble protein products as a dual genetic-serological axis with diagnostic and potential therapeutic relevance in lupus, warranting validation in larger, ethnically matched cohorts.