title: Determination of the loss of function complement C4 exon 29 CT insertion using a novel paralog-specific assay in healthy UK and Spanish populations.
abstract: Genetic variants resulting in non-expression of complement C4A and C4B genes are common in healthy European populations and have shown association with a number of diseases, most notably the autoimmune disease, systemic lupus erythematosus. The most frequent cause of a C4 "null" allele, following that of C4 gene copy number variation (CNV), is a non-sense mutation arising from a 2 bp CT insertion into codon 1232 of exon 29. Previous attempts to accurately genotype this polymorphism have not been amenable to high-throughput typing, and have been confounded by failure to account for CNV at this locus, as well as by inability to distinguish between paralogs. We have developed a novel, high-throughput, paralog-specific assay to detect the presence and copy number of this polymorphism. We have genotyped healthy cohorts from the United Kingdom (UK) and Spain. Overall, 30/719 (4.17%) individuals from the UK cohort and 8/449 (1.78%) individuals from the Spanish cohort harboured the CT insertion in a C4A gene. A single Spanish individual possessed a C4B CT insertion. There is weak correlation between the C4 CT insertion and flanking MHC polymorphism. Therefore it is important to note that, as with C4 gene CNV, disease-association due to this variant will be missed by current SNP-based genome-wide association strategies.
authors.affiliation: Division of Molecular Medicine and Genetics, Guy's Hospital, King's College London, London, United Kingdom.
authors.forename: Lora
authors.initials: L
authors.lastname: Boteva
authors.forename: Yee Ling
authors.initials: YL
authors.lastname: Wu
authors.forename: Josefina
authors.initials: J
authors.lastname: Cortes-Hernández
authors.forename: Javier
authors.initials: J
authors.lastname: Martin
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Vyse
authors.forename: Michelle M A
authors.initials: MM
authors.lastname: Fernando
mesh_terms: D001483:Base Sequence; D015331:Cohort Studies; D003181:Complement C4 / Q000235:genetics*; D015934:Complement C4a / Q000235:genetics; D015935:Complement C4b / Q000235:genetics; D056915:DNA Copy Number Variations; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D060005:Genotyping Techniques / Q000379:methods*; D059811:HLA-DRB1 Chains / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D013030:Spain; D006113:United Kingdom
chemical_list: D003181:Complement C4; D059811:HLA-DRB1 Chains; D015934:Complement C4a; D015935:Complement C4b