Epigenome-wide Association Study of DNA Methylation in Blood and Circulating Fibrinogen Levels

J. Hahn¹, J. Bressler¹, M.R. Brown¹, M. Fornage^1,2, J. Bell³, D.I. Boomsma⁴, A. Dehghan⁵, A. Domingo-Relloso^6,7, X. Guo⁸, A.D. Johnson^9,10, M. Kleber¹¹, D.L. McCartney¹², P.-E. Morange¹³, N.L. Smith^14,15,16, A. Teumer¹⁷, W. Zhao¹⁸, A.C. Morrison¹, P.S. de Vries¹, CHARGE Epigenetics and Hemostasis Working Groups

¹Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, United States, ²Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, United States, ³Department of Twin Research and Genetic Epidemiology, King’s College London, London, United Kingdom, ⁴Department of Biological Psychology, Neuroscience Campus Amsterdam, VU University, Amsterdam, Netherlands, ⁵Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom, ⁶Department of Chronic Diseases Epidemiology, National Center for Epidemiology, Carlos III Health Institute, Madrid, Spain, ⁷Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, United States, ⁸Statistical Genetics, Institute for Genomics and Population Sciences, The Lundquist Institute and Department of Pediatrics at Harbor-UCLA Medical Center, Torrance, United States, ⁹Division of Intramural Research, Population Sciences Branch, National Heart, Lung and Blood Institute, Bethesda, United States, ¹⁰The Framingham Heart Study, Framingham, United States, ¹¹Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany, ¹²Centre for Genomic and Experimental Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom, ¹³Aix-Marseille University, INSERM, INRAE, C2VN, Marseille, France, ¹⁴Department of Epidemiology, University of Washington, Seattle, United States, ¹⁵Kaiser Permanente Washington Health Research Institute, Seattle, United States, ¹⁶Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, United States, ¹⁷Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany, ¹⁸Department of Epidemiology, University of Michigan, Ann Arbor, United States

Abstract Number: LPB0063

Meeting: ISTH 2021 Congress

Theme: Fibrinogen, Fibrinolysis and Proteolysis » Fibrinogen and Factor XIII

Background: DNA methylation of cytosine-phosphate-guanine (CpG) sites across the genome is an epigenetic mechanism that regulates levels of gene expression. Fibrinogen plays an essential role in blood coagulation and inflammatory pathways. Inter-individual differences in DNA methylation may be associated with varying levels of fibrinogen. No epigenome-wide association study (EWAS) of circulating fibrinogen levels has been performed to date.

Aims: To perform an EWAS to examine an association between blood DNA methylation levels and circulating fibrinogen levels to better understand its biological and pathophysiological actions.

Methods: We performed an EWAS of circulating fibrinogen levels in 18,037 participants representing 13 studies from the CHARGE consortium. DNA methylation in blood of 12,904 participants was measured using the Illumina 450K array, and of 5,133 using the 850K array. This sample included individuals of European (n=11,357) and African (n=4,007) ancestries, American Indians (n=2,293) and Hispanics (n=380). Significant associations were identified using Bonferroni corrected p-values, and they were cross-replicated. A sensitivity analysis was performed within the ARIC study comparing models with and without C-reactive protein (CRP) adjustment to examine a potential confounding effect of inflammation.

Results: We identified 208 and 87 significant CpG sites associated with fibrinogen from the 450K (p<1.03E-7) and 850K arrays (p<5.78E-8), respectively. There were 78 associations from the 450K analysis that replicated in the 850K analysis, and 26 vice versa. After accounting for the overlapping sites, there were 83 replicated CpG sites located in 61 independent loci. Examples of genes located near these CpG sites were SOCS3, AIM2, and SBNO2, which are involved in inflammatory pathways. The sensitivity analysis showed the associations for all 83 replicated CpG sites were attenuated after CRP adjustment, although many remained significant.

Conclusions: We identified 83 CpG sites associated with fibrinogen levels. These associations are partially driven by the inflammatory pathway shared by both fibrinogen and CRP.

To cite this abstract in AMA style:

Hahn J, Bressler J, Brown MR, Fornage M, Bell J, Boomsma DI, Dehghan A, Domingo-Relloso A, Guo X, Johnson AD, Kleber M, McCartney DL, Morange P-, Smith NL, Teumer A, Zhao W, Morrison AC, de Vries PS, CHARGE Epigenetics and Hemostasis Working Groups . Epigenome-wide Association Study of DNA Methylation in Blood and Circulating Fibrinogen Levels [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/epigenome-wide-association-study-of-dna-methylation-in-blood-and-circulating-fibrinogen-levels/. Accessed November 29, 2023.

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