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Coronary Heart Disease in Systemic Lupus Erythematosus Is Associated With Interferon Regulatory Factor-8 Gene Variants

Leonard, Dag ; Svenungsson, Elisabet ; Sandling, Johanna K. ; Berggren, Olof ; Jönsen, Andreas LU ; Bengtsson, Christine ; Wang, Chuan ; Jensen-Urstad, Kerstin ; Granstam, Sven-Olof and Bengtsson, Anders LU , et al. (2013) In Circulation: Cardiovascular Genetics 6(3). p.255-263
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. Methods and 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... (More)
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. Methods and 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, r(2)=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 1.9x10(-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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
lupus erythematosus, interferon regulatory factor-8, genes, disease, coronary, cardiovascular disease, carotid intima-media thickness, myocardial ischemia, systemic
in
Circulation: Cardiovascular Genetics
volume
6
issue
3
pages
255 - 263
publisher
American Heart Association
external identifiers
  • wos:000320580700006
  • scopus:84884498097
  • pmid:23661672
ISSN
1942-325X
DOI
10.1161/CIRCGENETICS.113.000044
language
English
LU publication?
yes
id
9a854f35-b7ba-4e87-bb95-70ac73298db4 (old id 3983160)
date added to LUP
2016-04-01 09:51:46
date last changed
2022-04-27 08:18:40
@article{9a854f35-b7ba-4e87-bb95-70ac73298db4,
  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. Methods and 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&lt;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, r(2)=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 1.9x10(-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&lt;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.}},
  author       = {{Leonard, Dag and Svenungsson, Elisabet and Sandling, Johanna K. and Berggren, Olof and Jönsen, Andreas and Bengtsson, Christine and Wang, Chuan and Jensen-Urstad, Kerstin and Granstam, Sven-Olof and Bengtsson, Anders and Gustafsson, Johanna T. and Gunnarsson, Iva and Rantapaa-Dahlqvist, Solbritt and Nordmark, Gunnel and Eloranta, Maija-Leena and Syvanen, Ann-Christine and Ronnblom, Lars}},
  issn         = {{1942-325X}},
  keywords     = {{lupus erythematosus; interferon regulatory factor-8; genes; disease; coronary; cardiovascular disease; carotid intima-media thickness; myocardial ischemia; systemic}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{255--263}},
  publisher    = {{American Heart Association}},
  series       = {{Circulation: Cardiovascular Genetics}},
  title        = {{Coronary Heart Disease in Systemic Lupus Erythematosus Is Associated With Interferon Regulatory Factor-8 Gene Variants}},
  url          = {{http://dx.doi.org/10.1161/CIRCGENETICS.113.000044}},
  doi          = {{10.1161/CIRCGENETICS.113.000044}},
  volume       = {{6}},
  year         = {{2013}},
}