HLA-DRB1*04/*13 alleles are associated with vascular disease and antiphospholipid antibodies in systemic lupus erythematosus.
OBJECTIVE
Vascular disease is common in systemic lupus erythematosus (SLE) and patients with antiphospholipid antibodies (aPL) are at high risk to develop arterial and venous thrombosis. Since HLA class II genotypes have been linked to the presence of pro-thrombotic aPL, we investigated the relationship between HLA-DRB1 alleles, aPL and vascular events in SLE patients.


METHODS
665 SLE patients of Caucasian origin and 1403 controls were included. Previous manifestations of ischaemic heart disease, ischaemic cerebrovascular disease (ICVD) and venous thromboembolism (together referred to as any vascular events (AVE)) were tabulated. aPL were measured with ELISA. Two-digit HLA-DRB1 typing was performed by sequence-specific primer-PCR.


RESULTS
HLA-DRB1*04 was more frequent among SLE patients with ICVD compared to unaffected patients. This association remained after adjustment for known traditional cardiovascular risk factors. HLA-DRB1*13 was associated with AVE. All measured specificities of aPL-cardiolipin IgG and IgM, β2-glycoprotein-1 IgG, prothrombin (PT) IgG and a positive lupus anticoagulant test were associated with HLA-DRB1*04-while HLA-DRB1*13 was associated with IgG antibodies (β2-glycoprotein-1, cardiolipin and PT). In patients with the combined risk alleles, HLA-DRB1*04/*13, there was a significant additive interaction for the outcomes AVE and ICVD.


CONCLUSIONS
The HLA-DRB1*04 and HLA-DRB1*13 alleles are associated with vascular events and an aPL positive immune-phenotype in SLE. Results demonstrate that a subset of SLE patients is genetically disposed to vascular vulnerability.
Department of Medicine, Rheumatology Unit, Karolinska Institutet/Karolinska University Hospital, Stockholm, Sweden.
Emeli
E
Lundström
Johanna T
JT
Gustafsson
Andreas
A
Jönsen
Dag
D
Leonard
Agneta
A
Zickert
Kerstin
K
Elvin
Gunnar
G
Sturfelt
Gunnel
G
Nordmark
Anders A
AA
Bengtsson
Ulf
U
Sundin
Henrik
H
Källberg
Johanna K
JK
Sandling
Ann-Christine
AC
Syvänen
Lars
L
Klareskog
Iva
I
Gunnarsson
Lars
L
Rönnblom
Leonid
L
Padyukov
Elisabet
E
Svenungsson
D000328:Adult; D000368:Aged; D017152:Antibodies, Antiphospholipid / Q000276:immunology*; D002545:Brain Ischemia / Q000235:genetics / Q000276:immunology; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000235:genetics / Q000276:immunology; D058729:Peripheral Arterial Disease / Q000235:genetics / Q000276:immunology; D014652:Vascular Diseases / Q000235:genetics* / Q000276:immunology; D054556:Venous Thromboembolism / Q000235:genetics / Q000276:immunology
D017152:Antibodies, Antiphospholipid; D059811:HLA-DRB1 Chains; C527195:HLA-DRB1*04 antigen; C506473:HLA-DRB1*13 antigen