Additive effects of the major risk alleles of IRF5 and STAT4 in primary Sjögren's syndrome

Abstract

Primary Sjö gren'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) 41.4 and P-values o0.01. 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 ¼ 2.5 Â 10 À9 . 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.

STAT4 is a confirmed genetic risk factor for Sjögren's syndrome and could be involved in type 1 interferon pathway signaling

“…8,11,[15][16][17][18] Interestingly, all these autoimmune diseases could be, to some extent type 1 IFN driven. This study provides additional data suggesting that STAT4 and IRF5 function independently on pSS genetic susceptibility, with an additive effect but with no epistatic interaction between both genes, which confirms the findings from Nordmark et al 6 in patients of North European ancestry.…”

“…Previous significant association of the allele with pSS was reported in populations from Northern Europe (Norway and Sweden) 6 and from the United States of America. 7 A thorough examination of previously reported studies of the association of STAT4 with STAT4 gene polymorphism associated with Sjögren's syndrome N Gestermann et al various autoimmune diseases concluded that minor allele frequencies among healthy controls vary, to some extent, by the geographic ancestry, even among the European Caucasians: 22% in Sweden and 23% in Norway, 6 and lower allelic frequencies reported among controls of Spanish (ranging from 19 to 20.8%) 10,11 or Greek origin (17%). 12 Thus, we considered that a replication study involving pSS patients and controls from the midwest region of Europe was necessary.…”

“…These observations have provided new insights into the genetics of pSS by focusing on genes involved in innate immunity and the IFN pathway; the same interferon regulatory factor 5 (IRF5) polymorphism has been found associated with both pSS and systemic lupus erythematosus. [4][5][6] STAT4 is not classically considered as a factor involved in the type 1 IFN pathway. Conversely, it has a critical role in cellular growth and T-helper 1 differentiation, with interleukin 12 binding to its receptor.…”

“…6,7 However, the functional consequence of this genetic association has not been studied in patients with pSS or with other autoimmune diseases. In the present study, we aimed to replicate the association between pSS and STAT4 polymorphism in two independent cohorts of patients with pSS.…”

The CGGGG insertion/deletion polymorphism of the IRF5 promoter is a strong risk factor for primary Sjögren's syndrome

“…When both cohorts were analyzed as a combined group (385 patients with primary SS and 439 healthy controls), the association was pronounced for multifactorial disease (OR 2.00 [95% CI 1.48-2.73], P ϭ 6.6 ϫ 10 Ϫ6 ). Recently, Nordmark et al (12) reported an association of the CGGGG insertion/deletion polymorphism of the IRF5 promoter with primary SS but did not report any functional data. Thus, our study is an important confirmation of the association of primary SS with the IRF5 CGGGG insertion/deletion polymorphism.…”