Please use this identifier to cite or link to this item:
|Title:||Genetic analysis of leukocyte type-I interferon production and risk of coronary artery disease|
|Authors:||Nelson, Christopher P.|
Samani, Nilesh J.
|Publisher:||American Heart Association, Lippincott, Williams & Wilkins|
|Citation:||Arteriosclerosis, Thrombosis and Vascular Biology, 2015, 35 (6), pp. 1456-1462|
|Abstract:||Objective: Patients with systemic lupus erythematosus (SLE) are genetically predisposed to enhanced production of the type-I interferon IFN-α, and are also at elevated risk of developing atherosclerosis compared to healthy subjects. We aimed to test whether or not genetic predisposition to increased type-I interferon production affects risk of coronary artery disease (CAD). Approach and results: Using a list of 11 SNPs from the results of genome-wide association studies for SLE, which we hypothesised would be enriched in variants that regulate type-I IFN production, we identified a genetic risk score (GRS) based on 3 SNPs (rs10516487, rs3131379 and rs7574865) which correlated significantly with production of IFN-α by human peripheral leukocytes stimulated with CpG-oligonucleotide (n=60, P=1.50x10-5 ). These SNPs explained 27.8% of variation in the CpG-oligonucleotide induced IFN-α response and were also associated with Toll-like receptor (TLR)7/8- and TLR9-dependent IFN-α and IFN-β responses, but were not associated with inflammatory cytokine production in response to TLR4 stimulation, or risk of CAD in 22,233 cases and 64,762 controls (OR 1.00, 95%CI 0.98-1.02) using Mendelian randomization-based analyses. CAD risk was also not associated with the full panel of 11 SLE SNPs, or loci responsible for the monogenic type-I interferonopathies Aicardi-Goutières syndrome and Spondyloenchondrodysplasia with immune dysregulation. Conclusion: The results argue against the potential utility of drugs targeting type-I interferon production for CAD. The use of genetic variants that modify leukocyte signalling pathways, rather than circulating biomarkers, as instruments in Mendelian randomization analyses may be useful for studies investigating causality of other candidate pathways of atherogenesis.|
|Rights:||Archived with reference to SHERPA/RoMEO and publisher website.|
|Description:||The online-only Data Supplement is available with this article at http://atvb.ahajournals.org/lookup/suppl/doi:10.1161/ATVBAHA.114.304925/-/DC1|
|Appears in Collections:||Published Articles, Dept. of Cardiovascular Sciences|
Files in This Item:
|Nelson et al CAD interferon MR v2.pdf||Post-review (final submitted)||324.14 kB||Adobe PDF||View/Open|
Items in LRA are protected by copyright, with all rights reserved, unless otherwise indicated.