Three functional variants of IFN regulatory factor 5 ( IRF5 ) define risk and protective haplotypes for human lupus

Abstract

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.interferon pathway ͉ systemic lupus erythematosus

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

“…Again, when conditioned upon, rs3807306 removed all other associations within the haplotype. In Caucasians, we observed an association with the risk TCA haplotype (P ¼ 0.0004) and the protective GTG haplotype (P ¼ 0.001); however, we did not observe significance with the previously reported GTA protective haplotype 13 (Table 5). HF using these loci from a previous study are also provided in Table 5 for comparison.…”

“…13 In African Americans, we observed a marginal protective effect with the GTG haplotype (P ¼ 0.03; HF ¼ 0.39 cases and 0.45 controls). The risk TCA haplotype was observed, but its frequency was extremely low (P ¼ 0.01; OR ¼ 1.9 (1.1-3.5); HF ¼ 0.04 cases and 0.02 controls).…”

“…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.…”