DNA methylation analysis is used to identify novel genetic loci associated with circulating fibrinogen levels in blood.

Julie Hahn, Jan Bressler, Arce Domingo-Relloso, Ming-Huei Chen, Daniel L McCartney, Alexander Teumer, Jenny van Dongen, Marcus E Kleber, Dylan Aïssi, Brenton R Swenson, Jie Yao, Wei Zhao, Jian Huang, Yujing Xia, Michael R Brown, Ricardo Costeira, Eco J C de Geus, Graciela E Delgado, Dre'Von A Dobson, Paul Elliott, Hans J Grabe, Xiuqing Guo, Sarah E Harris, Jennifer E Huffman, Sharon L R Kardia, Yongmei Liu, Stefan Lorkowski, Riccardo E Marioni, Matthias Nauck, Scott M Ratliff, Maria Sabater-Lleal, Tim D Spector, Pierre Suchon, Kent D Taylor, Florian Thibord, David-Alexandre Trégouët, Kerri L Wiggins, Gonneke Willemsen, Jordana T Bell, Dorret I Boomsma, Shelley A Cole, Simon R Cox, Abbas Dehghan, Andreas Greinacher, Karin Haack, Winfried März, Pierre-Emmanuel Morange, Jerome I Rotter, Nona Sotoodehnia, Maria Tellez-Plaza, Ana Navas-Acien, Jennifer A Smith, Andrew D Johnson, Myriam Fornage, Nicholas L Smith, Alisa S Wolberg, Alanna C Morrison, Paul S de Vries

Journal: Journal of thrombosis and haemostasis : JTH 2023;21(5):1135-1147

PMID: 36716967

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Abstract

BACKGROUND

Fibrinogen plays an essential role in blood coagulation and inflammation. Circulating fibrinogen levels may be determined based on interindividual differences in DNA methylation at cytosine-phosphate-guanine (CpG) sites and vice versa.

OBJECTIVES

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 epigenome-wide association study of circulating fibrinogen levels in 18 037 White, Black, American Indian, and Hispanic participants, representing 14 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. Circulating leukocyte DNA methylation was measured using the Illumina 450K array in 12 904 participants and using the EPIC array in 5133 participants. In each study, an epigenome-wide association study of fibrinogen was performed using linear mixed models adjusted for potential confounders. Study-specific results were combined using array-specific meta-analysis, followed by cross-replication of epigenome-wide significant associations. We compared models with and without CRP adjustment to examine the role of inflammation.

RESULTS

We identified 208 and 87 significant CpG sites associated with fibrinogen levels from the 450K (p < 1.03 × 10) and EPIC arrays (p < 5.78 × 10), respectively. There were 78 associations from the 450K array that replicated in the EPIC array and 26 vice versa. After accounting for overlapping sites, there were 83 replicated CpG sites located in 61 loci, of which only 4 have been previously reported for fibrinogen. The examples of genes located near these CpG sites were SOCS3 and AIM2, which are involved in inflammatory pathways. The associations of all 83 replicated CpG sites were attenuated after CRP adjustment, although many remained significant.

CONCLUSION

We identified 83 CpG sites associated with circulating fibrinogen levels. These associations are partially driven by inflammatory pathways shared by both fibrinogen and CRP.

Address: Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA. Electronic address: [email protected].; Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA.; Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, New York, USA; Department of Chronic Diseases Epidemiology, National Center for Epidemiology, Carlos III Health Institutes, Madrid, Spain; Department of Statistics and Operations Research, University of Valencia, Burjassot, Spain.; Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Framingham, Massachusetts, USA.; Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom.; Department SHIP/Clinical-Epidemiological Research, Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany; Department of Population Medicine and Lifestyle Diseases Prevention, Medical University of Bialystok, Bialystok, Poland.; Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; Amsterdam Public Health Research Institute, Amsterdam, The Netherlands.; Vth Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; SYNLAB MVZ Humangenetik Mannheim, Mannheim, Germany.; Univ. Bordeaux, INSERM, Bordeaux Population Health Research Center, UMR 1219, Molecular Epidemiology of Vascular and Brain Disorders, Bordeaux, France.; Cardiovascular Health Research Unit, School of Public Health, University of Washington, Seattle, Washington, USA.; Pediatrics, Genomic Outcomes, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA.; Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA; Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.; Department of Twin Research and Genetic Epidemiology, St Thomas Hospital Campus, King's College London, London, United Kingdom.; Vth Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.; Pathology and Laboratory Medicine and UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; Department of Epidemiology and Biostatistics, MRC Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom; UK Dementia Research Institute, Imperial College London, London, United Kingdom; British Heart Foundation Centre for Research Excellence, Imperial College London, London, United Kingdom.; Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany; German Center for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Greifswald, Germany.; Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom.; Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, Massachusetts, USA.; Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.; Medicine, Cardiology, Duke Molecular Physiology Institute, Durham, North Carolina, USA.; Institute of Nutritional Sciences, Friedrich Schiller University Jena, Jena, Germany; Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD) Halle-Jena-Leipzig, Jena, Germany.; DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany; Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.; Genomics of Complex Disease Unit, Sant Pau Biomedical Research Institute (IIB Sant Pau), Barcelona, Spain; Department of Medicine, Cardiovascular Medicine Unit, Karolinska Institutet, Stockholm, Sweden.; Center for CardioVascular and Nutrition research (C2VN), INSERM 1263, INRAE 1260, Hematology Laboratory, La Timone University Hospital of Marseille, Aix-Marseille University, Marseille, France.; Population Sciences Branch, National Heart, Lung, and Blood Institute, Framingham, Massachusetts, USA.; Department of Medicine, Division of General Internal Medicine, University of Washington, Seattle, Washington, USA.; Population Health Program, Texas Biomedical Research Institute, San Antonio, Texas, USA.; Institute for Immunology and Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany.; Vth Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; SYNLAB Academy, SYNLAB Holding Deutschland GmbH, Mannheim, Germany; Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.; Cardiovascular and Nutrition Reserach Center (C2VN), INSERM, INRAE, Aix-Marseille University, Marseille, France.; Department of Medicine, Division of Cardiology, University of Washington, Seattle, Washington, USA.; Department of Chronic Diseases Epidemiology, National Center for Epidemiology, Carlos III Health Institutes, Madrid, Spain.; Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, New York, USA.; Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA; Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.; Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington, USA; Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, Washington, USA; Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, Washington, USA.; Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA. Electronic address: [email protected].

DOI: 10.1016/j.jtha.2023.01.015

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MeSH Terms: Humans, DNA Methylation, Epigenesis, Genetic, Genome-Wide Association Study, Genetic Loci, Inflammation, Fibrinogen, CpG Islands