Association of STAT4 and BLK, but not BANK1 or IRF5, with primary antiphospholipid syndrome

Abstract

Objective. Primary antiphospholipid syndrome (APS) is formally classified by the presence of antiphospholipid antibodies, recurrent thrombosis, and/or pregnancy morbidity in the absence of any underlying fullblown systemic autoimmune disease. However, systemic manifestations in patients with primary APS have been recently reported, as has the presence of serologic markers in common with systemic lupus erythematosus (SLE). In spite of similarities between the 2 diseases, only a minority of cases of primary APS evolve into full-blown SLE, even after a long followup period. The aim of this study was to investigate whether the analysis of SLE susceptibility genes may provide at least a partial explanation for such a discrepancy.Methods. One hundred thirty-three patients with primary APS classified according to the Sydney criteria and 468 healthy control subjects from the same geographic area were recruited. We genotyped 3 singlenucleotide polymorphisms (SNPs) in IRF5 (rs2004640, rs2070197, and rs10954213), 4 SNPs in STAT4 (rs1467199, rs3821236, rs3024866, and rs7574865), 2 SNPs in BANK1 (rs10516487 and rs3733197), and 1 SNP in BLK (rs2736340).Results. STAT4 and BLK displayed a strong genetic association with primary APS (for rs7574865, odds ratio [OR] 2.19, P ‫؍‬ 5.17 ؋ 10 ؊7 ; for rs2736340, OR 2.06, P ‫؍‬ 1.78 ؋ 10 ؊6 ), while a weak association with IRF5 and no association with BANK1 were observed.Conclusion. The presence of a strong genetic association with only a few SLE susceptibility genes and the absence of a more complex gene association may contribute to the lack of cases of full-blown SLE developing in patients with primary APS, in spite of the clinical and serologic similarities between SLE and primary APS.Antiphospholipid syndrome (APS) is characterized by the persistent positivity of antibodies against phospholipid-binding proteins in the presence of recurrent arterial/venous thrombotic events and/or pregnancy morbidity. Although APS was originally described in patients with systemic lupus erythematosus (SLE), more than 50% of cases of APS are now recognized in patients without any underlying full-blown systemic autoimmune disease (e.g., primary APS) (1).Understanding of the clinical spectrum of primary APS has evolved in the past years, with a gradual recognition that it is not merely an autoimmune thrombophilic disorder but, rather, a more systemic disease having several clinical manifestations in common with SLE (1). The similarity of the 2 diseases is further supported by additional biologic findings, i.e., 1) the role of complement activation and, at least for some manifestations, the involvement of inflammatory processes in APS pathogenesis (1), 2) the recent demonstration of the occurrence of antichromatin (i.e., antinucleosome) autoantibodies at medium/high titers in a large propor-

Platelet transcriptional profile and protein expression in patients with systemic lupus erythematosus: up-regulation of the type I interferon system is strongly associated with vascular disease

“…16 A STAT4 risk allele has also recently been associated with the primary APS. 37 In summary, genetic variants within the type I IFN system (STAT4) associated with VD and IFN␣ mediated endothelial dysfunction all contribute to the pathogenesis of VD. The correlation found between type I IFN-regulated proteins and platelet activation markers demonstrated in this paper adds a novel mechanism for development of VD in SLE.…”

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

“…Moreover, the significant association of both STAT4 and IRF5 polymorphisms has been also reported for other autoimmune diseases or inflammatory conditions, such as systemic sclerosis, 14 rheumatoid arthritis, 15 lupus. 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.…”

“…Abelson et al 8 reported a modest but significant correlation between STAT4 rs7574865 polymorphism (in complete LD with STAT4 rs7582694) and STAT4a mRNA level in PBMCs from 73 healthy volunteers. Sigurdsson et al 17 reported an increased expression of the risk allele of STAT4b in primary cells of mesenchymal origin (osteoblasts). None of the previous studies has addressed the functional consequences of STAT4 rs7582694 or STAT4 rs7574865 polymorphism among pSS patients.…”

Role of the C8orf13-BLK region in biopsy-proven giant cell arteritis

“…Furthermore, antiendothelial antibodies have been demonstrated in up to 50% of GCA patients [38]. Since an association between BLK and primary antiphospholipid syndrome was previously described [39], we aimed to determine whether a potential association of the C8orf13-BLK gene region with GCA might exist. However, in the present study, we could not confirm an association of GCA with rs13277113 and rs2736340 variants located within the C8orf13-BLK region.…”