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Abstract Number: 1673

Human C4 Gene Copy Number Influences Cell-Bound Complement Activation Product (CB-CAP) C4d in Systemic Lupus Erythematosus

Chau-Ching Liu1, Joseph Ahearn2, Amy Xiaoqin Tang2, Yee Ling Wu3, CHACK-YUNG Yu3 and Susan Manzi2, 1Lupuc Center of Excellence, Allegheny Health Network Research Institute, Pittsburgh, PA, 2Lupus Center of Excellence, Allegheny Health Network Research Institute, Pittsburgh, PA, 3Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital, Columbus, OH

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: Biomarkers, complement and systemic lupus erythematosus (SLE)

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Session Information

Date: Monday, November 6, 2017

Session Title: Systemic Lupus Erythematosus – Human Etiology and Pathogenesis Poster I

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.


Disclosure: C. C. Liu, Exagen Diagnostics, 7; J. Ahearn, Exagen Diagnostics, 7; A. X. Tang, None; Y. L. Wu, None; C. Y. Yu, None; S. Manzi, Exagen Diagnostics, 7.

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/

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