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

被引：7

作者：

Hahn, Julie ^{[1
,48
]}

Bressler, Jan ^{[1
]}

Domingo-Relloso, Arce ^{[2
,3
,4
]}

Chen, Ming-Huei ^{[5
]}

McCartney, Daniel L. ^{[6
]}

Teumer, Alexander ^{[7
,8
,9
]}

van Dongen, Jenny ^{[10
,11
]}

Kleber, Marcus E. ^{[12
,13
]}

Aissi, Dylan ^{[14
]}

Swenson, Brenton R. ^{[15
]}

Yao, Jie ^{[16
]}

Zhao, Wei ^{[17
,18
]}

Huang, Jian ^{[19
]}

Xia, Yujing ^{[20
]}

Brown, Michael R. ^{[1
]}

Costeira, Ricardo

de Geus, Eco J. C. ^{[10
,11
]}

Delgado, Graciela E. ^{[12
]}

Dobson, Dre'Von A. ^{[21
]}

Elliott, Paul ^{[22
,23
,24
]}

Grabe, Hans J. ^{[25
,26
]}

Guo, Xiuqing ^{[16
]}

Harris, Sarah E. ^{[27
]}

Huffman, Jennifer E. ^{[28
]}

Kardia, Sharon L. R. ^{[17
]}

Liu, Yongmei ^{[29
]}

Lorkowski, Stefan ^{[30
,31
]}

Marioni, Riccardo E. ^{[6
]}

Nauck, Matthias ^{[8
,32
]}

Ratliff, Scott M. ^{[17
]}

Sabater-Lleal, Maria ^{[33
,34
]}

Spector, Tim D.

Suchon, Pierre ^{[35
]}

Taylor, Kent D. ^{[16
]}

Thibord, Florian ^{[36
]}

Tregouet, David-Alexandre ^{[14
]}

Wiggins, Kerri L. ^{[37
]}

Willemsen, Gonneke ^{[10
,11
]}

Bell, Jordana T. ^{[20
]}

Boomsma, Dorret I. ^{[10
,11
]}

Cole, Shelley A. ^{[38
]}

Cox, Simon R. ^{[27
]}

Dehghan, Abbas ^{[19
]}

Greinacher, Andreas ^{[39
]}

Haack, Karin ^{[38
]}

Marz, Winfried ^{[40
,41
]}

Morange, Pierre-Emmanuel ^{[42
]}

Rotter, Jerome I. ^{[16
]}

Sotoodehnia, Nona ^{[43
]}

Tellez-Plaza, Maria ^{[3
]}

机构：

[1] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Houston, TX USA

[2] Columbia Univ, Dept Environm Hlth Sci, Mailman Sch Publ Hlth, New York, NY USA

[3] Carlos III Hlth Inst, Natl Ctr Epidemiol, Dept Chron Dis Epidemiol, Madrid, Spain

[4] Univ Valencia, Dept Stat & Operat Res, Burjassot, Spain

[5] Natl Heart Lung & Blood Inst, Div Intramural Res, Populat Sci Branch, Framingham, MA USA

[6] Univ Edinburgh, Inst Genet & Canc, Ctr Genom & Expt Med, Edinburgh, Scotland

[7] Univ Med Greifswald, Inst Community Med, Dept SHIP Clin Epidemiol Res, Greifswald, Germany

[8] DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany

[9] Med Univ Bialystok, Dept Populat Med & Lifestyle Dis Prevent, Bialystok, Poland

[10] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands

[11] Amsterdam Publ Hlth Res Inst, Amsterdam, Netherlands

[12] Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany

[13] SYNLAB MVZ Humangenet Mannheim, Mannheim, Germany

[14] Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, INSERM, UMR 1219,Mol Epidemiol Vasc & Brain Disorders, Bordeaux, France

[15] Univ Washington, Sch Publ Hlth, Cardiovasc Hlth Res Unit, Seattle, WA USA

[16] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Lundquist Inst Biomed Innovat, Pediat Genom Outcomes, Torrance, CA USA

[17] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI USA

[18] Univ Michigan, Inst Social Res, Survey Res Ctr, Ann Arbor, MI USA

[19] Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England

[20] Kings Coll London, Dept Twin Res & Genet Epidemiol, St Thomas Hosp Campus, London, England

[21] Univ North Carolina Chapel Hill, Pathol & Lab Med, Chapel Hill, NC USA

[22] Imperial Coll London, MRC Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England

[23] Imperial Coll London, Dementia Res Inst, London, England

[24] Imperial Coll London, British Heart Fdn Ctr Res Excellence, London, England

[25] Univ Med Greifswald, Dept Psychiat & Psychotherapy, Greifswald, Germany

[26] German Ctr Neurodegenerat Dis DZNE, Site Rostock Greifswald, Greifswald, Germany

[27] Univ Edinburgh, Dept Psychol, Lothian Birth Cohorts, Edinburgh, Scotland

[28] VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MAV, Boston, MA USA

[29] Duke Mol Physiol Inst, Med, Cardiol, Durham, NC USA

[30] Friedrich Schiller Univ Jena, Inst Nutr Sci, Jena, Germany

[31] Competence Cluster Nutr & Cardiovasc Hlth nutriCAR, Jena, Germany

[32] Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany

[33] St Pau Biomed Res Inst IIB St Pau, Genom Complex Dis Unit, Barcelona, Spain

[34] Karolinska Inst, Dept Med, Cardiovasc Med Unit, Stockholm, Sweden

[35] Aix Marseille Univ, La Timone Univ Hosp Marseille, Ctr Cardiovasc & Nutr Res C2VN, Hematol Lab,INSERM 1263,INRAE 1260, Marseille, France

[36] Natl Heart Lung & Blood Inst, Populat Sci Branch, Framingham, MA USA

[37] Univ Washington, Dept Med, Div Gen Internal Med, Seattle, WA USA

[38] Texas Biomed Res Inst, Populat Hlth Program, San Antonio, TX USA

[39] Univ Med Greifswald, Inst Immunol & Transfus Med, Greifswald, Germany

[40] SYNLAB Holding Deutschland GmbH, SYNLAB Acad, Mannheim, Germany

[41] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria

[42] Aix Marseille Univ, Cardiovasc & Nutr Reserach Ctr C2VN, INSERM, INRAE, Marseille, France

[43] Univ Washington, Dept Med, Div Cardiol, Seattle, WA USA

[44] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, McGovern Med Sch, Houston, TX USA

[45] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA USA

[46] Kaiser Permanente Washington, Kaiser Permanente Washington Hlth Res Inst, Seattle, WA USA

[47] Dept Vet Affairs, Seattle Epidemiol Res & Informat Ctr, Off Res & Dev, Seattle, WA USA

[48] Univ Texas Hlth Sci Ctr Houston, Dept Epidemiol Human Genet & Environm Sci, 1200 Pressler St,Suite E-435, Houston, TX 77030 USA

[49] Univ Texas Hlth Sci Ctr Houston, Dept Epidemiol Human Genet & Environm Sci, 1200 Pressler St,Suite E-429, Houston, TX 77030 USA

来源：

JOURNAL OF THROMBOSIS AND HAEMOSTASIS | 2023年 / 21卷 / 05期

基金：

英国生物技术与生命科学研究理事会;

关键词：

DNA methylation; epigenome-wide association study; fibrinogen; inflammation; Mendelian randomization; EPIGENOME-WIDE ASSOCIATION; NF-KAPPA-B; METAANALYSIS; EXPRESSION; PHOSPHO1; DESIGN;

D O I：

10.1016/j.jtha.2023.01.015

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 x 10-7) and EPIC arrays (p < 5.78 x 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.

引用

页码：1135 / 1147

页数：13

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