Genetically Determined Partial Complement C4 Deficiency States Are Not Independent Risk Factors for SLE in UK and Spanish Populations

• Published in: American journal of human genetics Vol. 90; no. 3; pp. 445 - 456
• Main Authors: Boteva, Lora, Morris, David L., Cortés-Hernández, Josefina, Martin, Javier, Vyse, Timothy J., Fernando, Michelle M.A.
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 09.03.2012; Cell Press; Elsevier
• Subjects: Alleles; Autoimmune diseases; Biological and medical sciences; C4B gene; Case-Control Studies; Cohort Studies; Complement C4a - deficiency; Complement C4a - genetics; Complement C4b - deficiency; Complement C4b - genetics; complement component C4; copy number; DNA Copy Number Variations; Exons; Fundamental and applied biological sciences. Psychology; Gene Dosage; Gene Frequency; Gene loci; Gene polymorphism; General aspects. Genetic counseling; Genetic Predisposition to Disease; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genotype & phenotype; Haplotypes; Histocompatibility antigen HLA; HLA-DRB1 Chains - genetics; Homozygote; Humans; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Insertion; Linkage Disequilibrium; Logistic Models; Lupus; Lupus Erythematosus, Systemic - genetics; Major histocompatibility complex; Major Histocompatibility Complex - genetics; Medical genetics; Medical sciences; Molecular and cellular biology; Polymorphism; Polymorphism, Single Nucleotide; Risk Factors; Single-nucleotide polymorphism; Spain; Systemic lupus erythematosus; United Kingdom; White People - genetics; United Kingdom; Europe; Spain; United Kingdom > UK; British Isles; Human; Immunopathology; Connective tissue disease; Skin disease; Complement C4; Autoimmune disease; Immune deficiency; Systemic lupus erythematosus; Partial; Systemic disease; Complement deficiency; Risk factor; Genetics; Population; Spanish
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2012.01.012

Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease. Complete deficiency of complement component C4 confers strong genetic risk for SLE. Partial C4 deficiency states have also shown association with SLE, but despite much effort over the last 30 years, it has not been established whether this association is primarily causal or secondary to long-range linkage disequilibrium. The complement C4 locus, located in the major histocompatibility complex (MHC) class III region, exhibits copy-number variation (CNV) and C4 itself exists as two paralogs, C4A and C4B. In order to determine whether partial C4 deficiency is an independent genetic risk factor for SLE, we investigated C4 CNV in the context of HLA-DRB1 and MHC region SNP polymorphism in the largest and most comprehensive complement C4 study to date. Specifically, we genotyped 2,207 subjects of northern and southern European ancestry (1,028 SLE cases and 1,179 controls) for total C4, C4A, and C4B gene copy numbers, and the loss-of-function C4 exon 29 CT indel. We used multiple logistic regression to determine the independence of C4 CNV from known SNP and HLA-DRB1 associations. We clearly demonstrate that genetically determined partial C4 deficiency states are not independent risk factors for SLE in UK and Spanish populations. These results are further corroborated by the lack of association shown by the C4A exon 29 CT insertion in either cohort. Thus, although complete homozygous deficiency of complement C4 is one of the strongest genetic risk factors for SLE, partial C4 deficiency states do not independently predispose to the disease.