Opposed independent effects and epistasis in the complex association of IRF5 to SLE

Abstract

Genetic variation in the interferon regulatory factor 5 (IRF5) gene affects systemic lupus erythematosus (SLE) susceptibility. However, association is complex and incompletely defined. We obtained fourteen European sample collections with a total of 1383 SLE patients and 1614 controls to better define the role of the different IRF5 variants. Eleven polymorphisms were studied, including nine tag single nucleotide polymorphisms (SNPs) and two extra functional polymorphisms. Two tag SNPs showed independent and opposed associations: susceptibility (rs10488631, Po10 À17) and protection (rs729302, Po10 À6 ). Haplotype analyses showed that the susceptibility haplotype, identified by the minor allele of rs10488631, can be due to epistasis between three IRF5 functional polymorphisms. These polymorphisms determine increased mRNA expression, a splice variant with a different exon 1 and a longer proline-rich region in exon 6. This result is striking as none of the three polymorphisms had an independent effect on their own. Protection was independent of these polymorphisms and seemed to reside in the 5 0 side of the gene. In conclusion, our results help to understand the role of the IRF5 locus in SLE susceptibility by clearly separating protection from susceptibility as caused by independent polymorphisms. In addition, we have found evidence for epistasis between known functional polymorphisms for the susceptibility effect.

Association of IRF5 polymorphisms with systemic lupus erythematosus in a Japanese population: Support for a crucial role of intron 1 polymorphisms

“…The association of IRF5 rs2004640 SNP was subsequently replicated in other Caucasian (8)(9)(10)(11)(12)(13) and Korean (14) populations. In fact, the results of all replication studies conducted thus far have supported an association between the IRF5 gene and SLE.…”

“…On the other hand, neither the exon 6 insertion nor the rs10954213A allele at the poly(A) signal, which constituted part of the risk haplotype in Caucasians (9)(10)(11)13), was associated with SLE in Japanese. This finding may be related to the difference in the haplotype structure between Japanese and Caucasians.…”

“…Subsequent detailed analyses have revealed that the SLE risk haplotype in Caucasians carried 4 polymorphisms: rs2004640T, a 30-nucleotide in-frame insertion in exon 6, rs2070197C, and rs10954213A (9)(10)(11)13). Three of them were functional polymorphisms.…”

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

“…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.…”

Analysis of the functional relevance of a putative regulatory SNP of PDCD1, PD1.3, associated with systemic lupus erythematosus

“…This is very relevant because SLE has a clear genetic component, recurrence sibling ratio of 20-40, and few genetic factors identified. 10,11 In addition, PDCD1 is a critical regulator of acquired immunity, and relevant genetic variants could have repercussion in other diseases. 12 It has two characteristic tyrosine domains in the cytoplasmic tail: an immunoreceptor tyrosine-based inhibition motif and an immunoreceptor tyrosine-based switch motif (ITSM).…”