A STAT4 risk allele is associated with ischaemic cerebrovascular events and anti-phospholipid antibodies in systemic lupus erythematosus.
OBJECTIVE
To investigate whether 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 prothrombotic anti-phospholipid antibodies (aPL) in patients with SLE.


METHODS
Two independent groups of unrelated patients with SLE of Swedish ethnicity (n=424 and 154) were genotyped, and occurrence of previous manifestations of ischaemic heart disease (IHD), ischaemic cerebrovascular disease (ICVD) and venous thromboembolic events (VTE) was tabulated. aPL values were measured by ELISA. Matched controls (n=492 and 194) were genotyped.


RESULTS
The STAT4 risk allele was more frequent in patients with SLE with previous arterial events (combined OR (OR(c))=1.5, 95% CI 1.1 to 2.0) compared to patients without such events. The association was mainly attributable to an accumulation of the risk allele among patients with ICVD (OR(c)=2.3, CI 1.6 to 3.3). There was no association with IHD or VTE. The presence of two or more aPLs was associated with the risk allele (OR(c)=1.6, 95% CI 1.2 to 2.0). In multivariable-adjusted logistic regression analyses treatment for hypertension, at least one STAT4 risk allele, older age, IgG anti-cardiolipin antibodies and longer SLE duration remained independently associated with previous ICVD (p<or=0.02 for all).


CONCLUSIONS
Patients with SLE with the STAT4 risk allele had a strikingly increased risk of ICVD, comparable in magnitude to that of hypertension. The results imply that a genetic predisposition is an important and previously unrecognised risk factor for ICVD in SLE, and that aPLs may be one underlying mechanism.
Svenungsson
Elisabet
E
Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Solna, SE-17176 Stockholm, Sweden. elisabet.svenungsson@ki.se
Gustafsson
Johanna
J
Leonard
Dag
D
Sandling
Johanna
J
Gunnarsson
Iva
I
Nordmark
Gunnel
G
Jönsen
Andreas
A
Bengtsson
Anders A
AA
Sturfelt
Gunnar
G
Rantapää-Dahlqvist
Solbritt
S
Elvin
Kerstin
K
Sundin
Ulf
U
Garnier
Sophie
S
Simard
Julia F
JF
Sigurdsson
Snaevar
S
Padyukov
Leonid
L
Syvänen
Ann-Christine
AC
Rönnblom
Lars
L
D000328:Adult; D000368:Aged; D000483:Alleles; D017152:Antibodies, Antiphospholipid / Q000097:blood*; D002545:Brain Ischemia / Q000209:etiology / Q000235:genetics* / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000150:complications / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D050797:STAT4 Transcription Factor / Q000235:genetics*
D017152:Antibodies, Antiphospholipid; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human