1. ¹Section of Rheumatology, Uppsala University, Uppsala, Sweden
2. ²Molecular Medicine, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
3. ³Department of Rheumatology, University Hospital, Malmö, Sweden
4. ⁴Department of Rheumatology, University Hospital, Linköping, Sweden
5. ⁵Department of Rheumatology, Haukeland University Hospital, Bergen, Norway
6. ⁶Section for Rheumatology, Institute of Medicine, University of Bergen, Bergen, Norway
7. ⁷Department of Medicine, Rheumatology Unit, Karolinska Institutet/Karolinska University Hospital, Stockholm, Sweden
8. ⁸Institute of Laboratory Medicine Section of MIG, Lund University, Lund, Sweden
9. ⁹Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden
10. ¹⁰Broegelmann Research Laboratory, The Gade Institute, University of Bergen, Bergen, Norway

Correspondence: Dr G Nordmark, Rheumatology Clinic, Entrance 30, Uppsala University Hospital, Uppsala SE-75185, Sweden. E-mail: Gunnel.Nordmark@medsci.uu.se

¹¹These authors contributed equally to this work.

Received 16 June 2008; Revised 11 November 2008; Accepted 12 November 2008; Published online 18 December 2008.

Abstract

Primary Sjögren's syndrome (SS) shares many features with systemic lupus erythematosus (SLE). Here we investigated the association of the three major polymorphisms in IRF5 and STAT4 found to be associated with SLE, in patients from Sweden and Norway with primary SS. These polymorphisms are a 5-bp CGGGG indel in the promoter of IRF5, the single nucleotide polymorphism (SNP) rs10488631 downstream of IRF5 and the STAT4 SNP rs7582694, which tags the major risk haplotype of STAT4. We observed strong signals for association between all three polymorphisms and primary SS, with odds ratios (ORs) >1.4 and P-values <0.01. We also found a strong additive effect of the three risk alleles of IRF5 and STAT4 with an overall significance between the number of risk alleles and primary SS of P=2.5 10^-9. The OR for primary SS increased in an additive manner, with an average increase in OR of 1.78. For carriers of two risk alleles, the OR for primary SS is 1.43, whereas carriers of five risk alleles have an OR of 6.78. IRF5 and STAT4 are components of the type I IFN system, and our findings emphasize the importance of this system in the etiopathogenesis of primary SS.