Xiaoling Zhang1,2,3,4, Jeroen G J van Rooij5, Yoshiyuki Wakabayashi6, Shih-Jen Hwang7,8, Yanqin Yang6, Mohsen Ghanbari5, Daniel Bos9,10, Daniel Levy7,8, Andrew D Johnson7,8, Joyce B J van Meurs5, Maryam Kavousi5, Jun Zhu6, Christopher J O'Donnell11,12,13. 1. Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD, USA. zhangxl@bu.edu. 2. The National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA. zhangxl@bu.edu. 3. Department of Medicine (Biomedical Genetics), Boston University School of Medicine, 72 East Concord Street, Boston, MA, 02118-2526, USA. zhangxl@bu.edu. 4. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA. zhangxl@bu.edu. 5. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands. 6. DNA Sequencing and Genomics Core, National Heart, Lung and Blood Institute, Bethesda, MD, USA. 7. Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD, USA. 8. The National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA. 9. Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands. 10. Department of Radiology and Nuclear Medicine, Erasmus Medical Center, Rotterdam, the Netherlands. 11. Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD, USA. Christopher.ODonnell@va.gov. 12. The National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA. Christopher.ODonnell@va.gov. 13. Cardiology Section, Veteran's Administration Boston Healthcare System, Boston, USA. Christopher.ODonnell@va.gov.
Abstract
BACKGROUND: Coronary artery calcification (CAC) is a noninvasive measure of coronary atherosclerosis, the proximal pathophysiology underlying most cases of myocardial infarction (MI). We sought to identify expression signatures of early MI and subclinical atherosclerosis in the Framingham Heart Study (FHS). In this study, we conducted paired-end RNA sequencing on whole blood collected from 198 FHS participants (55 with a history of early MI, 72 with high CAC without prior MI, and 71 controls free of elevated CAC levels or history of MI). We applied DESeq2 to identify coding-genes and long intergenic noncoding RNAs (lincRNAs) differentially expressed in MI and high CAC, respectively, compared with the control. RESULTS: On average, 150 million paired-end reads were obtained for each sample. At the false discovery rate (FDR) < 0.1, we found 68 coding genes and 2 lincRNAs that were differentially expressed in early MI versus controls. Among them, 60 coding genes were detectable and thus tested in an independent RNA-Seq data of 807 individuals from the Rotterdam Study, and 8 genes were supported by p value and direction of the effect. Immune response, lipid metabolic process, and interferon regulatory factor were enriched in these 68 genes. By contrast, only 3 coding genes and 1 lincRNA were differentially expressed in high CAC versus controls. APOD, encoding a component of high-density lipoprotein, was significantly downregulated in both early MI (FDR = 0.007) and high CAC (FDR = 0.01) compared with controls. CONCLUSIONS: We identified transcriptomic signatures of early MI that include differentially expressed protein-coding genes and lincRNAs, suggesting important roles for protein-coding genes and lincRNAs in the pathogenesis of MI.
BACKGROUND:Coronary artery calcification (CAC) is a noninvasive measure of coronary atherosclerosis, the proximal pathophysiology underlying most cases of myocardial infarction (MI). We sought to identify expression signatures of early MI and subclinical atherosclerosis in the Framingham Heart Study (FHS). In this study, we conducted paired-end RNA sequencing on whole blood collected from 198 FHS participants (55 with a history of early MI, 72 with high CAC without prior MI, and 71 controls free of elevated CAC levels or history of MI). We applied DESeq2 to identify coding-genes and long intergenic noncoding RNAs (lincRNAs) differentially expressed in MI and high CAC, respectively, compared with the control. RESULTS: On average, 150 million paired-end reads were obtained for each sample. At the false discovery rate (FDR) < 0.1, we found 68 coding genes and 2 lincRNAs that were differentially expressed in early MI versus controls. Among them, 60 coding genes were detectable and thus tested in an independent RNA-Seq data of 807 individuals from the Rotterdam Study, and 8 genes were supported by p value and direction of the effect. Immune response, lipid metabolic process, and interferon regulatory factor were enriched in these 68 genes. By contrast, only 3 coding genes and 1 lincRNA were differentially expressed in high CAC versus controls. APOD, encoding a component of high-density lipoprotein, was significantly downregulated in both early MI (FDR = 0.007) and high CAC (FDR = 0.01) compared with controls. CONCLUSIONS: We identified transcriptomic signatures of early MI that include differentially expressed protein-coding genes and lincRNAs, suggesting important roles for protein-coding genes and lincRNAs in the pathogenesis of MI.
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