1. ¹Laboratorio Investigacion 2 and Rheumatology Unit, Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain
2. ²Clinical Immunology, University of Milan and Fondazione IRCCS Ospedale Maggiore Policlinico, Milan, Italy
3. ³UO Complessa di Reumatologia, Ospedale S. Camillo – Forlanini, Rome, Italy
4. ⁴Servicio de Reumatologia, CH Universitario Juan Canalejo, A Coruña, Spain
5. ⁵Institute of Clinical Biochemistry, Martin Faculty Hospital, Martin, Slovakia
6. ⁶Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, Groningen, The Netherlands
7. ⁷Pathophysiology Department, Athens University Medical School, Athens, Greece
8. ⁸Rheumatology Unit, Second University of Naples, Caserta, Italy
9. ⁹Department of Medical Sciences and IRCAD, Eastern Piedmont University, Novara, Italy
10. ¹⁰Molecular Biology and Immunogenetics Department, Institute of Rheumatology, Prague, Czech Republic
11. ¹¹Division of Clinical Immunology, Hannover Medical School, Hannover, Germany
12. ¹²Department of Histocompatibility and Immunology, Evangelismos Hospital, Athens, Greece
13. ¹³Paediatrics Department, University of Szeged, Szeged, Hungary
14. ¹⁴Internal Medicine, Research Laboratory in Autoimmune Diseases, Hospital Vall d'Hebron, Barcelona, Spain
15. ¹⁵Rheumatology Unit, Hospital 12 de Octubre, Madrid, Spain
16. ¹⁶Department of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain

Correspondence: Dr A Gonzalez, Laboratorio de Investigacion 2, Hospital Clinico Universitario de Santiago, 15706-Santiago de Compostela, Travesia Choupana, A Coruña, Spain. E-mail: Antonio.Gonzalez.Martinez.Pedrayo@sergas.es

¹⁷Current address: Gerontology Research Center, NIA, NIH, Baltimore, MD, USA.

Received 3 April 2007; Revised 15 May 2007; Accepted 15 May 2007; Published online 14 June 2007.

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.