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      Causal Inference for Genetically Determined Levels of High-Density Lipoprotein Cholesterol and Risk of Infectious Disease

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          Abstract

          Supplemental Digital Content is available in the text.

          Objective:

          HDL (high-density lipoprotein) cholesterol (HDL-C) and LDL (low-density lipoprotein) cholesterol (LDL-C) are inversely associated with infectious hospitalizations. Whether these represent causal relationships is unknown.

          Approach and Results:

          Adults of 40 to 69 years of age were recruited from across the United Kingdom between 2006 and 2010 and followed until March 31, 2016, as part of the UK Biobank. We determined HDL-C, LDL-C, and triglyceride polygenic scores for UK Biobank participants of British white ancestry (n=407 558). We examined the association of lipid levels and polygenic scores with infectious hospitalizations, antibiotic usage, and 28-day sepsis survival using Cox proportional hazards or logistic regression models. Measured levels of HDL-C and LDL-C were inversely associated with risk of infectious hospitalizations, while triglycerides displayed a positive association. A 1-mmol/L increase in genetically determined levels of HDL-C associated with a hazard ratio for infectious disease of 0.84 ([95% CI, 0.75–0.95]; P=0.004). Mendelian randomization using genetic variants associated with HDL-C as an instrumental variable was consistent with a causal relationship between elevated HDL-C and reduced risk of infectious hospitalizations (inverse weighted variance method, P=0.001). Furthermore, of 3222 participants who experienced an index episode of sepsis, there was a significant inverse association between continuous HDL-C polygenic score and 28-day mortality (adjusted hazard ratio, 0.37 [95% CI, 0.14–0.96] per 1 mmol/L increase; P=0.04). LDL-C and triglyceride polygenic scores were not significantly associated with hospitalization for infection, antibiotic use, or sepsis mortality.

          Conclusions:

          Our results provide causal inference for an inverse relationship between HDL-C, but not LDL-C or triglycerides, and risk of an infectious hospitalization.

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          Most cited references29

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          Mendelian Randomization.

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            High density lipoprotein mediates anti-inflammatory transcriptional reprogramming of macrophages via the transcriptional repressor ATF3

            High Density Lipoprotein (HDL) mediates reverse cholesterol transport and it is known to be protective against atherosclerosis. In addition, HDL has potent anti-inflammatory properties that may be critical for protection against other inflammatory diseases. The molecular mechanisms of how HDL can modulate inflammation, particularly in immune cells such as macrophages, remain poorly understood. Here we identify the transcriptional repressor ATF3, as an HDL-inducible target gene in macrophages that down-regulates the expression of Toll-like receptor (TLR)-induced pro-inflammatory cytokines. The protective effects of HDL against TLR-induced inflammation were fully dependent on ATF3 in vitro and in vivo. Our findings may explain the broad anti-inflammatory and metabolic actions of HDL and provide the basis for predicting the success of novel HDL-based therapies.
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              Genetic Analysis in UK Biobank Links Insulin Resistance and Transendothelial Migration Pathways to Coronary Artery Disease

              UK Biobank is among the world’s largest repositories for phenotypic and genotypic information in individuals of European ancestry 1 . We performed a genome-wide association study in UK Biobank testing ~9 million DNA sequence variants for association with coronary artery disease (4,831 cases; 115,455 controls) and carried out meta-analysis with previously published results. We identified fifteen novel loci, bringing the total number of coronary artery disease-associated loci to 95. Phenome-wide association scanning revealed that CCDC92 likely affects coronary artery disease through insulin resistance pathways whereas experimental analysis suggests that ARHGEF26 impacts the transendothelial migration of leukocytes.
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                Author and article information

                Journal
                Arterioscler Thromb Vasc Biol
                Arterioscler. Thromb. Vasc. Biol
                ATV
                Arteriosclerosis, Thrombosis, and Vascular Biology
                Lippincott Williams & Wilkins
                1079-5642
                1524-4636
                January 2020
                07 November 2019
                : 40
                : 1
                : 267-278
                Affiliations
                [1 ]From the Centre for Heart Lung Innovation (M.T., K.R.W., J.H.B., L.R.B.), associated with the University of British Columbia, Vancouver, Canada.
                [2 ]Department of Experimental Medicine Program (M.T., J.H.B., L.R.B.), associated with the University of British Columbia, Vancouver, Canada.
                [3 ]Department of Medicine (K.R.W., J.H.B., L.R.B.) associated with the University of British Columbia, Vancouver, Canada.
                Author notes
                Correspondence to: Liam R. Brunham, MD, PhD, Centre for Heart Lung Innovation, Room 166-1081, Burrard St, Vancouver, BC V6Z 1Y6. Email liam.brunham@ 123456ubc.ca
                Article
                00027
                10.1161/ATVBAHA.119.313381
                6946100
                31694394
                bb428221-5541-4706-9e21-7e742c58b30c
                © 2019 The Authors.

                Arteriosclerosis, Thrombosis, and Vascular Biology is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.

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                Categories
                10021
                10030
                10034
                10084
                Clinical and Population Studies
                Custom metadata
                TRUE
                AL

                adult,genetics,humans,immune system,infection
                adult, genetics, humans, immune system, infection

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