Journal Article

Determination of the Loss of Function Complement C4 Exon 29 CT Insertion Using a Novel Paralog-Specific Assay in Healthy UK and Spanish Populations

Martin, Javier, Cortes-Hernández, Josefina, Fernando, Michelle M. A., Vyse, Timothy J., Boteva, Lora, Wu, Yee Ling

2011

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Arthritis / Autoimmune diseases / Base Sequence / Biology / C4A protein / Chronic conditions / Codons / Cohort Studies / Complement C4 - genetics / Complement C4a - genetics / Complement C4b - genetics / Complement component C4 / Copy number / Disease / DNA Copy Number Variations / Exons - genetics / Female / Gene expression / Gene Frequency / Gene polymorphism / Genes / Genetic aspects / Genetic diversity / Genetic polymorphisms / Genetic variance / Genetics / Genomes / Genomics / Genotype / Genotypes / Genotyping Techniques - methods / Haplotypes / HLA-DRB1 Chains - genetics / Hospitals / Humans / Immunology / Infections / Inflammatory diseases / Insertion / Lupus / Lupus Erythematosus, Systemic - genetics / Major histocompatibility complex / Male / Medicine / Molecular Sequence Data / Mutagenesis, Insertional / Mutation / Pedigree / Polymorphism / Polymorphism, Single Nucleotide / Population genetics / Populations / Principal components analysis / Proteins / Single-nucleotide polymorphism / Spain / Systemic lupus erythematosus / United Kingdom