Association between complement 4 copy number variation and systemic lupus erythematosus: a meta-analysis

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by multiple genetic mutations. Complement 4 (C4) copy number variation (CNV) is a target-of-interest located on chromosome 6. C4 encodes for either of the two C4 paralogs, C4A or C4B, and low C4 levels have been associated with SLE activity. In this study, we conducted a meta-analysis to comprehensively understand the role of C4 CNV in SLE. Three databases (PubMed, Embase, and Web of Science) were searched for relevant studies. Two investigators independently extracted and evaluated data from eligible studies. Associations between C4 CNV and SLE were estimated by odds ratios (OR) and 95% confidence intervals (95% CI). Further analysis was conducted using the STATA 12.0 software. A total of eight case-control studies were included in the analysis with 4107 SLE patients and 5889 healthy controls. Six studies used TaqMan real-time PCR to genotype C4 CNV, with 1 study used paralog ratio test and other one used multiplex ligation-dependent probe amplification (MLPA). Lower total C4 CNV and C4A CNV were associated with SLE in the overall analysis (pooled OR: 1.55, 95% CI: 1.23-1.95; pooled OR: 1.86, 95% CI: 1.51-2.29). The subgroup analysis found that total C4 CNV and lower C4A CNV were significantly associated with SLE in Caucasians (pooled OR: 1.84, 95% CI: 1.60-2.12; pooled OR: 2.23, 95% CI:1.92-2.59). However, the association was not detected in East Asians. Lastly, SLE was not associated with C4B CNV, long C4 CNV, or short C4 CNV. The meta-analysis confirmed that lower total C4 CNV and lower C4A CNV are associated with SLE in certain populations. Future studies should consider other ethnic groups to further investigate the relationship between the C4 gene and SLE.