Abstract
Dysfunction in various parts of immune defence, such as immune response, immune complex clearance, and inflammation, has an impact on pathogenesis in systemic lupus erythematosus (SLE). We hypothesised that combinations of common variants of genes involved in these immune functions are associated with susceptibility to SLE. The following variants were analysed: HLA DR3, HLA DQ2, C4AQ0, Fcγ receptor IIa (FcγRIIa) genotype R/R, Fcγ receptor IIIa (FcRγIIIa) genotype F/F, mannan-binding lectin (MBL) genotype conferring a low serum concentration of MBL (MBL-low), and interleukin-1 receptor antagonist (IL-1Ra) genotype 2/2. Polymorphisms were analysed in 143 Caucasian patients with SLE and 200 healthy controls. HLA DR3 in SLE patients was in 90% part of the haplotype HLA DR3-DQ2-C4AQ0, which was strongly associated with SLE (odds ratio [OR] 2.8, 95% CI 1.7–4.5). Analysis of combinations of gene variants revealed that the strong association with SLE for HLA DR3-DQ2-C4AQ0 remained after combination with FcγRIIa R/R, FcγRIIIa F/F, and MBL-low (OR>2). Furthermore, the combination of the FcγRIIa R/R and IL-1Ra 2/2 genotypes yielded a strong correlation with SLE (OR 11.8, 95% CI 1.5–95.4). This study demonstrates that certain combinations of gene variants may increase susceptibility to SLE, suggesting this approach for future studies. It also confirms earlier findings regarding the HLA DR3-DQ2-C4AQ0 haplotype.
Highlights
The genetic contribution to the aetiology of systemic lupus erythematosus (SLE) is high, as is indicated by familial aggregation and a higher concordance rate in monozygotic than dizygotic twins [1]
The major histocompatibility complex (MHC) haplotype HLA DR3-DQ2-C4AQ0 is strongly associated with SLE in Caucasians [2,3]
In the present study we found that the combination of the Fcγ receptor IIa (FcγRIIa) R/R genotype with the interleukin-1 receptor antagonist (IL-1Ra) 2/2 genotype was strongly associated with SLE
Summary
The genetic contribution to the aetiology of systemic lupus erythematosus (SLE) is high, as is indicated by familial aggregation and a higher concordance rate in monozygotic than dizygotic twins [1]. The IgG Fc receptors appear to be important in the pathogenesis of SLE, as recently reviewed by Salmon and Pricop [4]. With the allelic variant of R (arginine) instead of H (histidine) on amino acid position 131, the ability of Fcγ receptor IIa (FcγRIIa) to bind IgG2 is diminished [5]. An amino acid substitution in position 158 (phenylalanine [F] instead of valine [V]) in the Fcγ receptor IIIa (FcγRIIIa) reduces the. IgG1-, IgG3-, and IgG4-binding capacity of the receptor [6]. These variants can result in suboptimal clearance of immune complexes from the circulation, which might contribute to the pathogenesis of immune-complex-mediated manifestations [7]
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