Structural insertion/deletion variation in IRF5 is associated with a risk haplotype and defines the precise IRF5 isoforms expressed in systemic lupus erythematosus

Kozyrev, Sergey V.; Lewēn, Susanna; Reddy, Prasad M. V. Linga; Pons-Estel, Bernardo A.; Witte, Torsten; Junker, Peter; Laustrup, Helle; Gutiérrez, Carmen; Suárez, Ana; González‐Escribano, María Francisca; Martı́n, Javier; Alarcón‐Riquelme, Marta E.

doi:10.1002/art.22497

Cited by 106 publications

(137 citation statements)

References 16 publications

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“…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).…”

Section: Association Of Sle and Irf5 Variantssupporting

confidence: 66%

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…Five SNPs were genotyped on all subjects (rs729302, rs2004640, rs752637, rs3807306 and rs2280714), and two SNPs (rs2070197 and rs10954213) were additionally genotyped in CASSLE participants to replicate recent haplotype-based findings in Caucasians. 13,14,17 Statistical analyses SNPs were found to be in Hardy-Weinberg equilibrium unless noted otherwise. Population-based case-control comparisons (allelic w 2 -statistics) were calculated using SAS v9.0.…”

Section: Participant Recruitment and Biological Sample Collectionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2008

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Increased expression of interferon (IFN)-inducible genes is implicated in the pathogenesis of systemic lupus erythematosus (SLE). One transcription factor responsible for regulating IFN, interferon regulatory factor-5 (IRF5), has been associated with SLE in genetic studies of Asian, Caucasian and Hispanic populations. We genotyped up to seven polymorphic loci in or near IRF5 in a total of 4870 African-American and Caucasian subjects (1829 SLE sporadic cases and 3041 controls) from two independent studies. Population-based case-control comparisons were performed using the Pearson's w 2 -test statistics and haplotypes were inferred using HaploView. We observed significant novel associations with the IRF5 variants rs2004640 and rs3807306 in African Americans and replicated previously reported associations in Caucasians. While we identified risk haplotypes, the majority of haplotypic effects were accounted for by one SNP (rs3807306) in conditional analyses. We conclude that genetic variants of IRF5 associate with SLE in multiple populations, providing evidence that IRF5 is likely to be a crucial component in SLE pathogenesis among multiple ethnic groups.

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Section: Association Of Sle and Irf5 Variantssupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Section: Participant Recruitment and Biological Sample Collectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2008

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

Kawasaki¹,

Kyogoku²,

Ohashi³

et al. 2008

Arthritis & Rheumatism

100

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Objective. To determine whether the IRF5 gene, which encodes interferon regulatory factor 5, is associated with systemic lupus erythematosus (SLE) in a Japanese population.Methods. A case-control study was performed in 277 SLE patients and 201 healthy controls. Associations between the IRF5 genotype and levels of messenger RNA (mRNA) for interferon (IFN) pathway genes were examined using an mRNA expression database of HapMap samples.Results. Carriers of the rs2004640T single-nucleotide polymorphism (SNP) were slightly increased among SLE patients (58.8%) as compared with controls (50.2%). When data from our Japanese population were combined with previously published data from a Korean population, the T allele frequency was found to be significantly increased in SLE patients (P ‫؍‬ 8.3 ؋ 10 ؊5 ). While no association was observed for the rs10954213 SNP or the exon 6 insertion/deletion, significant associations with 3 intron 1 SNPs (-4001, rs6953165, and rs41298401) were found. The allele frequency of rs41298401G was significantly decreased in SLE patients (13.0% versus 18.7% in controls; P ‫؍‬ 0.017), and the allele frequency of rs6953165G, which was in absolute linkage disequilibrium with -4001A, was increased in SLE patients (8.8% versus 5.2% in controls; P ‫؍‬ 0.034). The Caucasian risk haplotype was not present; instead, a protective haplotype carrying rs2004640G, rs41298401G, the deletion in exon 6, and rs10954213A was identified. SNP rs10954213, but not intron 1 SNPs, was associated with IRF5 at the mRNA level; nevertheless, intron 1 SNPs were also associated with levels of mRNA for several IFN pathway genes, suggesting a functional role.Conclusion. IRF5 was found to be associated with SLE in Asian populations. Intron 1 SNPs, rather than exon 6 and 3 -untranslated region polymorphisms, appeared to play a crucial role.Over the last 2 decades, evidence has emerged of the involvement of type I interferon (IFN) in the pathogenesis of systemic lupus erythematosus (SLE) (1). Elevated serum levels of IFN in SLE patients have been reported (2), and gene expression analyses using microarrays have revealed IFN-inducible genes to be upregulated in peripheral blood cells from SLE patients (3-6).Recently, analyses of single-nucleotide polymorphisms (SNPs) in genes of the type I IFN pathway

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Association of interferon regulatory factor 5 haplotypes, similar to that found in systemic lupus erythematosus, in a large subgroup of patients with rheumatoid arthritis

Dieguez-Gonzalez

Calaza

Pérez‐Pampín

et al. 2008

Arthritis & Rheumatism

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Objective. Previous studies have shown either a lack of effect of IRF5 polymorphisms or an association of the IRF5 gene in only a minor subset of rheumatoid arthritis (RA) patients in whom anti-citrullinated protein antibodies (ACPAs) are absent. The present study was undertaken to investigate the role of genetic variation in IRF5 in susceptibility to RA.Methods. Nine IRF5 single-nucleotide polymorphisms (SNPs) were studied in 1,338 patients with RA and 1,342 control subjects in analyses of exploratory and replication sample collections, with stratification according to sex and by the presence or absence of ACPAs, rheumatoid factor, the shared epitope, the 620W PTPN22 allele, and erosions. A meta-analysis that included results from previous studies was also carried out.Results. Our findings together with those from previous studies, in a total of 4,620 RA patients and 3,741 controls, showed a significant association of the rs2004640 IRF5 SNP in RA patients as a whole (odds ratio [OR] 0.88, 95% confidence interval [95% CI] 0.83-0.94; P ‫؍‬ 6.5 ؋ 10 ؊5 versus controls). This association was stronger in ACPA؊ patients, but was also present in ACPA؉ patients (from 3 sample collections). Further analysis of our exploratory sample collection showed that only patients in the ACPA؉ and SE؊ group lacked an association with IRF5 SNPs. All of the remaining RA patients (ACPA؊ or SE؉) showed a strong association with IRF5 SNPs, which followed a complex pattern of opposing effects mediated by independent haplotypes. The susceptibility haplotype showed an OR of 1.8 (95% CI 1.4-2.3; P ‫؍‬ 1.2 ؋ 10 ؊6 versus controls), whereas the protective haplotype showed an OR of 0.76 (95% CI 0.6-0.98; P ‫؍‬ 0.046 versus controls).Conclusion. IRF5 polymorphisms seem to influence RA susceptibility in a large subgroup of patients, following a pattern of association very similar to that described in patients with systemic lupus erythematosus.

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Structural insertion/deletion variation in IRF5 is associated with a risk haplotype and defines the precise IRF5 isoforms expressed in systemic lupus erythematosus

Cited by 106 publications

References 16 publications

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

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

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

Association of interferon regulatory factor 5 haplotypes, similar to that found in systemic lupus erythematosus, in a large subgroup of patients with rheumatoid arthritis

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