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

doi:10.1016/j.jtha.2023.01.015

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 ElliottHans 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^*

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

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 × 10⁻⁷) and EPIC arrays (p < 5.78 × 10⁻⁸), 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.

Original language	English
Pages (from-to)	1135-1147
Number of pages	13
Journal	Journal of Thrombosis and Haemostasis
Volume	21
Issue number	5
Early online date	27 Jan 2023
DOIs	https://doi.org/10.1016/j.jtha.2023.01.015
Publication status	Published - May 2023

Bibliographical note

Funding Information:
National Heart, Lung, and Blood Institute (NHLBI); Grant Number: R01 HL141291 NHLBI; Grant Number: R01 HL134894 NHLBI; Grant number: R01 HL105756This study was supported by National Heart, Lung, and Blood Institute (NHLBI) grant R01 HL141291. The CHARGE Hemostasis Working Group is further supported by NHLBI grant R01 HL134894, whereas infrastructure for the CHARGE Consortium is supported, in part, by the NHLBI grant R01 HL105756. Study-specific acknowledgments are provided in Supplementary Methods. P.E. A.D.J. S.L.R.K. J.A.S. S.E.H. S.R.C. M.E.K. S.L. P.S. D.-A.T. P.-E.M. Y.L. K.D.T. J.I.R. G.W. E.J.C.d.G. D.I.B. H.J.G. M.N. A.G. A.N.-A. S.A.C. Y.X. R.C. T.D.S. and J.T.B. contributed to phenotype acquisition or harmonization (including design or funding of contributing studies). J.B. M.F. N.S. W.Z. S.L.R.K. J.A.S. R.E.M. M.E.K. D.A. D.-A.T. Y.L. J.v.D. G.W. D.I.B. A.T. H.J.G. K.H. M.T.-P. Y.X. R.C. T.D.S. and J.T.B. contributed to acquisition of methylation data and its quality control process. J.H. P.D. M.R.B. M.F. J.H. B.R.S. M.C. W.Z. S.M.R. D.L.M. S.E.H. M.E.K. G.E.D. D.A. D.-A.T. J.Y. X.G. J.v.D. A.T. A.D.-R. Y.X. and R.C. contributed to statistical analyses. J.H. P.S.d.V. A.C.M. J.H. A.D. N.L.S. D.-A.T. X.G. Y.L. K.D.T. J.I.R. J.v.D. Y.X. J.T.B. M.S.-L. and J.E.H. contributed to the interpretation of the results. J.H. J.B. P.S.d.V. and A.C.M. contributed to drafting of the manuscript. All authors contributed to revision of the manuscript. P.E. acknowledges support from the Medical Research Council for the MRC Centre for Environment and Health (MR/S019669/1). P.E. is supported by the UK Dementia Research Institute (UKDRI), which receives funding from a UKDRI-sponsored consortium of the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK (MC_PC_17114). D.-A.T. was supported by the EPIDEMIOM-VT Senior Chair from the University of Bordeaux initiative of excellence IdEX. J.v.D. is supported by NWO Large Scale infrastructures, X-Omics (184.034.019). D.I.B. acknowledges the Royal Netherlands Academy of Science Professor Award (PAH/6635). H.J.G. has received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm, Servier, and Janssen Cilag as well as research funding from Fresenius Medical Care. M.S.-L. is supported by a Miguel Servet contract from the Instituto de Salud Carlos III (ISCIII) Spanish Health Institute (CP17/00142) and cofinanced by the European Social Fund. The remaining authors state that they have no conflicts of interest to declare.

Funding Information:
P.E. acknowledges support from the Medical Research Council for the MRC Centre for Environment and Health (MR/S019669/1). P.E. is supported by the UK Dementia Research Institute (UKDRI) , which receives funding from a UKDRI-sponsored consortium of the Medical Research Council , Alzheimer’s Society and Alzheimer’s Research UK (MC_PC_17114). D.-A.T. was supported by the EPIDEMIOM-VT Senior Chair from the University of Bordeaux initiative of excellence IdEX. J.v.D. is supported by NWO Large Scale infrastructures, X-Omics (184.034.019). D.I.B. acknowledges the Royal Netherlands Academy of Science Professor Award (PAH/6635). H.J.G. has received travel grants and speakers honoraria from Fresenius Medical Care , Neuraxpharm , Servier , and Janssen Cilag as well as research funding from Fresenius Medical Care. M.S.-L. is supported by a Miguel Servet contract from the Instituto de Salud Carlos III (ISCIII) Spanish Health Institute (CP17/00142) and cofinanced by the European Social Fund. The remaining authors state that they have no conflicts of interest to declare.

Funding Information:
National Heart, Lung , and Blood Institute (NHLBI); Grant Number: R01 HL141291 NHLBI; Grant Number: R01 HL134894 NHLBI; Grant number: R01 HL105756

Funding Information:
This study was supported by National Heart , Lung , and Blood Institute (NHLBI) grant R01 HL141291. The CHARGE Hemostasis Working Group is further supported by NHLBI grant R01 HL134894, whereas infrastructure for the CHARGE Consortium is supported, in part, by the NHLBI grant R01 HL105756.

Publisher Copyright:
© 2023 International Society on Thrombosis and Haemostasis

Funding

National Heart, Lung, and Blood Institute (NHLBI); Grant Number: R01 HL141291 NHLBI; Grant Number: R01 HL134894 NHLBI; Grant number: R01 HL105756This study was supported by National Heart, Lung, and Blood Institute (NHLBI) grant R01 HL141291. The CHARGE Hemostasis Working Group is further supported by NHLBI grant R01 HL134894, whereas infrastructure for the CHARGE Consortium is supported, in part, by the NHLBI grant R01 HL105756. Study-specific acknowledgments are provided in Supplementary Methods. P.E. A.D.J. S.L.R.K. J.A.S. S.E.H. S.R.C. M.E.K. S.L. P.S. D.-A.T. P.-E.M. Y.L. K.D.T. J.I.R. G.W. E.J.C.d.G. D.I.B. H.J.G. M.N. A.G. A.N.-A. S.A.C. Y.X. R.C. T.D.S. and J.T.B. contributed to phenotype acquisition or harmonization (including design or funding of contributing studies). J.B. M.F. N.S. W.Z. S.L.R.K. J.A.S. R.E.M. M.E.K. D.A. D.-A.T. Y.L. J.v.D. G.W. D.I.B. A.T. H.J.G. K.H. M.T.-P. Y.X. R.C. T.D.S. and J.T.B. contributed to acquisition of methylation data and its quality control process. J.H. P.D. M.R.B. M.F. J.H. B.R.S. M.C. W.Z. S.M.R. D.L.M. S.E.H. M.E.K. G.E.D. D.A. D.-A.T. J.Y. X.G. J.v.D. A.T. A.D.-R. Y.X. and R.C. contributed to statistical analyses. J.H. P.S.d.V. A.C.M. J.H. A.D. N.L.S. D.-A.T. X.G. Y.L. K.D.T. J.I.R. J.v.D. Y.X. J.T.B. M.S.-L. and J.E.H. contributed to the interpretation of the results. J.H. J.B. P.S.d.V. and A.C.M. contributed to drafting of the manuscript. All authors contributed to revision of the manuscript. P.E. acknowledges support from the Medical Research Council for the MRC Centre for Environment and Health (MR/S019669/1). P.E. is supported by the UK Dementia Research Institute (UKDRI), which receives funding from a UKDRI-sponsored consortium of the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK (MC_PC_17114). D.-A.T. was supported by the EPIDEMIOM-VT Senior Chair from the University of Bordeaux initiative of excellence IdEX. J.v.D. is supported by NWO Large Scale infrastructures, X-Omics (184.034.019). D.I.B. acknowledges the Royal Netherlands Academy of Science Professor Award (PAH/6635). H.J.G. has received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm, Servier, and Janssen Cilag as well as research funding from Fresenius Medical Care. M.S.-L. is supported by a Miguel Servet contract from the Instituto de Salud Carlos III (ISCIII) Spanish Health Institute (CP17/00142) and cofinanced by the European Social Fund. The remaining authors state that they have no conflicts of interest to declare. P.E. acknowledges support from the Medical Research Council for the MRC Centre for Environment and Health (MR/S019669/1). P.E. is supported by the UK Dementia Research Institute (UKDRI) , which receives funding from a UKDRI-sponsored consortium of the Medical Research Council , Alzheimer’s Society and Alzheimer’s Research UK (MC_PC_17114). D.-A.T. was supported by the EPIDEMIOM-VT Senior Chair from the University of Bordeaux initiative of excellence IdEX. J.v.D. is supported by NWO Large Scale infrastructures, X-Omics (184.034.019). D.I.B. acknowledges the Royal Netherlands Academy of Science Professor Award (PAH/6635). H.J.G. has received travel grants and speakers honoraria from Fresenius Medical Care , Neuraxpharm , Servier , and Janssen Cilag as well as research funding from Fresenius Medical Care. M.S.-L. is supported by a Miguel Servet contract from the Instituto de Salud Carlos III (ISCIII) Spanish Health Institute (CP17/00142) and cofinanced by the European Social Fund. The remaining authors state that they have no conflicts of interest to declare. National Heart, Lung , and Blood Institute (NHLBI); Grant Number: R01 HL141291 NHLBI; Grant Number: R01 HL134894 NHLBI; Grant number: R01 HL105756 This study was supported by National Heart , Lung , and Blood Institute (NHLBI) grant R01 HL141291. The CHARGE Hemostasis Working Group is further supported by NHLBI grant R01 HL134894, whereas infrastructure for the CHARGE Consortium is supported, in part, by the NHLBI grant R01 HL105756.

Funders	Funder number
Koninklijke Nederlandse Akademie van Wetenschappen	PAH/6635
Spanish Health Institute	CP17/00142
National Heart, Lung, and Blood Institute	R01 HL134894, R01 HL141291, R01 HL105756
National Heart, Lung, and Blood Institute
Fresenius Medical Care North America
Medical Research Council
Alzheimer's Society
Alzheimer’s Research UK	MC_PC_17114
Alzheimer’s Research UK
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	184.034.019
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Instituto de Salud Carlos III
European Social Fund
UK Dementia Research Institute
MRC-PHE Centre for Environment and Health	MR/S019669/1
MRC-PHE Centre for Environment and Health

Keywords

DNA methylation
epigenome-wide association study
fibrinogen
inflammation
Mendelian randomization

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.jtha.2023.01.015

https://linkinghub.elsevier.com/retrieve/pii/S1538783623000508

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Cite this

Hahn, J., Bressler, J., Domingo-Relloso, A., Chen, M. H., McCartney, D. L., Teumer, A., van Dongen, J., Kleber, M. E., Aïssi, D., Swenson, B. R., Yao, J., Zhao, W., Huang, J., Xia, Y., Brown, M. R., Costeira, R., de Geus, E. J. C., Delgado, G. E., Dobson, DV. A., ... de Vries, P. S. (2023). DNA methylation analysis is used to identify novel genetic loci associated with circulating fibrinogen levels in blood. Journal of Thrombosis and Haemostasis, 21(5), 1135-1147. https://doi.org/10.1016/j.jtha.2023.01.015

@article{e26e0c3fae84494aab82cd58445a473f,

title = "DNA methylation analysis is used to identify novel genetic loci associated with circulating fibrinogen levels in blood",

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 × 10−7) and EPIC arrays (p < 5.78 × 10−8), 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.",

keywords = "DNA methylation, epigenome-wide association study, fibrinogen, inflammation, Mendelian randomization",

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

note = "Funding Information: National Heart, Lung, and Blood Institute (NHLBI); Grant Number: R01 HL141291 NHLBI; Grant Number: R01 HL134894 NHLBI; Grant number: R01 HL105756This study was supported by National Heart, Lung, and Blood Institute (NHLBI) grant R01 HL141291. The CHARGE Hemostasis Working Group is further supported by NHLBI grant R01 HL134894, whereas infrastructure for the CHARGE Consortium is supported, in part, by the NHLBI grant R01 HL105756. Study-specific acknowledgments are provided in Supplementary Methods. P.E. A.D.J. S.L.R.K. J.A.S. S.E.H. S.R.C. M.E.K. S.L. P.S. D.-A.T. P.-E.M. Y.L. K.D.T. J.I.R. G.W. E.J.C.d.G. D.I.B. H.J.G. M.N. A.G. A.N.-A. S.A.C. Y.X. R.C. T.D.S. and J.T.B. contributed to phenotype acquisition or harmonization (including design or funding of contributing studies). J.B. M.F. N.S. W.Z. S.L.R.K. J.A.S. R.E.M. M.E.K. D.A. D.-A.T. Y.L. J.v.D. G.W. D.I.B. A.T. H.J.G. K.H. M.T.-P. Y.X. R.C. T.D.S. and J.T.B. contributed to acquisition of methylation data and its quality control process. J.H. P.D. M.R.B. M.F. J.H. B.R.S. M.C. W.Z. S.M.R. D.L.M. S.E.H. M.E.K. G.E.D. D.A. D.-A.T. J.Y. X.G. J.v.D. A.T. A.D.-R. Y.X. and R.C. contributed to statistical analyses. J.H. P.S.d.V. A.C.M. J.H. A.D. N.L.S. D.-A.T. X.G. Y.L. K.D.T. J.I.R. J.v.D. Y.X. J.T.B. M.S.-L. and J.E.H. contributed to the interpretation of the results. J.H. J.B. P.S.d.V. and A.C.M. contributed to drafting of the manuscript. All authors contributed to revision of the manuscript. P.E. acknowledges support from the Medical Research Council for the MRC Centre for Environment and Health (MR/S019669/1). P.E. is supported by the UK Dementia Research Institute (UKDRI), which receives funding from a UKDRI-sponsored consortium of the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK (MC_PC_17114). D.-A.T. was supported by the EPIDEMIOM-VT Senior Chair from the University of Bordeaux initiative of excellence IdEX. J.v.D. is supported by NWO Large Scale infrastructures, X-Omics (184.034.019). D.I.B. acknowledges the Royal Netherlands Academy of Science Professor Award (PAH/6635). H.J.G. has received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm, Servier, and Janssen Cilag as well as research funding from Fresenius Medical Care. M.S.-L. is supported by a Miguel Servet contract from the Instituto de Salud Carlos III (ISCIII) Spanish Health Institute (CP17/00142) and cofinanced by the European Social Fund. The remaining authors state that they have no conflicts of interest to declare. Funding Information: P.E. acknowledges support from the Medical Research Council for the MRC Centre for Environment and Health (MR/S019669/1). P.E. is supported by the UK Dementia Research Institute (UKDRI) , which receives funding from a UKDRI-sponsored consortium of the Medical Research Council , Alzheimer{\textquoteright}s Society and Alzheimer{\textquoteright}s Research UK (MC_PC_17114). D.-A.T. was supported by the EPIDEMIOM-VT Senior Chair from the University of Bordeaux initiative of excellence IdEX. J.v.D. is supported by NWO Large Scale infrastructures, X-Omics (184.034.019). D.I.B. acknowledges the Royal Netherlands Academy of Science Professor Award (PAH/6635). H.J.G. has received travel grants and speakers honoraria from Fresenius Medical Care , Neuraxpharm , Servier , and Janssen Cilag as well as research funding from Fresenius Medical Care. M.S.-L. is supported by a Miguel Servet contract from the Instituto de Salud Carlos III (ISCIII) Spanish Health Institute (CP17/00142) and cofinanced by the European Social Fund. The remaining authors state that they have no conflicts of interest to declare. Funding Information: National Heart, Lung , and Blood Institute (NHLBI); Grant Number: R01 HL141291 NHLBI; Grant Number: R01 HL134894 NHLBI; Grant number: R01 HL105756 Funding Information: This study was supported by National Heart , Lung , and Blood Institute (NHLBI) grant R01 HL141291. The CHARGE Hemostasis Working Group is further supported by NHLBI grant R01 HL134894, whereas infrastructure for the CHARGE Consortium is supported, in part, by the NHLBI grant R01 HL105756. Publisher Copyright: {\textcopyright} 2023 International Society on Thrombosis and Haemostasis",

year = "2023",

month = may,

doi = "10.1016/j.jtha.2023.01.015",

language = "English",

volume = "21",

pages = "1135--1147",

journal = "Journal of Thrombosis and Haemostasis",

issn = "1538-7836",

publisher = "Elsevier B.V.",

number = "5",

}

Hahn, J, Bressler, J, Domingo-Relloso, A, Chen, MH, McCartney, DL, Teumer, A, van Dongen, J, Kleber, ME, Aïssi, D, Swenson, BR, Yao, J, Zhao, W, Huang, J, Xia, Y, Brown, MR, Costeira, R, de Geus, EJC, Delgado, GE, Dobson, DVA, Elliott, P, Grabe, HJ, Guo, X, Harris, SE, Huffman, JE, Kardia, SLR, Liu, Y, Lorkowski, S, Marioni, RE, Nauck, M, Ratliff, SM, Sabater-Lleal, M, Spector, TD, Suchon, P, Taylor, KD, Thibord, F, Trégouët, DA, Wiggins, KL, Willemsen, G, Bell, JT, Boomsma, DI, Cole, SA, Cox, SR, Dehghan, A, Greinacher, A, Haack, K, März, W, Morange, PE, Rotter, JI, Sotoodehnia, N, Tellez-Plaza, M, Navas-Acien, A, Smith, JA, Johnson, AD, Fornage, M, Smith, NL, Wolberg, AS, Morrison, AC & de Vries, PS 2023, 'DNA methylation analysis is used to identify novel genetic loci associated with circulating fibrinogen levels in blood', Journal of Thrombosis and Haemostasis, vol. 21, no. 5, pp. 1135-1147. https://doi.org/10.1016/j.jtha.2023.01.015

TY - JOUR

T1 - DNA methylation analysis is used to identify novel genetic loci associated with circulating fibrinogen levels in blood

AU - Hahn, Julie

AU - Bressler, Jan

AU - Domingo-Relloso, Arce

AU - Chen, Ming Huei

AU - McCartney, Daniel L.

AU - Teumer, Alexander

AU - van Dongen, Jenny

AU - Kleber, Marcus E.

AU - Aïssi, Dylan

AU - Swenson, Brenton R.

AU - Yao, Jie

AU - Zhao, Wei

AU - Huang, Jian

AU - Xia, Yujing

AU - Brown, Michael R.

AU - Costeira, Ricardo

AU - de Geus, Eco J.C.

AU - Delgado, Graciela E.

AU - Dobson, Dre'Von A.

AU - Elliott, Paul

AU - Grabe, Hans J.

AU - Guo, Xiuqing

AU - Harris, Sarah E.

AU - Huffman, Jennifer E.

AU - Kardia, Sharon L.R.

AU - Liu, Yongmei

AU - Lorkowski, Stefan

AU - Marioni, Riccardo E.

AU - Nauck, Matthias

AU - Ratliff, Scott M.

AU - Sabater-Lleal, Maria

AU - Spector, Tim D.

AU - Suchon, Pierre

AU - Taylor, Kent D.

AU - Thibord, Florian

AU - Trégouët, David Alexandre

AU - Wiggins, Kerri L.

AU - Willemsen, Gonneke

AU - Bell, Jordana T.

AU - Boomsma, Dorret I.

AU - Cole, Shelley A.

AU - Cox, Simon R.

AU - Dehghan, Abbas

AU - Greinacher, Andreas

AU - Haack, Karin

AU - März, Winfried

AU - Morange, Pierre Emmanuel

AU - Rotter, Jerome I.

AU - Sotoodehnia, Nona

AU - Tellez-Plaza, Maria

AU - Navas-Acien, Ana

AU - Smith, Jennifer A.

AU - Johnson, Andrew D.

AU - Fornage, Myriam

AU - Smith, Nicholas L.

AU - Wolberg, Alisa S.

AU - Morrison, Alanna C.

AU - de Vries, Paul S.

N1 - Funding Information: National Heart, Lung, and Blood Institute (NHLBI); Grant Number: R01 HL141291 NHLBI; Grant Number: R01 HL134894 NHLBI; Grant number: R01 HL105756This study was supported by National Heart, Lung, and Blood Institute (NHLBI) grant R01 HL141291. The CHARGE Hemostasis Working Group is further supported by NHLBI grant R01 HL134894, whereas infrastructure for the CHARGE Consortium is supported, in part, by the NHLBI grant R01 HL105756. Study-specific acknowledgments are provided in Supplementary Methods. P.E. A.D.J. S.L.R.K. J.A.S. S.E.H. S.R.C. M.E.K. S.L. P.S. D.-A.T. P.-E.M. Y.L. K.D.T. J.I.R. G.W. E.J.C.d.G. D.I.B. H.J.G. M.N. A.G. A.N.-A. S.A.C. Y.X. R.C. T.D.S. and J.T.B. contributed to phenotype acquisition or harmonization (including design or funding of contributing studies). J.B. M.F. N.S. W.Z. S.L.R.K. J.A.S. R.E.M. M.E.K. D.A. D.-A.T. Y.L. J.v.D. G.W. D.I.B. A.T. H.J.G. K.H. M.T.-P. Y.X. R.C. T.D.S. and J.T.B. contributed to acquisition of methylation data and its quality control process. J.H. P.D. M.R.B. M.F. J.H. B.R.S. M.C. W.Z. S.M.R. D.L.M. S.E.H. M.E.K. G.E.D. D.A. D.-A.T. J.Y. X.G. J.v.D. A.T. A.D.-R. Y.X. and R.C. contributed to statistical analyses. J.H. P.S.d.V. A.C.M. J.H. A.D. N.L.S. D.-A.T. X.G. Y.L. K.D.T. J.I.R. J.v.D. Y.X. J.T.B. M.S.-L. and J.E.H. contributed to the interpretation of the results. J.H. J.B. P.S.d.V. and A.C.M. contributed to drafting of the manuscript. All authors contributed to revision of the manuscript. P.E. acknowledges support from the Medical Research Council for the MRC Centre for Environment and Health (MR/S019669/1). P.E. is supported by the UK Dementia Research Institute (UKDRI), which receives funding from a UKDRI-sponsored consortium of the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK (MC_PC_17114). D.-A.T. was supported by the EPIDEMIOM-VT Senior Chair from the University of Bordeaux initiative of excellence IdEX. J.v.D. is supported by NWO Large Scale infrastructures, X-Omics (184.034.019). D.I.B. acknowledges the Royal Netherlands Academy of Science Professor Award (PAH/6635). H.J.G. has received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm, Servier, and Janssen Cilag as well as research funding from Fresenius Medical Care. M.S.-L. is supported by a Miguel Servet contract from the Instituto de Salud Carlos III (ISCIII) Spanish Health Institute (CP17/00142) and cofinanced by the European Social Fund. The remaining authors state that they have no conflicts of interest to declare. Funding Information: P.E. acknowledges support from the Medical Research Council for the MRC Centre for Environment and Health (MR/S019669/1). P.E. is supported by the UK Dementia Research Institute (UKDRI) , which receives funding from a UKDRI-sponsored consortium of the Medical Research Council , Alzheimer’s Society and Alzheimer’s Research UK (MC_PC_17114). D.-A.T. was supported by the EPIDEMIOM-VT Senior Chair from the University of Bordeaux initiative of excellence IdEX. J.v.D. is supported by NWO Large Scale infrastructures, X-Omics (184.034.019). D.I.B. acknowledges the Royal Netherlands Academy of Science Professor Award (PAH/6635). H.J.G. has received travel grants and speakers honoraria from Fresenius Medical Care , Neuraxpharm , Servier , and Janssen Cilag as well as research funding from Fresenius Medical Care. M.S.-L. is supported by a Miguel Servet contract from the Instituto de Salud Carlos III (ISCIII) Spanish Health Institute (CP17/00142) and cofinanced by the European Social Fund. The remaining authors state that they have no conflicts of interest to declare. Funding Information: National Heart, Lung , and Blood Institute (NHLBI); Grant Number: R01 HL141291 NHLBI; Grant Number: R01 HL134894 NHLBI; Grant number: R01 HL105756 Funding Information: This study was supported by National Heart , Lung , and Blood Institute (NHLBI) grant R01 HL141291. The CHARGE Hemostasis Working Group is further supported by NHLBI grant R01 HL134894, whereas infrastructure for the CHARGE Consortium is supported, in part, by the NHLBI grant R01 HL105756. Publisher Copyright: © 2023 International Society on Thrombosis and Haemostasis

PY - 2023/5

Y1 - 2023/5

N2 - 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 × 10−7) and EPIC arrays (p < 5.78 × 10−8), 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.

AB - 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 × 10−7) and EPIC arrays (p < 5.78 × 10−8), 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.

KW - DNA methylation

KW - epigenome-wide association study

KW - fibrinogen

KW - inflammation

KW - Mendelian randomization

UR - http://www.scopus.com/inward/record.url?scp=85153792979&partnerID=8YFLogxK

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U2 - 10.1016/j.jtha.2023.01.015

DO - 10.1016/j.jtha.2023.01.015

M3 - Article

C2 - 36716967

SN - 1538-7836

VL - 21

SP - 1135

EP - 1147

JO - Journal of Thrombosis and Haemostasis

JF - Journal of Thrombosis and Haemostasis

IS - 5

ER -

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

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