Association of IRF5 polymorphisms with activation of the interferon α pathway

Abstract

Objective The genetic association of interferon regulatory factor 5 (IRF5) with systemic lupus erythematosus (SLE) susceptibility has been convincingly established. To gain understanding of the effect of IRF5 variation in individuals without SLE, a study was undertaken to examine whether such genetic variation predisposes to activation of the interferon α (IFNα) pathway. Methods Using a computer simulated approach, 14 single nucleotide polymorphisms (SNPs) and haplotypes of IRF5 were tested for association with mRNA expression levels of IRF5, IFNα and IFN-inducible genes and chemokines in lymphoblastoid cell lines (LCLs) from individuals of European (CEU), Han Chinese (CHB), Japanese (JPT) and Yoruba Nigerian (YRI) backgrounds. IFN-inducible gene expression was assessed in LCLs from children with SLE in the presence and absence of IFNα stimulation. Results The major alleles of IRF5 rs13242262 and rs2280714 were associated with increased IRF5 mRNA expression levels in the CEU, CHB+JPT and YRI samples. The minor allele of IRF5 rs10488631 was associated with increased IRF5, IFNα and IFN-inducible chemokine expression in CEU (pc=0.0005, 0.01 and 0.04, respectively). A haplotype containing these risk alleles of rs13242262, rs10488631 and rs2280714 was associated with increased IRF5, IFNα and IFN-inducible chemokine expression in CEU LCLs. In vitro studies showed specific activation of IFN-inducible genes in LCLs by IFNα. Conclusions SNPs of IRF5 in healthy individuals of a number of ethnic groups were associated with increased mRNA expression of IRF5. In European-derived individuals, an IRF5 haplotype was associated with increased IRF5, IFNα and IFN-inducible chemokine expression. Identifying individuals genetically predisposed to increased IFN-inducible gene and chemokine expression may allow early detection of risk for SLE.

Recent insights into the genetic basis of systemic lupus erythematosus

“…Another robust example is that of IRF5 , whereby IRF5 haplotypes determine the risk of increased IFN-α activity in SLE, which is influenced by the presence of autoantibody subsets 16. There may, in fact, be baseline increases in IFN activity in healthy individuals based on the IRF5 haplotype, potentially leading to an increased risk for the development of autoantibodies and autoimmune disease 74. An association of ITGAM and STAT4 also with anti-dsDNA antibody positivity in human SLE among several population groups additionally suggests the possibility of ‘autoantibody propensity loci’ in SLE,15 which may influence disease subphenotype.…”

Interferon regulatory factor 5 gene variants and pharmacological and clinical outcome of Interferonβ therapy in multiple sclerosis

“…SNPs at rs2004604, rs4728142 and rs10954213 were found to be associated with IRF5 mRNA expression. 13,20 SNPs in the DNA samples obtained at the VUmc and CEM-Cat were genotyped using Taqman Genotyping Assay (rs2004640 by assay C__9491614_10; rs4728142 by assay C__2691222_10 (both from Applied Biosystems), and rs10954213 by a customized assay). The 30-bp indel was amplified as a 115/145 bp fragment using conventional PCR and separated on a 2.5% agarose gel and visualized using ethidium bromide staining.…”

“…10 Genetic variation in the IRF5 gene has been found to be strongly associated with systemic lupus erythematosus, a disease wherein type I IFNs are clearly associated with disease activity and severity, and IFN response gene activity. [11][12][13] The aim of this study was to investigate whether polymorphisms in the IRF5 gene are associated with the pharmacological response and, if such an association was found, if it is related to clinical response to IFNb in MS.…”

Validation of IRF5 as multiple sclerosis risk gene: putative role in interferon beta therapy and human herpes virus-6 infection

“…26 The major alleles of IRF5, rs13242262 (r 2 ¼ 61% with rs4728142) and rs2280714 (r 2 ¼ 66% with rs3807306) have been recently associated with increased IRF5 mRNA expression levels in subjects of different ethnic backgrounds. 27 Considering our data, the following scenario may be envisioned: the MS susceptibility allele rs3807306T or some other strongly correlated with it would be associated with lowlevel production of IRF5. Assuming that HHV6 can interact and neutralize IRF5, HHV6 infection would abolish induction of IFN via neutralization of the lower amount of available IRF5 derived from the rs3807306T variant which would facilitate viral spread and trigger onset of MS.…”