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. 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 1.9×10 –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.

Genetic Analysis of Leukocyte Type-I Interferon Production and Risk of Coronary Artery Disease

“…Accordingly, the IRF8 SNPs which are associated with risk of SLE were not associated with CAD risk in SLE patients. 28 Together, these observations suggest that the IRF8 SNPs mediate their effect on CAD risk in SLE patients via mechanisms which are independent of IFN-I. These findings also add weight to the notion that a common mediator of distinct cellular responses (eg, inflammatory or antiviral responses) can be differentially regulated by distinct proximal SNPs (as explained in Figure V in the online-only Data Supplement).…”

“…To further explore the potential involvement of this pathway in CAD and because SLE patients may be chronically exposed to IFN-inducing stimuli which are low or absent in the healthy CARDIoGRAM population, we also examined whether IFN-I regulating SNPs may modify CAD risk in SLE patients by performing pathway analysis of the 50 independent loci reported to be associated with CAD risk in SLE patients by Leonard et al 28 Consistent with the earlier analyses, these pathways showed no relationship to IFN-I signaling ( Figure IV in the online-only Data Supplement), and none of the IFN-I or SLE GWAS SNPs cited above were associated with risk of CAD in SLE patients. 28 Interestingly, 2 of the SNPs associated with CAD risk in SLE patients were identified near the IRF8 gene, 28 which play a key role in monocyte and B-cell differentiation, but may also contribute to IFN-I signaling.…”

“…28 Interestingly, 2 of the SNPs associated with CAD risk in SLE patients were identified near the IRF8 gene, 28 which play a key role in monocyte and B-cell differentiation, but may also contribute to IFN-I signaling. 12 However, the 2 IRF8 SNPs associated with CAD risk were not in linkage disequillibrium with those reported previously to be associated with risk of SLE itself or with SLE severity, which tracks serum IFN-α levels.…”

Type I interferon–mediated autoimmune diseases: pathogenesis, diagnosis and targeted therapy

“…Intriguingly, high IFN-I activity seems to be a heritable risk factor being clustered in specific families in both SLE patients and their healthy first-degree relatives (49). The risk haplotypes in the interferon regulatory factors IRF5 and IRF7 are associated with increased IFN-I activity and the risk is dependent on particular autoantibodies (53)(54)(55)(56)(57)(58). The risk haplotype of IRF5 is also associated with risk of progression to clinical disease in ANA positive individuals (56).…”

Interferon Regulatory Factor 8 Modulates Phenotypic Switching of Smooth Muscle Cells by Regulating the Activity of Myocardin

“…In recent years, the roles of IRF8 in cardiovascular diseases have been revealed. By comparing allele frequencies between systemic lupus erythematosus patients with and without coronary heart disease, single nucleotide polymorphisms located in the IRF8 gene were identified to be associated with the presence of carotid plaques and increased intima-media thickness (40). Thus, these findings suggest a potential involvement of IRF8 in neointima formation and the development of vascular occlusive diseases.…”