RESUMEN
Systematic genome-wide studies to map genomic regions associated with human diseases are becoming more practical. Increasingly, efforts will be focused on the identification of the specific functional variants responsible for the disease. The challenges of identifying causal variants include the need for complete ascertainment of genetic variants and the need to consider the possibility of multiple causal alleles. We recently reported that risk of systemic lupus erythematosus (SLE) is strongly associated with a common SNP in IFN regulatory factor 5 (IRF5), and that this variant altered spicing in a way that might provide a functional explanation for the reproducible association to SLE risk. Here, by resequencing and genotyping in patients with SLE, we find evidence for three functional alleles of IRF5: the previously described exon 1B splice site variant, a 30-bp in-frame insertion/deletion variant of exon 6 that alters a proline-, glutamic acid-, serine- and threonine-rich domain region, and a variant in a conserved polyA+ signal sequence that alters the length of the 3' UTR and stability of IRF5 mRNAs. Haplotypes of these three variants define at least three distinct levels of risk to SLE. Understanding how combinations of variants influence IRF5 function may offer etiological and therapeutic insights in SLE; more generally, IRF5 and SLE illustrates how multiple common variants of the same gene can together influence risk of common disease.
Asunto(s)
Predisposición Genética a la Enfermedad , Variación Genética , Haplotipos , Factores Reguladores del Interferón/genética , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/metabolismo , Estudios de Casos y Controles , Línea Celular Transformada , Regulación de la Expresión Génica/fisiología , Humanos , Factores Reguladores del Interferón/biosíntesis , Factores Reguladores del Interferón/fisiología , Lupus Eritematoso Sistémico/etiología , Isoformas de Proteínas/biosíntesis , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiología , Factores de RiesgoRESUMEN
In order to better understand the genetic factors that initiate systemic lupus erythematosus (SLE), we are using both linkage and association approaches to identify susceptibility genes for the disease. Association studies have recently identified three HLA Class II haplotypes as well as a functional missense polymorphism in protein tyrosine phosphatase (PTP) PTPN22 as important risk alleles for SLE. Here, we will review these data, and explain how these findings contribute to an understanding of the genetic architecture of human SLE.
Asunto(s)
Lupus Eritematoso Sistémico/genética , Alelos , Antígenos HLA/genética , Haplotipos , Humanos , Mutación Missense , Polimorfismo Genético , Proteínas Tirosina Fosfatasas/genéticaRESUMEN
We genotyped 525 independent North American white individuals with systemic lupus erythematosus (SLE) for the PTPN22 R620W polymorphism and compared the results with data generated from 1,961 white control individuals. The R620W SNP was associated with SLE (genotypic P=.00009), with estimated minor (T) allele frequencies of 12.67% in SLE cases and 8.64% in controls. A single copy of the T allele (W620) increases risk of SLE (odds ratio [OR]=1.37; 95% confidence interval [CI] 1.07-1.75), and two copies of the allele more than double this risk (OR=4.37; 95% CI 1.98-9.65). Together with recent evidence showing association of this SNP with type 1 diabetes and rheumatoid arthritis, these data provide compelling evidence that PTPN22 plays a fundamental role in regulating the immune system and the development of autoimmunity.