Objective: To investigate if the risk allele for systemic lupus erythematosus (SLE) in the signal transducer and activator of transcription factor 4 (STAT4) gene, defined by the single nucleotide polymorphism (SNP) rs10181656(G), is associated with vascular events and/or presence of pro-thrombotic antiphospholipid antibodies (aPL) in SLE patients.
Methods: We genotyped two independent groups of unrelated SLE patients of Swedish ethnicity (n=424 and 154) and tabulated occurrence of previous manifestations of ischemic heart disease (IHD), ischemic cerebrovascular disease (ICVD) and venous thromboembolic events (VTE). aPL were measured with ELISA. Matched controls (n=492 and 194) were genotyped.
Results: The STAT4 risk allele was more frequent in SLE patients with previous arterial events [combined odds ratio (ORc)=1.5, 95% confidence interval (CI) 1.1-2.0] compared to patients without such events. The association was mainly attributable to an accumulation of the risk allele among patients with ICVD (ORc=2.3, CI 1.6-3.3). There was no association with IHD or VTE. The presence of two or more aPLs was associated with the risk allele (ORc=1.6, CI 1.2-2.0). In multivariable-adjusted logistic regression analyses treatment for hypertension, at least one STAT4 risk allele, older age, IgG anticardiolipin antibodies and longer SLE duration remained independently associated with previous ICVD (p≤0.02 for all).
Conclusion: SLE patients with the STAT4 risk allele had a strikingly increased risk of ICVD, comparable in magnitude to that of hypertension. Our results imply that a genetic predisposition is an important and previously unrecognized risk factor for ICVD in SLE, and that aPLs may be one underlying mechanism.