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Original Research

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

Christopher P. Nelson, Heribert Schunkert, Nilesh J. Samani, Clett Erridge
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https://doi.org/10.1161/ATVBAHA.114.304925
Arteriosclerosis, Thrombosis, and Vascular Biology. 2015;ATVBAHA.114.304925
Originally published April 16, 2015
Christopher P. Nelson
From the Department of Cardiovascular Sciences, University of Leicester, Leicester, UK (C.P.N., N.J.S., C.E.); National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK (C.P.N., N.J.S., C.E.); German Centre for Cardiovascular Research (DZHK), Munich Heart Alliance, Munich, Germany (H.S.); and Deutsches Herzzentrum München, Technische Universität München, Munich, Germany (H.S.).
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Heribert Schunkert
From the Department of Cardiovascular Sciences, University of Leicester, Leicester, UK (C.P.N., N.J.S., C.E.); National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK (C.P.N., N.J.S., C.E.); German Centre for Cardiovascular Research (DZHK), Munich Heart Alliance, Munich, Germany (H.S.); and Deutsches Herzzentrum München, Technische Universität München, Munich, Germany (H.S.).
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Nilesh J. Samani
From the Department of Cardiovascular Sciences, University of Leicester, Leicester, UK (C.P.N., N.J.S., C.E.); National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK (C.P.N., N.J.S., C.E.); German Centre for Cardiovascular Research (DZHK), Munich Heart Alliance, Munich, Germany (H.S.); and Deutsches Herzzentrum München, Technische Universität München, Munich, Germany (H.S.).
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Clett Erridge
From the Department of Cardiovascular Sciences, University of Leicester, Leicester, UK (C.P.N., N.J.S., C.E.); National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK (C.P.N., N.J.S., C.E.); German Centre for Cardiovascular Research (DZHK), Munich Heart Alliance, Munich, Germany (H.S.); and Deutsches Herzzentrum München, Technische Universität München, Munich, Germany (H.S.).
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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.

  • coronary artery disease
  • genetic association
  • immune system
  • systemic lupus erythematosus
  • Received November 4, 2014.
  • Accepted April 4, 2015.
  • © 2015 American Heart Association, Inc.
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    Genetic Analysis of Leukocyte Type-I Interferon Production and Risk of Coronary Artery Disease
    Christopher P. Nelson, Heribert Schunkert, Nilesh J. Samani and Clett Erridge
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2015;ATVBAHA.114.304925, originally published April 16, 2015
    https://doi.org/10.1161/ATVBAHA.114.304925

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    Genetic Analysis of Leukocyte Type-I Interferon Production and Risk of Coronary Artery Disease
    Christopher P. Nelson, Heribert Schunkert, Nilesh J. Samani and Clett Erridge
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2015;ATVBAHA.114.304925, originally published April 16, 2015
    https://doi.org/10.1161/ATVBAHA.114.304925
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