Date: Monday, November 6, 2017
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: Human complement C4 protein is the product of two isotypic genes C4A and C4B that are located on chromosome 6 in various copy numbers. Recent studies by us and others have demonstrated that cell-bound complement activation product (CB-CAP) C4d is a valuable diagnostic and monitoring biomarker for systemic lupus erythematosus (SLE). The current study was based upon the hypothesis that CB-CAP C4d levels may be influenced not only by SLE disease status but also by C4 gene copy number variation (CNV). Specifically, a low C4 gene copy number may lead to persistently low CB-C4d levels in some SLE patients, thereby reducing the diagnostic sensitivity of CB-C4d as biomarkers in such patients. This study was focused on elucidating the correlation between C4 gene CNV and CB-C4d levels in patients with SLE so as to improve the utility of CB-CAP biomarker assays for lupus diagnosis, monitoring and stratification.
Methods: We conducted a cross-sectional study of 195 SLE patients. Variations in gene copy numbers for total C4, C4A, and C4B genes were determined using various genotyping technologies. CB-C4d levels on peripheral blood cells of respective patients were measured by flow cytometry. Correlations between CB-C4d levels and C4 gene CNV were examined by statistical analysis using Kruskal-Wallis test and post hoc pairwise comparison as well as linear regression analysis (for continuous variables). Categorical variables were analyzed using Fisher’s exact test or chi-square test.
Results: The results demonstrated that higher CB-C4d levels, particularly those of T cell-bound C4d (T-C4d) and B cell-bound C4d (B-C4d), were associated with increasing numbers of C4 genes. Patients with greater than 4 copies of the C4 genes were more likely to be in the highest quartile of T-C4d/B-C4d levels than were patients with fewer copies of the C4 genes. Remarkably, patients with no C4A genes (homozygous C4A deficiency) had normal/low T-C4d/B-C4d. Patients with partial C4 genetic deficiencies were more likely to be missed as false negatives using individual CB-CAPs (e.g. BC4d alone) for the diagnosis of SLE. Not all CB-CAPs were influence equally by C4 CNV.
Conclusion: Together, results of the present study suggest a positive correlation of T-C4d and B-C4d levels with CNV of the C4 gene, particularly the C4A gene, in patients with SLE. These observations support our hypothesis that individual CB-CAP C4d levels such as TC4d and BC4d should be interpreted with simultaneous determination of C4 gene copy numbers as well as other CB-CAPs such as EC4d, PC4d, RC4d, etc. as components of lupus biomarker panels for diagnosis, monitoring and stratification.
To cite this abstract in AMA style:Liu CC, Ahearn J, Tang AX, Wu YL, Yu CY, Manzi S. Human C4 Gene Copy Number Influences Cell-Bound Complement Activation Product (CB-CAP) C4d in Systemic Lupus Erythematosus [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/human-c4-gene-copy-number-influences-cell-bound-complement-activation-product-cb-cap-c4d-in-systemic-lupus-erythematosus/. Accessed February 3, 2023.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/human-c4-gene-copy-number-influences-cell-bound-complement-activation-product-cb-cap-c4d-in-systemic-lupus-erythematosus/