Jane F Ferguson1, Chenyi Xue2, Yuanfeng Gao2,3, Tian Tian4, Jianting Shi2, Xuan Zhang2, Ying Wang2, Yuhuang D Li2, Zhi Wei4, Mingyao Li5, Hanrui Zhang2, Muredach P Reilly2. 1. Division of Cardiovascular Medicine, and Vanderbilt Translational and Clinical Cardiovascular Research Center (VTRACC), Vanderbilt University Medical Center, Nashville, TN (J.F.F.). 2. Cardiology Division, Department of Medicine, Columbia University Medical Center, New York, NY (C.X., Y.G., J.S., X.Z., Y.W., Y.D.L., H.Z., M.P.R.). 3. Department of Cardiology, Beijing Chao-Yang Hospital, Capital Medical University, China (Y.G.). 4. Department of Computer Science, New Jersey Institute of Technology, Newark (T.T., Z.W.). 5. Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia (M.L.).
Abstract
BACKGROUND: Cytokine responses to activation of innate immunity differ between individuals, yet the genomic and tissue-specific transcriptomic determinants of inflammatory responsiveness are not well understood. We hypothesized that tissue-specific mRNA and long intergenic noncoding RNA (lincRNA) induction differs between individuals with divergent evoked inflammatory responses. METHODS: In the GENE Study (Genetics of Evoked Response to Niacin and Endotoxemia), we performed an inpatient endotoxin challenge (1 ng/kg lipopolysaccharide [LPS]) in healthy humans. We selected individuals in the top (high responders) and bottom (low responders) extremes of inflammatory responses and applied RNA sequencing to CD14 monocytes (N=15) and adipose tissue (N=25) before and after LPS administration. RESULTS: Although only a small number of genes were differentially expressed at baseline, there were clear differences in the magnitude of the transcriptional response post-LPS between high and low responders, with a far greater number of genes differentially expressed by endotoxemia in high responders. Furthermore, tissue responses differed during inflammation, and we found a number of tissue-specific differentially expressed lincRNAs post-LPS, which we validated. Relative to nondifferentially expressed lincRNAs, differentially expressed lincRNAs were equally likely to be nonconserved as conserved between human and mouse, indicating that conservation is not a predictor of lincRNAs associated with human inflammatory pathophysiology. Differentially expressed genes also were enriched for signals with inflammatory and cardiometabolic disease in published genome-wide association studies. CTB-41I6.2 ( AC002091.1), a nonconserved human-specific lincRNA, is one of the top lincRNAs regulated by endotoxemia in monocytes, but not in adipose tissue. Knockdown experiments in THP-1 monocytes suggest that this lincRNA enhances LPS-induced interleukin 6 ( IL6) expression in monocytes, and we now refer to this as monocyte LPS-induced lincRNA regulator of IL6 ( MOLRIL6). CONCLUSIONS: We highlight mRNAs and lincRNAs that represent novel candidates for modulation of innate immune and metabolic responses in humans. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00953667.
BACKGROUND: Cytokine responses to activation of innate immunity differ between individuals, yet the genomic and tissue-specific transcriptomic determinants of inflammatory responsiveness are not well understood. We hypothesized that tissue-specific mRNA and long intergenic noncoding RNA (lincRNA) induction differs between individuals with divergent evoked inflammatory responses. METHODS: In the GENE Study (Genetics of Evoked Response to Niacin and Endotoxemia), we performed an inpatient endotoxin challenge (1 ng/kg lipopolysaccharide [LPS]) in healthy humans. We selected individuals in the top (high responders) and bottom (low responders) extremes of inflammatory responses and applied RNA sequencing to CD14 monocytes (N=15) and adipose tissue (N=25) before and after LPS administration. RESULTS: Although only a small number of genes were differentially expressed at baseline, there were clear differences in the magnitude of the transcriptional response post-LPS between high and low responders, with a far greater number of genes differentially expressed by endotoxemia in high responders. Furthermore, tissue responses differed during inflammation, and we found a number of tissue-specific differentially expressed lincRNAs post-LPS, which we validated. Relative to nondifferentially expressed lincRNAs, differentially expressed lincRNAs were equally likely to be nonconserved as conserved between human and mouse, indicating that conservation is not a predictor of lincRNAs associated with human inflammatory pathophysiology. Differentially expressed genes also were enriched for signals with inflammatory and cardiometabolic disease in published genome-wide association studies. CTB-41I6.2 ( AC002091.1), a nonconserved human-specific lincRNA, is one of the top lincRNAs regulated by endotoxemia in monocytes, but not in adipose tissue. Knockdown experiments in THP-1 monocytes suggest that this lincRNA enhances LPS-induced interleukin 6 ( IL6) expression in monocytes, and we now refer to this as monocyte LPS-induced lincRNA regulator of IL6 ( MOLRIL6). CONCLUSIONS: We highlight mRNAs and lincRNAs that represent novel candidates for modulation of innate immune and metabolic responses in humans. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00953667.
Authors: Yichuan Liu; Jane F Ferguson; Chenyi Xue; Rachel L Ballantyne; Ian M Silverman; Sager J Gosai; Jacquelyn Serfecz; Michael P Morley; Brian D Gregory; Mingyao Li; Muredach P Reilly Journal: Arterioscler Thromb Vasc Biol Date: 2014-02-06 Impact factor: 8.311
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Authors: Katrina M de Lange; Loukas Moutsianas; James C Lee; Christopher A Lamb; Yang Luo; Nicholas A Kennedy; Luke Jostins; Daniel L Rice; Javier Gutierrez-Achury; Sun-Gou Ji; Graham Heap; Elaine R Nimmo; Cathryn Edwards; Paul Henderson; Craig Mowat; Jeremy Sanderson; Jack Satsangi; Alison Simmons; David C Wilson; Mark Tremelling; Ailsa Hart; Christopher G Mathew; William G Newman; Miles Parkes; Charlie W Lees; Holm Uhlig; Chris Hawkey; Natalie J Prescott; Tariq Ahmad; John C Mansfield; Carl A Anderson; Jeffrey C Barrett Journal: Nat Genet Date: 2017-01-09 Impact factor: 41.307