Association Of Chemokine/Chemokine Receptor Single Nucleotide Polymorphisms With Systemic Lupus Erythematosus

Objective:Systemic lupus erythematosus (SLE) is a chronic and systemic autoimmune disease characterized by immune dysregulation that results in diverse clinical features and polyorgan involvement. Chemokines and chemokine receptors play important roles in the process of immune response and inflammation. According to the former studies, chemokine CCL2, CCL5 and CXCL12 are involved in the pathogenesis of SLE through binding to their specific receptors CCR2, CCR5 and CXCR4. Since the expression level of chemokines and their receptors is regulated by gene polymorphisms, we investigated the influence of the single nucleotide polymorphisms of chemokine CCL2, CCL5, CXCL12 and chemokine receptors CCR2, CCR5 upon disease susceptibility in SLE.Methods:298 patients with SLE and 243 healthy controls were enrolled in this study in a Han Chinese population. The single nucleotide polymorphisms of CCL2-2518A/G (rs1024611), CCR2-G190A(rs 1799864), CCL5-28C/G (rs1800825), CCR5-59029G/A (rs1799987) and CXCL12-3' G801A (rs1801157) were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The plasma levels of CCL2 and CXCL12 were also analyzed in a subset of SLE patients and healthy subjects.Results:A detailed analysis of the distributions of above chemokines and chemokine receptor gene polymorphisms in SLE patients and healthy controls was conducted, and we found that:(1) The distributions of CCL2-2518 A/G, CCR2-G190A, CCL5-28C/G, CCR5-59029 G/A and CXCL12-3'G801A alleles and genotypes were all in Hardy-Weinberg equilibrium for the SLE group and the control group.(2) CXCL12-3'G801A polymorphism is involved in the susceptibility of SLE, G/G homozygote is more common in the SLE group(x2=5.876, P=0.015), while G/A genotype is significantly more common in HC group(x2=6:930, P=0.008). There is no association of CCL2-2518 A/G, CCR2-G190A, CCL5-28C/G, CCR5-59029 G/A with susceptibility of SLE.(3) CCL2-2518 A/G polymorphism is associated with the occurrence of renal damage. SLE patients carrying G/G homozygote are more prone to develop lupus nephritis (LN) (x2=6.538, P=0.038), paralleling with significantly higher levels of plasma CCL2 (F=3.252, P=0.042).(4) As for CCR2-G190A polymorphism, SLE patients carrying A allele had higher prevalence of antibodies against dsDNA (x2=7.065, P=0.029), histone (x2=11.555, P=0.003), nucleosomes (x2= 10.626, P=0.005) and SSB(x2=13.910,P=0.001).(5) SLE patients with CXCL12-3'G801A G/G homozygote were more prone to develop photosensitivity (x2=12.766, P=0.002), renal damage(x 2=6.865, P=0.032) and to produce anti-dsDNA antibody (x2=8.247, P=0.016), anti-nucleosomes antibody (x2=9.351, P=0.009), whereas the prevalence of anti-U1-snRNP(x2=5.305, P=0.070) antibody and anti-Sm antibody(x2=8.192, P=0.017) is significantly lower.Conclusion:Our study support that CXCL12-3' G801A polymorphism as a genetic factor influencing systemic lupus erythematosus susceptibility and clinical features. CCL2-2518 A/G and CCR2-G190A polymorphism may involve in the process of organ involvement and auto-antibodies production in SLE.