Effect of Combined Genotypes on SLE Susceptibility
Effect of Combined Genotypes on SLE Susceptibility
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 1.74.5). 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 1.595.4). 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.
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. The major histocompatibility complex (MHC) haplotype HLA DR3-DQ2-C4AQ0 is strongly associated with SLE in Caucasians. The IgG Fc receptors appear to be important in the pathogenesis of SLE, as recently reviewed by Salmon and Pricop. 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. Similarly, 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. These variants can result in suboptimal clearance of immune complexes from the circulation, which might contribute to the pathogenesis of immune-complex-mediated manifestations.
Mannan-binding lectin (MBL) is structurally similar to C1q and has the ability to activate the complement cascade through the lectin pathway. Point mutations are found in the structural gene that affect the MBL serum concentration and the stability of MBL complex formation required for efficient complement activation. In the promoter regions, there are two polymorphisms that influence serum concentration, with LX conferring the lowest MBL level, LY a medium level, and HY the highest. MBL variant alleles have been suggested as a minor risk factor in susceptibility to SLE in several populations. Interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring competitive inhibitor of IL-1. The IL-1Ra gene contains a polymorphism in intron 2 consisting of a variable number of copies of an 86-base-pair repeat sequence (two, three, four, five, or six copies). An association has been found between the IL-1Ra 2 allele and SLE. Multiple genes are involved in the development of SLE, and the relative importance of these genes may vary between populations and with environmental exposure. We investigated common variant alleles involved in the immune response, immune complex clearance, and regulation of inflammation, with the hypothesis that combinations of polymorphic candidate genes could have synergistic effects on disease susceptibility. Therefore, we have analysed polymorphisms in the genes HLA DR, HLA DQ, C4A, FcγRIIa, FcγRIIIa, MBL, and IL-1Ra and their association with the development of SLE.
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 1.74.5). 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 1.595.4). 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.
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. The major histocompatibility complex (MHC) haplotype HLA DR3-DQ2-C4AQ0 is strongly associated with SLE in Caucasians. The IgG Fc receptors appear to be important in the pathogenesis of SLE, as recently reviewed by Salmon and Pricop. 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. Similarly, 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. These variants can result in suboptimal clearance of immune complexes from the circulation, which might contribute to the pathogenesis of immune-complex-mediated manifestations.
Mannan-binding lectin (MBL) is structurally similar to C1q and has the ability to activate the complement cascade through the lectin pathway. Point mutations are found in the structural gene that affect the MBL serum concentration and the stability of MBL complex formation required for efficient complement activation. In the promoter regions, there are two polymorphisms that influence serum concentration, with LX conferring the lowest MBL level, LY a medium level, and HY the highest. MBL variant alleles have been suggested as a minor risk factor in susceptibility to SLE in several populations. Interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring competitive inhibitor of IL-1. The IL-1Ra gene contains a polymorphism in intron 2 consisting of a variable number of copies of an 86-base-pair repeat sequence (two, three, four, five, or six copies). An association has been found between the IL-1Ra 2 allele and SLE. Multiple genes are involved in the development of SLE, and the relative importance of these genes may vary between populations and with environmental exposure. We investigated common variant alleles involved in the immune response, immune complex clearance, and regulation of inflammation, with the hypothesis that combinations of polymorphic candidate genes could have synergistic effects on disease susceptibility. Therefore, we have analysed polymorphisms in the genes HLA DR, HLA DQ, C4A, FcγRIIa, FcγRIIIa, MBL, and IL-1Ra and their association with the development of SLE.