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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, P<10−17) and protection (rs729302, P<10−6). 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′ 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.

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Acknowledgements

Cristina Fernandez-Lopez and Marta Picado have provided outstanding technical assistance. This work has been supported by Fondo de Investigacion Sanitaria, Instituto de Salud Carlos III (Spain), Grants 04/1651 and 06/0620 that are partially financed by the FEDER program of the EU and by Grants from the Xunta de Galicia. SR and CD were supported by Grant 00023728 of the Ministry of Health of the Czech Republic. RES and TW were supported by BMBF, KN Rheuma C2.12. Work by SD’A was supported by Telethon (Grant E1221) and the CARIPLO Foundation.

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Correspondence to A Gonzalez.

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Supplementary information accompanies the paper on Genes and Immunity web site (http://www.nature.com/gene)

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Ferreiro-Neira, I., Calaza, M., Alonso-Perez, E. et al. Opposed independent effects and epistasis in the complex association of IRF5 to SLE. Genes Immun 8, 429–438 (2007). https://doi.org/10.1038/sj.gene.6364407

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