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

Abstract

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 > or =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 > or =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.

Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex

“…[35][36][37][38][39][40][41][42][43] Within our associated region, a segmental duplication is reported, 44 which is situated between the two associated regions on the DRB1*0401-DQA1*03-DQB1*0302 haplotypic background and caused a 223-kb gap not genotyped in our study. This segmental duplication has, to our knowledge, not been studied regarding human diseases.…”

Implications of gene copy-number variation in health and diseases

“…The risk of SLE was found to be increased in subjects with low C4 copies but decreased in those with high C4 copies. 48 Asthma Asthma is a chronic inflammatory genetic disorder characterized by a condition marked by recurrent attacks of dyspnea and constriction of the bronchii, also termed as bronchial asthma whereas the bronchial asthma due to allergy is called atopic asthma.…”

Fine-tuned characterization of RCCX copy number variants and their relationship with extended MHC haplotypes

“…Observed frequencies of C4A, C4B, C4(L) and C4(S) genes, as well as of haplotypes with zero or two CYP21A2 copies, were similar to literature data (Table 1). 2,15 RCCX modular variations in healthy Hungarian Caucasians Considering all C4 and CYP21 gene variations examined, 15 different RCCX structures could be detected (Figure 2 Figure 1. Trimodular RCCX structure with binding sites of long PCR primers used.…”

“…Characterization of RCCX variants Z Bánlaki et al occurrence of RCCX length variants was consistent with data obtained from literature (Table 1). 2,15 Monomodular variants contained either a long C4A or a short C4B gene. Among bimodular structures, the most prevalent one was A(L)-B(L), followed by A(L)-B(S) and A(L)-A(L).…”