Background Rheumatoid arthritis (RA) is a chronic, autoimmune disease characterized by hyperplasia and inflammatory changes within the synovium. The recruitment and accumulation of monocytes in the synovium contribute to inflammatory response and bone destruction. Fractalkine (FKN) is a chemotactic cytokine that promotes monocyte transmigration and adhesion. The CX3C chemokine receptor 1 (CX3CR1) is a chemotactic and adhesion receptor for FKN. Both are highly expressed in human RA3. Two missense, conservative single nucleotide polymorphisms (SNPs) located in the sixth and seventh transmembrane domains of CX3CR1 affect FKN binding to peripheral blood mononuclear cells (PBMCs) (rs3732379 (G/A = V249I) and rs3732378 (C/T = T280M), respectively)1,2. FKN binding to PBMCs is significantly reduced in patients with coronary artery disease heterozygous for rs3732379 and in human immunodeficiency virus (HIV) positive patients homozygous for the rs3732379 variant allele1,4. Moatti et. al., suggested that the rs3732379 variant allele may contribute to reduced CX3CR1 expression and monocyte chemotaxis4.
Objectives Association analysis between two CX3CR1 SNPs, rs3732378 and rs3732379, and RA susceptibility in a Caucasian case control cohort.
Methods Cases (n=384) were selected based upon an established diagnosis of RA. Recruitment took place at Cork University Hospital (CUH) and Kerry General Hospital, Ireland. Age-matched controls (n=483) were selected from the Osteoporosis Genetics Database that was generated in the Bone Densitometry Unit, CUH for osteoporosis genetics studies. Genomic DNA was extracted from whole blood using the MagNA Pure LC instrument. All genotyping was performed blind to case control status by KBioscience. SPSS and PLINK were used for statistical analysis.
Results The genotype distributions did not deviate from Hardy Weinberg Equilibrium (HWE) (P >0.05). CX3CR1 SNPs were in strong but incomplete linkage disequilibrium (LD) (D’ =1.0, r2 =0.53). Significant association was observed between rs3732379 and RA risk under a dominant model for the minor allele following 1000 permutations (AA+AG vs GG; OR: 1.18 (95% CI, 1.18 – 1.36); P =0.017). There was a higher frequency of AA or AG carriers in the controls (53.6%) versus the cases (45.4%). There was a higher frequency of rs3732379 A alleles in the controls (31.0%) versus cases (26.6%), however, this was not significant (OR: 0.81, (95% CI, 0.65-1.00); P =0.055). No association was observed between rs3732378 and RA risk (P >0.05). There was no association observed between CX3CR1 haplotypes and RA risk (P >0.05).
Conclusions Individuals with one or more copies of the rs3732379 variant allele had a significantly reduced risk of RA compared to individuals that were homozygous for the wild-type allele. Monocyte recruitment and adhesion to the synovium contributes to the RA phenotype and is influenced by FKN binding to CX3CR1. FKN binding to CX3CR1 in rs3732379 allele specific RA patients will need to be investigated following an independent replication of these association results.
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Disclosure of Interest None Declared
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