期刊
CIRCULATION-CARDIOVASCULAR GENETICS
卷 6, 期 3, 页码 255-263出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCGENETICS.113.000044
关键词
cardiovascular disease; carotid intima-media thickness; coronary disease; genes; interferon regulatory factor-8; lupus erythematosus, systemic; myocardial ischemia
资金
- Knut and Alice Wallenberg Foundation [2011.0073]
- Swedish Research Council for Medicine and Health [A0280001, A0258801, B0295701]
- Swedish Research Council for Science and Technology [90559401]
- Swedish Rheumatism Foundation
- King Gustaf V's 80-year Foundation
- Selander Foundation
- Agnes and Mac Rudberg Foundation
- Gustaf Prim Foundation
- Torsten Soderberg Foundation
- Access to Learning Fund from Uppsala County Council
- Access to Learning Fund from Uppsala University Hospital
- Access to Learning Fund from Stockholm County Council
- Access to Learning Fund from Karolinska Institutet
- Swedish Heart-Lung Foundation
- Swedish Society of Medicine
- Ake Wiberg Foundation
- Foundation in memory of Clas Groschinsky
- Karolinska Institutet Foundations
- COMBINE
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.
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