Background Patients with Systemic Lupus Erythematosus (SLE) have increased morbidity and mortality in coronary heart disease (CHD). Modern treatment has reduced the risk of death in SLE due to inflammation in major organs, but the mortality in cardiovascular disease shows no such decline. Both traditional cardiovascular risk factors and SLE disease specific risk factors are of importance for the development of CHD in SLE.
Objectives We asked if there was a genetic influence on CHD in SLE.
Methods We performed a genetic association analysis in two cohorts (n=575 and n=227) of Swedish SLE patients using a 12k custom made array (Illumina). The allele frequencies were compared for SLE patients with (n=66) and without (n=509) CHD in cohort 1. We found 61 SNPs with an association (p<0.01) to CHD. Next, the allele frequencies of these 61 SNPs were compared in patients with (n=27) and without CHD (n=212) in the second cohort. In the first cohort 203 patients were examined by carotid ultrasound. Further, peripheral blood mononuclear cells from patients (non-risk allele=13, risk allele=7) were analyzed by flow cytometry. Next, the alleles of 14 SNPs in IRF8 were subjected to analysis by electrophoretic mobility shift assay (EMSA).
Results We found two highly linked (LD, r 2 =0.83) single nucleotide polymorphisms (SNPs) in the interferon regulatory factor 8 (IRF8) gene to be associated with CHD in both cohorts. Meta-analysis of the strongest associated SNP gave an odds ratio of 3.6 (2.1-6.3), p-value 1.9 x 10-6. The identified IRF8 allele remained as a risk factor for CHD after adjustment for traditional CHD risk factors in a logarithmic multivariable model. Further, patients with the IRF8 risk allele had more carotid plaques (p<0.001) and increased intima-media thickness (p=0.01). By EMSA we could show weaker binding of protein to a SNP highly linked to the risk allele. By flow cytometry we noted a significantly reduced frequency of circulating B cells in patients with the IRF8 risk allele
Conclusions We have identified a novel genetic locus in IRF8 to be associated to CHD in patients with SLE. The study highlight the fact that non-traditional risk factors for arteriosclerosis are important in SLE and that new therapeutic strategies targeting pro-inflammatory pathways are important for improving CHD morbidity and mortality among these patients.
Disclosure of Interest None Declared
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