Background/Purpose: Human SLE is characterized by fluctuating serum levels of complement proteins. There are frequent copy number variations (CNVs) of complement C4A and C4B genes among different individuals. Previously, we demonstrated that C4A deficiency is a strong genetic risk factor for SLE. Our current objectives are to investigate how CNVs of C4 contribute to the great variability of C4 serum levels and how deficiencies of C4A or C4B modulate the clinical presentations, including organ damage, of SLE.

Methods: Our study population included 499 patients from Hong Kong, who fulfilled ≥4 of the 2013 ACR/SLICC criteria for SLE. Among them 93% were women, the mean age of SLE onset was 32.8±13.0 years, and SLE duration was 14.4±7.6 years. Gene copy numbers (GCNs) of total C4 (C4T), C4A and C4B were determined by real-time PCRs. Serial serum levels over the past 5 years for C4 and C3 of each patient were retrieved through the laboratory data registry system. Serum C4 and C3 levels are shown as mg/100 ml (unit). Clinical manifestations and organ damage of SLE were correlated with CNVs of C4 genes and serum levels. Continuous data between groups were compared by t-tests and categorical data by χ² analyses. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals for effects of C4 CNVs on cumulative clinical manifestations of SLE and accrued organ damage, adjusted for durations of disease.

Results: Serum levels for C4 varied from 1-84 units (Median: 17) and for C3 from 8-314 units (Median: 86). There was a very strong correlation between C4 and C3 protein levels (R= 0.70, p= 5.3×10^-75). The GCN of C4T varied between 2 and 9 with a median of 4 copies (54%), followed by 2 and 3 copies (21%). Each additional gene copy correlated to an increase of 4 and 6 units for the mean and maximum serum C4 levels, respectively. A higher GCN of C4T (≥3 vs <3) was protective against the development of neuropsychiatric disorder over time [OR 0.45 (0.21-0.98), p=0.04]. A high GCN of C4L (≥3 vs <3), or the absence of C4S (GCN=0), was negatively associated with the occurrence of thrombocytopenia [OR 0.64 (0.42-0.97), p=0.04]. A high GCN of C4B was associated with damage to any organ [OR 1.76 (1.05-2.93), p=0.03], but a high GCN of C4A (≥3 vs <3) was associated with cardiovascular damage [OR 2.30 (1.06-5.00), p=0.04]. Among the SLE patients studied, 18.3% had persistently low levels of C4 (mean ≤10.0 units). These patients mostly had GCNs of C4T=2 or 3 [OR 4.02 (2.47-6.56), p= 4.7×10^-8], or C4B=0 or 1 [OR 3.06 (1.89-4.96), p= 9.0×10^-6]. Patients with persistently low C4 levels had increased prevalence of mucosal ulceration [OR 2.09 (1.15-3.78), p=0.02], lymphopenia [OR 1.76 (1.01-3.05), p=0.045] and gastrointestinal disorders [OR 2.52 (1.31-4.84), p=0.005].

Conclusion: CNVs of C4 genes confer great variability of serum C4 levels among SLE patients. While C4A deficiency contributes to genetic predisposition of SLE, persistently low levels of serum C4 among patients were strongly correlated with low GCN of total C4 and C4B deficiency. Elucidating C4-CNVs may have prognostic significance of SLE as high GCNs of C4B and C4A appeared to correlate with organ damage and cardiovascular disease, respectively.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/complement-c4-gene-copy-number-variations-bestow-large-ranges-of-serum-c4-protein-levels-in-chinese-patients-with-systemic-lupus-erythematosus-sle-and-contribute-to-organ-and-cardiovascular-damages/