Gene Copy-Number Variation and Associated Polymorphisms of Complement Component C4 in Human Systemic Lupus Erythematosus (SLE): Low Copy Number Is a Risk Factor for and High Copy Number Is a Protective Factor against SLE Susceptibility in European Americans

• Published in: American journal of human genetics Vol. 80; no. 6; pp. 1037 - 1054
• Main Authors: Yang, Yan, Chung, Erwin K., Wu, Yee Ling, Savelli, Stephanie L., Nagaraja, Haikady N., Zhou, Bi, Hebert, Maddie, Jones, Karla N., Shu, Yaoling, Kitzmiller, Kathryn, Blanchong, Carol A., McBride, Kim L., Higgins, Gloria C., Rennebohm, Robert M., Rice, Robert R., Hackshaw, Kevin V., Roubey, Robert A.S., Grossman, Jennifer M., Tsao, Betty P., Birmingham, Daniel J., Rovin, Brad H., Hebert, Lee A., Yung Yu, C.
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.06.2007; University of Chicago Press; Cell Press; The American Society of Human Genetics
• Subjects: Adult; Alleles; Biological and medical sciences; Case-Control Studies; Cohort Studies; Complement C4 - genetics; Disease Susceptibility; Female; Fundamental and applied biological sciences. Psychology; Gene Dosage; Gene Frequency; General aspects. Genetic counseling; Genes; Genetic research; Genetic Variation; Genetics of eukaryotes. Biological and molecular evolution; Genetics, Population; Genomics; Haplotypes; Health risk assessment; Humans; Lupus; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Male; Medical genetics; Medical sciences; Middle Aged; Minority & ethnic groups; Molecular and cellular biology; Polymorphism, Genetic; Reproducibility of Results; Risk Factors; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; White People - genetics; Europe; Human; Immunopathology; Connective tissue disease; High risk; Skin disease; American; Copy number; Pathogenesis; Variations; Autoimmune disease; Complement; Concentration; European; Genetic determinism; Prevention; Sensitivity; Systemic lupus erythematosus; Gene; Systemic disease; Risk factor; Predisposition; Genetics; Polymorphism
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/518257

Interindividual gene copy-number variation (CNV) of complement component C4 and its associated polymorphisms in gene size (long and short) and protein isotypes (C4A and C4B) probably lead to different susceptibilities to autoimmune disease. We investigated the C4 gene CNV in 1,241 European Americans, including patients with systemic lupus erythematosus (SLE), their first-degree relatives, and unrelated healthy subjects, by definitive genotyping and phenotyping techniques. The gene copy number (GCN) varied from 2 to 6 for total C4, from 0 to 5 for C4A, and from 0 to 4 for C4B. Four copies of total C4, two copies of C4A, and two copies of C4B were the most common GCN counts, but each constituted only between one-half and three-quarters of the study populations. Long C4 genes were strongly correlated with C4A ( R=0.695; P<.0001). Short C4 genes were correlated with C4B ( R=0.437; P<.0001). In comparison with healthy subjects, patients with SLE clearly had the GCN of total C4 and C4A shifting to the lower side. The risk of SLE disease susceptibility significantly increased among subjects with only two copies of total C4 (patients 9.3%; unrelated controls 1.5%; odds ratio [OR] = 6.514; P=.00002) but decreased in those with ≥5 copies of C4 (patients 5.79%; controls 12%; OR=0.466; P=.016). Both zero copies (OR=5.267; P=.001) and one copy (OR=1.613; P=.022) of C4A were risk factors for SLE, whereas ≥3 copies of C4A appeared to be protective (OR=0.574; P=.012). Family-based association tests suggested that a specific haplotype with a single short C4B in tight linkage disequilibrium with the −308A allele of TNFA was more likely to be transmitted to patients with SLE. This work demonstrates how gene CNV and its related polymorphisms are associated with the susceptibility to a human complex disease.