A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by activation of the type I interferon (IFN) pathway. Here we convincingly replicate association of the IFN regulatory factor 5 (IRF5) rs2004640 T allele with SLE in four independent case-control cohorts (P = 4.4 x 10(-16)) and by family-based transmission disequilibrium test analysis (P = 0.0006). The rs2004640 T allele creates a 5' donor splice site in an alternate exon 1 of IRF5, allowing expression of several unique IRF5 isoforms. We also identify an independent cis-acting variant associated with elevated expression of IRF5 and linked to the exon 1B splice site. Haplotypes carrying the variant associated with elevated expression and lacking the exon 1B donor site do not confer risk of SLE. Thus, a common IRF5 haplotype driving elevated expression of multiple unique isoforms of IRF5 is an important genetic risk factor for SLE, establishing a causal role for type I IFN pathway genes in human autoimmunity.

Interferon regulatory factor-5 is genetically associated with systemic lupus erythematosus in African Americans

“…12,14,[17][18][19] Similar to African Americans, we again found the strongest associations at rs2004640 (P ¼ 2.2 Â 10 À9 ) and rs3807306 (P ¼ 3.0 Â 10 À9 ) in both OMRF and CASSLE and in both studies combined. Allele frequencies were similar to Caucasian populations previously reported (Table 2).…”

“…18 Since then, several additional studies have evaluated the association between IRF5 and SLE in Caucasian, [12][13][14]17,19 Korean 16 and Hispanic (Mexican) 15 populations, emphasizing the importance of this gene in SLE etiology. However, no studies have been reported to date in African Americans.…”

“…The T allele at rs2004640 creates a GT donor splice site for exon 1b, 12 the A allele at rs10954213 results in more stable IRF5 transcripts leading to higher IRF5 levels 17 and a 30-bp insertion/deletion at exon 6 differentiates the ability of IRF5 to initiate transcription of target genes. 13 Genetic associations at these loci may provide clues about which mechanisms cause improper regulation of IFN responses during SLE pathogenesis.…”

“…9 Interferon regulatory factor-5 (IRF5), a transcription factor, regulates the expression of IFN-a genes, 10,11 thus making it a good candidate gene for SLE susceptibility. Recent publications have reported a significant association between single nucleotide polymorphisms (SNPs) and haplotypes of IRF5 and SLE, both in familyand population-based studies of patients from multiple ethnicities [12][13][14][15][16][17][18][19][20][21] (including meta-analyses) 16 ; however, these studies have not examined African Americans.…”

“…24 Examples of ethnic-specific differences in SLE genetic association studies include an association of the p53 gene in Koreans 25 that did not replicate in a Spanish Caucasian population, 26 an association of the heat-shock-protein-encoding gene, HSP70, in Spaniards and Africans but not in Mexicans 27 and the varying levels of significance of CTLA4 associated with SLE in Asians and Europeans. 28 There are even differences in levels of significance within association studies of IRF5 and SLE, such as with studies of Caucasian, 12,14,[17][18][19] Hispanic (Mexican) 15 and Asian subjects. 16 In this report, we evaluate genetic associations of IRF5 with SLE in independent studies (Oklahoma Medical Research Foundation (OMRF) and 'Cases of SLE' (CASSLE) based at the University of Alabama at Birmingham (UAB)) comprised of African-American and Caucasian patients and controls (n ¼ 4870).…”