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Objective: Complement component C4 copy number variations are associated with various inflammatory diseases. This study was undertaken to investigate whether copy number variations of C4 are also involved in the pathogenesis of Behçet's disease (BD)., Methods: Gene expression was examined by enzyme-linked immunosorbent assay (ELISA) or real-time polymerase chain reaction (PCR). Copy number variations of C4 isotypes (C4A and C4B) were detected by real-time PCR in 905 patients with BD, 205 patients with ankylosing spondylitis (AS) and acute anterior uveitis, and 1,238 controls. The activation of CD4+ T cells was analyzed by flow cytometry, and cytokine production was detected by ELISA., Results: Protein expression of total C4 in serum was significantly increased in patients with active BD compared with those with inactive BD or controls (Bonferroni corrected P [Pcorr ] = 1.64 × 10(-4) and Pcorr = 0.037, respectively), but not in patients with AS and acute anterior uveitis. Copy number variation analysis identified a significantly increased frequency of more than 2 copies of C4A in BD patients (P = 1.65 × 10(-7) , odds ratio [OR] 2.84). HLA-B51, which is located on the same chromosome as C4, showed a strong association with BD in the Han Chinese population (P = 8.90 × 10(-65) , OR 5.05), but logistic regression showed that C4A copy number variation was an independent risk factor for BD. A significantly increased expression of C4A was observed in the high copy number groups (>2 copies or 2 copies) versus the low copy number group (Pcorr = 0.019 and Pcorr = 0.044, respectively). Increased production of interleukin-6 (IL-6) was also observed in the high C4A copy number group (Pcorr = 0.037). No effect of C4 copy number variation on the expression of T cell activation markers was detected., Conclusion: Our findings indicate that a high copy number of C4A confers risk for BD by modulating the expression of C4A and enhancing IL-6 production., (Copyright © 2013 by the American College of Rheumatology.)

Objective: To study autoimmune diseases and autoantibodies in Icelandic multicase systemic lupus erythematosus (SLE) families and to determine the association of 3 SLE susceptibility factors, PD-1.3A, C4AQ0, and low levels of mannan-binding lectin (MBL), with autoimmune disease in this population., Methods: Eight SLE multicase families were studied, comprising a total of 124 family members (23 patients with SLE and 101 relatives). The diagnosis of an autoimmune disease was established and autoantibodies were measured in each family. In addition, PD-1.3A alleles were genotyped, and C4AQ0 allotypes were established by electrophoresis and haplotype analysis. Low levels of MBL were determined using enzyme-linked immunosorbent assay and variant-allele genotyping., Results: In the SLE multicase families there was a high frequency of other autoimmune diseases (32.2%) and a high frequency of autoantibodies (53.2%). Of all family members, 59.7% were determined to have SLE, other autoimmune diseases, antinuclear antibodies, and/or other autoantibodies. The families showed genetic heterogeneity for PD-1.3A, C4AQ0, and low MBL levels; the frequency of each factor ranged from 0% to 85%. The frequencies of PD-1.3A and C4AQ0 were significantly increased in patients with SLE, relatives with other autoimmune diseases, and non-autoimmune disease relatives compared with controls. In the 7 families whose members had low levels of MBL, this factor was significantly associated with SLE, but the frequency of low MBL was decreased in relatives with other autoimmune diseases as compared with non-autoimmune disease relatives and controls. There were indications of an additive effect, and 91% of patients with SLE, 78% of relatives with other autoimmune diseases, and 75% of non-autoimmune disease relatives carried at least 1 of the 3 factors., Conclusion: These results demonstrate a high frequency of autoimmune diseases and autoantibodies in SLE multicase families. PD-1.3A and C4AQ0 are part of a predisposing genetic background. Other genetic and/or environmental factors are necessary for disease expression, demonstrated by a high frequency of PD-1.3A and C4AQ0 in non-autoimmune disease relatives. Low MBL levels may be one such contributing factor. The results of this study provide an example of epistatic genetic effects and overlapping genetics in autoimmune diseases.