title: Coronary heart disease in systemic lupus erythematosus is associated with interferon regulatory factor-8 gene variants.
abstract: BACKGROUND
  Patients with systemic lupus erythematosus have increased morbidity and mortality in coronary heart disease (CHD). We asked whether there was a genetic influence on CHD in systemic lupus erythematosus.
  
  
  RESULTS
  The association between single-nucleotide polymorphisms (SNPs) and CHD in 2 populations of patients with systemic lupus erythematosus was assessed. Patients were genotyped on a custom 12k Illumina Array. The allele frequencies were compared between patients with (n=66) and without (n=509) CHD. We found 61 SNPs with an association (P<0.01) to CHD, with the strongest association for 3 SNPs located in the interferon regulatory factor-8 (IRF8) gene. Comparison of the allele frequencies of these 61 SNPs in patients with (n=27) and without (n=212) CHD in the second study population revealed that 2 SNPs, rs925994 and rs10514610 in IRF8 (linkage disequilibrium, r²=0.84), were associated with CHD in both study populations. Meta-analysis of the SNP rs925994 gave an odds ratio of 3.6 (2.1-6.3), P value 1.9×10⁻⁶. The identified IRF8 allele remained as a risk factor for CHD after adjustment for traditional CHD risk factors. The IRF8 risk allele was associated with the presence of carotid plaques (P<0.001) and increased intima-media thickness (P=0.01). By electrophoretic mobility shift assays, we show weaker binding of protein to the risk allele of the highly linked SNP rs11117415, and by flow cytometry, a reduced frequency of circulating B cells was detected in patients with the IRF8 risk allele.
  
  
  CONCLUSIONS
  There is a considerable genetic component for CHD in systemic lupus erythematosus, with IRF8 as a strong susceptibility locus.
authors: Section of Rheumatology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden. dag.leonard@medsci.uu.se
authors: Dag
authors: D
authors: Leonard
authors: Elisabet
authors: E
authors: Svenungsson
authors: Johanna K
authors: JK
authors: Sandling
authors: Olof
authors: O
authors: Berggren
authors: Andreas
authors: A
authors: Jönsen
authors: Christine
authors: C
authors: Bengtsson
authors: Chuan
authors: C
authors: Wang
authors: Kerstin
authors: K
authors: Jensen-Urstad
authors: Sven-Olof
authors: SO
authors: Granstam
authors: Anders A
authors: AA
authors: Bengtsson
authors: Johanna T
authors: JT
authors: Gustafsson
authors: Iva
authors: I
authors: Gunnarsson
authors: Solbritt
authors: S
authors: Rantapää-Dahlqvist
authors: Gunnel
authors: G
authors: Nordmark
authors: Maija-Leena
authors: ML
authors: Eloranta
authors: Ann-Christine
authors: AC
authors: Syvänen
authors: Lars
authors: L
authors: Rönnblom
mesh_terms: D000328:Adult; D000368:Aged; D003327:Coronary Disease / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D013548:Sweden; D044465:White People / Q000235:genetics; D055815:Young Adult; D000099185:Interferon Regulatory Factor-8
chemical_list: D050835:Interferon Regulatory Factors; D000099185:Interferon Regulatory Factor-8
keywords: cardiovascular disease; carotid intima-media thickness; coronary disease; genes; interferon regulatory factor-8; lupus erythematosus, systemic; myocardial ischemia