Association of a functional IRF7 variant with systemic lupus erythematosus

Abstract

Objective. A previous genome-wide association study conducted in a population of European ancestry identified rs4963128, a KIAA1542 single-nucleotide polymorphism (SNP) 23 kb telomeric to IRF7 (the gene for interferon regulatory factor 7 [IRF-7]), to be strongly associated with systemic lupus erythematosus (SLE). This study was undertaken to investigate whether genetic polymorphism within IRF7 is a risk factor for the development of SLE.Methods. We genotyped one KIAA1542 SNP (rs4963128) and one IRF7 SNP (rs1131665 [Q412R]) in an Asian population (1,302 cases, 1,479 controls), to assess their association with SLE. Subsequently, rs1131665 was further genotyped in independent panels of Chinese subjects (528 cases, 527 controls), European American subjects (446 cases, 461 controls), and African American subjects (159 cases, 115 controls) by TaqMan genotyping assay, to seek confirmation of association in various ethnic groups. A luciferase reporter assay was used to assess the effect of Q412R polymorphism on the activation of IRF-7.Results. Consistent association of rs1131665 (Q412R) with SLE was identified in Asian, European American, and African American populations (total 2,435 cases and 2,582 controls) (P meta ‫؍‬ 6.18 ؋ 10 ؊6 , odds ratio 1.42 [95% confidence interval 1.22-1.65]). Expression of the IRF7 412Q risk allele resulted in a 2-fold increase in interferon-stimulated response element transcriptional activity compared with expression of IRF7 412R (P ‫؍‬ 0.0003), suggesting that IRF7 412Q confers elevated IRF-7 activity and may therefore affect a downstream interferon pathway.

The interferon regulatory factors as novel potential targets in the treatment of cardiovascular diseases

“…One representative example is systemic lupus erythematosus (SLE), a genetic and environmental factors-triggered disease marked by high levels of type I IFNs in serum (Banchereau and Pascual, 2006;Yang et al, 2012). Several large-scale genetic association studies have shown that, the major alleles, rs2004640 and rs1131665 (412Q) in IRF5 and IRF7, respectively, predispose the host to the development of SLE in several ethnic groups, cumulatively providing direct genetic evidence that IRFs are closely linked to human autoimmune diseases (Sigurdsson et al, 2005;Graham et al, 2006;Cunninghame Graham et al, 2007;Fu et al, 2011).…”

“…One representative example is systemic lupus erythematosus (SLE), a genetic and environmental factors-triggered disease marked by high levels of type I IFNs in serum (Banchereau and Pascual, 2006;Yang et al, 2012). Several large-scale genetic association studies have shown that, the major alleles, rs2004640 and rs1131665 (412Q) in IRF5 and IRF7, respectively, predispose the host to the development of SLE in several ethnic groups, cumulatively providing direct genetic evidence that IRFs are closely linked to human autoimmune diseases (Sigurdsson et al, 2005;Graham et al, 2006;Cunninghame Graham et al, 2007;Fu et al, 2011).In terms of the relevance of IRFs to cardiovascular diseases, previous and ongoing studies have suggested the involvement of IRFs in cardiac remodelling, stroke and vascular injury, through the markedly altered expression levels of IRFs in response to the corresponding pathological cardiovascular conditions. For instance, IRF1, IRF4 and IRF8 are significantly down-regulated in failing human hearts compared with healthy controls (Jiang et al, 2013; 2014a,d), whereas IRF3 is profoundly up-regulated in the hearts of patients with dilated or hypertrophic cardiomyopathy (Lu et al, 2013a).…”

Association between functionalIRF7variant and systemic lupus erythematosus may need more critical examination: Comment on the article by Fu et al

“…We read with great interest the recent article by Fu et al (1). In their study, consistent association of IRF7 (the gene for interferon regulatory factor 7) rs1131665 polymorphism with systemic lupus erythematosus (SLE) was identified in Asian, European American, and African American populations.…”

“…More importantly, a majority of subjects (1,769 Korean, 302 Chinese, and 64 of other ancestry) in this discovery Asian panel were assessed for genetic ancestry using ancestry-informative markers and were subjected to principal components analysis, which showed no evidence of genetic heterogeneity among these subjects of Korean, Chinese, and other Asian ancestries. Accordingly, they were combined as an Asian ethnic group for association tests by our collaborators, as described in 2 other recent publications (1,2).…”

IRF-5 - A New Link to Autoimmune Diseases

“…Recently identified SNPs in IRF7 also seem to be associated with SLE. (Fu et al, 2011). It is unlikely that the alteration of the function of a single master gene will be responsible for the pathogenesis of SLE; rather it may be combination of malfunction of several genes.…”