Abstract
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. 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. 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.
Highlights
Much recent interest has been generated in the potential roles played by IFN-I in atherosclerosis because both pro- and antiatherogenic properties of IFN-I have been reported in murine models of the disease.[3,4,5,6,7,8]
Genetic Risk Score Based on 3 systemic lupus erythematosus (SLE) Single Nucleotide Polymorphisms Correlates With Peripheral Blood Mononuclear Cell IFN-I Responses To identify genetic variants with potential to regulate leukocyte IFN-I production, a list of 11 single nucleotide polymorphisms (SNPs) reported to be associated with SLE risk from 6 published reports of genome-wide association studies (GWAS) for SLE, and 9 SNPs which have been reported to be associated with serum IFN-α levels in candidate gene studies of SLE, was collated (Table 1; Table I in the online-only Data Supplement).[17,18,19,20,21,22]
Stratification of the results into genetic risk score (GRS) tertiles revealed that subjects in the highest GRS group produced significantly higher quantities of IFN-α and IFN-β in response to either R848 or CpG-ODN, compared with individuals in the lowest GRS group (Figure 1, P
Summary
As explained in Materials and Methods in the online-only Data Supplement, the effects of rs3131379 on CAD risk through total cholesterol and triglycerides were too small to have modified the conclusion, and repetition of the analysis with the omission of the pleiotropic SNP yielded the same results.
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