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

Abstract

Objective— Patients with systemic lupus erythematosus are genetically predisposed to enhanced production of the type-I interferon IFN-α and are also at elevated risk of developing atherosclerosis compared with healthy subjects. We aimed to test whether genetic predisposition to increased type-I IFN production affects risk of coronary artery disease. Approach and Results— Using a list of 11 single nucleotide polymorphisms from the results of genome-wide association studies for systemic lupus erythematosus, which we hypothesised would be enriched in variants that regulate type-I IFN production, we identified a genetic risk score based on 3 single nucleotide polymorphisms (rs10516487, rs3131379 and rs7574865), which correlated significantly with production of IFN-α by human peripheral leukocytes stimulated with CpG-oligonucleotide (n=60, P =1.50×10 −5 ). These single nucleotide polymorphisms explained 27.8% of variation in the CpG-oligonucleotide-induced IFN-α response and were also associated with Toll-like receptor-7/8– and Toll-like receptor-9–dependent IFN-α and IFN-β responses, but were not associated with inflammatory cytokine production in response to Toll-like receptor-4 stimulation or risk of coronary artery disease in 22 233 cases and 64 762 controls (odds ratio 1.00, 95% CI 0.98–1.02) using Mendelian randomization–based analyses. Coronary artery disease risk was also not associated with the full panel of 11 systemic lupus erythematosus single nucleotide polymorphisms or loci responsible for the monogenic type-I interferonopathies Aicardi-Goutières syndrome and Spondyloenchondrodysplasia with immune dysregulation. Conclusions— The results argue against the potential utility of drugs targeting type-I IFN production for coronary artery disease. The use of genetic variants that modify leukocyte signaling pathways, rather than circulating biomarkers, as instruments in Mendelian randomization analyses may be useful for studies investigating causality of other candidate pathways of atherogenesis.

Adverse Cardiovascular Effects of Anti-COVID-19 Drugs

“…In addition, it causes endothelial dysfunction by promoting the expression of factors related to oxidative stress ( Buie et al, 2017 ). IFN-α can also cause acute myocardial injury by enhancing atherosclerotic plaques polarization of in M1 macrophages and inhibit angiogenesis by regulating signal transduction and activator of transcription 1 (STAT1) and STAT3 ( Nelson et al, 2015 ; Hsu et al, 2017 ). The mode of administration of IFN-α is aerosol inhalation, and the recommended dose is 5 million units or equivalent mixed with 2 ml of sterile water twice per day for adults.…”

Type-I interferons in atherosclerosis

“…Although the role for type-I IFN in the pathogenesis and instability of atherosclerosis is supported by studies in both human and mouse models (Table 1; Goossens et al, 2010;Levy et al, 2003;Niessner et al, 2006), there is no statistically significant association between the risk of coronary artery events and IFN-α production-correlated single nucleotide polymorphisms (Nelson et al, 2015). Alternatively, mutations in some components of the IFN regulation and signaling, such as IRF8 and JAK2, are associated with the increased risk of cardiovascular events in different populations (Jaiswal et al, 2017;Leonard et al, 2013).…”

Phagocytosis-dependent ketogenesis in retinal pigment epithelium

“…The plate was light-protected and incubated at 37°C for 1 h with gentle shaking before absorbance at 492 nm was measured. Free fatty acids were measured using a colorimetric enzymatic fatty acid quantification assay (ab65341; Abcam) as described (48). No ␤-HB was detected with OS alone.…”