https://orcid.org/0000-0002-9672-2491
Key Points
Largest and most diverse genetic study of plasma fibrinogen identifies 54 regions (18 novel), housing 69 distinct variants (20 novel).
Links to (1) liver enzyme, blood cell, and lipid genetic signals, (2) liver regulatory elements, and (3) thrombotic and inflammatory disease.
Subjects:
Thrombosis and Hemostasis
Abstract
Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole-genome sequencing (WGS) data provide better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the National Heart, Lung, and Blood Institute’s Trans-Omics for Precision Medicine (TOPMed) program (n = 32 572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n = 131 340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, 4 are driven by common variants of small effect with reported minor allele frequency (MAF) at least 10 percentage points higher in African populations. Three signals (SERPINA1, ZFP36L2, and TLR10) contain predicted deleterious missense variants. Two loci, SOCS3 and HPN, each harbor 2 conditionally distinct, noncoding variants. The gene region encoding the fibrinogen protein chain subunits (FGG;FGB;FGA) contains 7 distinct signals, including 1 novel signal driven by rs28577061, a variant common in African ancestry populations but extremely rare in Europeans (MAFAFR = 0.180; MAFEUR = 0.008). Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation.
Subjects:
Thrombosis and Hemostasis
References
1.
Wolberg
AS
, Sang
Y
. Fibrinogen and factor XIII in venous thrombosis and thrombus stability
. Arterioscler Thromb Vasc Biol
. 2022
;42
(8
):931
-941
.2.
Pieters
M
, Wolberg
AS
. Fibrinogen and fibrin: an illustrated review
. Res Pract Thromb Haemost
. 2019
;3
(2
):161
-172
.3.
Vilar
R
, Fish
RJ
, Casini
A
, Neerman-Arbez
M
. Fibrin(ogen) in human disease: both friend and foe
. Haematologica
. 2020
;105
(2
):284
-296
.4.
Danesh
J
, Lewington
S
; Fibrinogen Studies Collaboration
. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis
. JAMA
. 2005
;294
(14
):1799
-1809
.5.
Machlus
KR
, Cardenas
JC
, Church
FC
, Wolberg
AS
. Causal relationship between hyperfibrinogenemia, thrombosis, and resistance to thrombolysis in mice
. Blood
. 2011
;117
(18
):4953
-4963
.6.
Vilar
R
, Lukowski
SW
, Garieri
M
, Di Sanza
C
, Neerman-Arbez
M
, Fish
RJ
. Chemical modulators of fibrinogen production and their impact on venous thrombosis
. Thromb Haemost
. 2021
;121
(4
):433
-448
.7.
Sabater-Lleal
M
, Huang
J
, Chasman
D
, et al. Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease
. Circulation
. 2013
;128
(12
):1310
-1324
.8.
Ward-Caviness
CK
, de Vries
PS
, Wiggins
KL
, et al. Mendelian randomization evaluation of causal effects of fibrinogen on incident coronary heart disease
. PLoS One
. 2019
;14
(5
):e0216222
.9.
Maners
J
, Gill
D
, Pankratz
N
, et al. A Mendelian randomization of γ’ and total fibrinogen levels in relation to venous thromboembolism and ischemic stroke
. Blood
. 2020
;136
(26
):3062
-3069
.10.
de Maat
MPM
, Bladbjerg
EM
, Hjelmborg
JvB
, Bathum
L
, Jespersen
J
, Christensen
K
. Genetic influence on inflammation variables in the elderly
. Arterioscler Thromb Vasc Biol
. 2004
;24
(11
):2168
-2173
.11.
Sas
AA
, Rijsdijk
FV
, Ormel
J
, Snieder
H
, Riese
H
. The relationship between neuroticism and inflammatory markers: a twin study
. Twin Res Hum Genet
. 2014
;17
(3
):177
-182
.12.
Williams
PT
. Quantile-specific heritability of plasma fibrinogen concentrations
. PLoS One
. 2022
;17
(1
):e0262395
.13.
de Lange
M
, Snieder
H
, Ariëns
RA
, Spector
TD
, Grant
PJ
. The genetics of haemostasis: a twin study
. Lancet
. 2001
;357
(9250
):101
-105
.14.
Kaptoge
S
, White
IR
, Thompson
SG
, et al; Fibrinogen Studies Collaboration
. Associations of plasma fibrinogen levels with established cardiovascular disease risk factors, inflammatory markers, and other characteristics: individual participant meta-analysis of 154,211 adults in 31 prospective studies: the fibrinogen studies collaboration
. Am J Epidemiol
. 2007
;166
(8
):867
-879
.15.
Folsom
AR
, Qamhieh
HT
, Flack
JM
, et al. Plasma fibrinogen: levels and correlates in young adults: the Coronary Artery Risk Development in Young Adults (CARDIA) Study
. Am J Epidemiol
. 1993
;138
(12
):1023
-1036
.16.
Lutsey
PL
, Cushman
M
, Steffen
LM
, et al. Plasma hemostatic factors and endothelial markers in four racial/ethnic groups: the MESA study
. J Thromb Haemost
. 2006
;4
(12
):2629
-2635
.17.
Ding
K
, Feng
D
, de Andrade
M
, et al. Genomic regions that influence plasma levels of inflammatory markers in hypertensive sibships
. J Hum Hypertens
. 2008
;22
(2
):102
-110
.18.
de Vries
PS
, Chasman
DI
, Sabater-Lleal
M
, et al. A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration
. Hum Mol Genet
. 2016
;25
(2
):358
-370
.19.
Huffman
JE
, de Vries
PS
, Morrison
AC
, et al. Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF
. Blood
. 2015
;126
(11
):e19
-e29
.20.
Wojcik
GL
, Fuchsberger
C
, Taliun
D
, et al. Imputation-aware tag SNP selection to improve power for large-scale, multi-ethnic association studies
. G3 (Bethesda)
. 2018
;8
(10
):3255
-3267
.21.
Kowalski
MH
, Qian
H
, Hou
Z
, et al. Use of ∖textgreater100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations
. PLoS Genet
. 2019
;15
(12
):e1008500
.22.
de Vries
PS
, Sabater-Lleal
M
, Chasman
DI
, et al. Comparison of HapMap and 1000 Genomes reference panels in a large-scale genome-wide association study
. PLoS One
. 2017
;12
(1
):e0167742
.23.
Taliun
D
, Harris
DN
, Kessler
MD
, et al. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program
. Nature
. 2021
;590
(7845
):290
-299
.24.
Psaty
BM
, O’Donnell
CJ
, Gudnason
V
, et al. Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium: design of prospective meta-analyses of genome-wide association studies from 5 cohorts
. Circ Cardiovasc Genet
. 2009
;2
(1
):73
-80
.25.
Gaziano
JM
, Concato
J
, Brophy
M
, et al. Million Veteran Program: a mega-biobank to study genetic influences on health and disease
. J Clin Epidemiol
. 2016
;70
:214
-223
.26.
Committee on the Use of Race, Ethnicity, and Ancestry as Population Descriptors in Genomics Research, Board on Health Sciences Policy
Committee on Population
. Using Population Descriptors in Genetics and Genomics Research: A New Framework for an Evolving Field. National Academies Press (US)
; 2023
.27.
Clauss
A
. Rapid physiological coagulation method in determination of fibrinogen [in German]
. Acta Haematol
. 1957
;17
(4
):237
-246
.28.
Brody
JA
, Morrison
AC
, Bis
JC
, et al. Analysis commons, a team approach to discovery in a big-data environment for genetic epidemiology
. Nat Genet
. 2017
;49
(11
):1560
-1563
.29.
McCarthy
S
, Das
S
, Kretzschmar
W
, et al. A reference panel of 64,976 haplotypes for genotype imputation
. Nat Genet
. 2016
;48
(10
):1279
-1283
.30.
Chen
H
, Huffman
JE
, Brody
JA
, et al. Efficient variant set mixed model association tests for continuous and binary traits in large-scale whole-genome sequencing studies
. Am J Hum Genet
. 2019
;104
(2
):260
-274
.31.
Winkler
TW
, Day
FR
, Croteau-Chonka
DC
, et al. Quality control and conduct of genome-wide association meta-analyses
. Nat Protoc
. 2014
;9
(5
):1192
-1212
.32.
Mägi
R
, Morris
AP
. GWAMA: software for genome-wide association meta-analysis
. BMC Bioinf
. 2010
;11
:288
.33.
Wu
Y
, Zheng
Z
, Visscher
PM
, Yang
J
. Quantifying the mapping precision of genome-wide association studies using whole-genome sequencing data
. Genome Biol
. 2017
;18
(1
):86
.34.
Yang
J
, Ferreira
T
, Morris
AP
, et al. Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits
. Nat Genet
. 2012
;44
(4
):369
-375
. S1-3.35.
Yang
J
, Lee
SH
, Goddard
ME
, Visscher
PM
. GCTA: a tool for genome-wide complex trait analysis
. Am J Hum Genet
. 2011
;88
(1
):76
-82
.36.
Maller
JB
, McVean
G
; Wellcome Trust Case Control Consortium
. Bayesian refinement of association signals for 14 loci in 3 common diseases
. Nat Genet
. 2012
;44
(12
):1294
-1301
.37.
Shim
H
, Chasman
DI
, Smith
JD
, et al. A multivariate genome-wide association analysis of 10 LDL subfractions, and their response to statin treatment, in 1868 Caucasians
. PLoS One
. 2015
;10
(4
):e0120758
.38.
McLaren
W
, Gil
L
, Hunt
SE
, et al. The ensembl variant effect predictor
. Genome Biol
. 2016
;17
(1
):122
.39.
Huang
L
, Rosen
JD
, Sun
Q
, et al. TOP-LD: a tool to explore linkage disequilibrium with TOPMed whole-genome sequence data
. Am J Hum Genet
. 2022
;109
(6
):1175
-1181
.40.
Rentzsch
P
, Witten
D
, Cooper
GM
, Shendure
J
, Kircher
M
. CADD: predicting the deleteriousness of variants throughout the human genome
. Nucleic Acids Res
. 2019
;47
(D1
):D886
-D894
.41.
Kircher
M
, Witten
DM
, Jain
P
, O'Roak
BJ
, Cooper
GM
, Shendure
J
. A general framework for estimating the relative pathogenicity of human genetic variants
. Nat Genet
. 2014
;46
(3
):310
-315
.42.
Fadista
J
, Oskolkov
N
, Hansson
O
, Groop
L
. LoFtool: a gene intolerance score based on loss-of-function variants in 60 706 individuals
. Bioinformatics
. 2017
;33
(4
):471
-474
.43.
Ng
PC
, Henikoff
S
. Predicting deleterious amino acid substitutions
. Genome Res
. 2001
;11
(5
):863
-874
.44.
Adzhubei
IA
, Schmidt
S
, Peshkin
L
, et al. A method and server for predicting damaging missense mutations
. Nat Methods
. 2010
;7
(4
):248
-249
.45.
Adzhubei
I
, Jordan
DM
, Sunyaev
SR
. Predicting functional effect of human missense mutations using PolyPhen-2. Current Protocols in Human Genetics. 2013
. Chapter 7:Unit 7.20.46.
Paysan-Lafosse
T
, Blum
M
, Chuguransky
S
, et al. InterPro in 2022
. Nucleic Acids Res
. 2023
;51
(D1
):D418
-D427
.47.
Pividori
M
, Rajagopal
PS
, Barbeira
A
, et al. PhenomeXcan: mapping the genome to the phenome through the transcriptome
. Sci Adv
. 2020
;6
(37
):eaba2083
.48.
Wen
X
, Pique-Regi
R
, Luca
F
. Integrating molecular QTL data into genome-wide genetic association analysis: probabilistic assessment of enrichment and colocalization
. PLoS Genet
. 2017
;13
(3
):e1006646
.49.
Gamazon
ER
, Wheeler
HE
, Shah
KP
, et al. A gene-based association method for mapping traits using reference transcriptome data
. Nat Genet
. 2015
;47
(9
):1091
-1098
.50.
Barbeira
AN
, Dickinson
SP
, Bonazzola
R
, et al. Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics
. Nat Commun
. 2018
;9
(1
):1825
.51.
Barbeira
AN
, Bonazzola
R
, Gamazon
ER
, et al. Exploiting the GTEx resources to decipher the mechanisms at GWAS loci
. Genome Biol
. 2021
;22
(1
):49
.52.
Barbeira
AN
, Pividori
M
, Zheng
J
, Wheeler
HE
, Nicolae
DL
, Im
HK
. Integrating predicted transcriptome from multiple tissues improves association detection
. PLoS Genet
. 2019
;15
(1
):e1007889
.53.
Mancuso
N
, Freund
MK
, Johnson
R
, et al. Probabilistic fine-mapping of transcriptome-wide association studies
. Nat Genet
. 2019
;51
(4
):675
-682
.54.
Denny
JC
, Ritchie
MD
, Basford
MA
, et al. PheWAS: demonstrating the feasibility of a phenome-wide scan to discover gene-disease associations
. Bioinformatics
. 2010
;26
(9
):1205
-1210
.55.
Temprano-Sagrera
G
, Sitlani
CM
, Bone
WP
, et al. Multi-phenotype analyses of hemostatic traits with cardiovascular events reveal novel genetic associations
. J Thromb Haemost
. 2022
;20
(6
):1331
-1349
.56.
Yengo
L
, Sidorenko
J
, Kemper
KE
, et al. Meta-analysis of genome-wide association studies for height and body mass index in ∼700000 individuals of European ancestry
. Hum Mol Genet
. 2018
;27
(20
):3641
-3649
.57.
Yengo
L
, Vedantam
S
, Marouli
E
, et al. A saturated map of common genetic variants associated with human height
. Nature
. 2022
;610
(7933
):704
-712
.58.
Talens
S
, Malfliet
JJMC
, van Hal
PTW
, Leebeek
FWG
, Rijken
DC
. Identification and characterization of alpha1 -antitrypsin in fibrin clots
. J Thromb Haemost
. 2013
;11
(7
):1319
-1328
.59.
Ercetin
E
, Richtmann
S
, Delgado
BM
, et al. Clinical significance of SERPINA1 gene and its encoded alpha1-antitrypsin protein in NSCLC
. Cancers
. 2019
;11
(9
):1306
.60.
Strnad
P
, McElvaney
NG
, Lomas
DA
. Alpha1-antitrypsin deficiency
. N Engl J Med
. 2020
;382
(15
):1443
-1455
.61.
Chen
M-H
, Raffield
LM
, Mousas
A
, et al. Trans-ethnic and ancestry-specific blood-cell genetics in 746,667 individuals from 5 global populations
. Cell
. 2020
;182
(5
):1198
-1213.e14
.62.
Astle
WJ
, Elding
H
, Jiang
T
, et al. The allelic landscape of human blood cell trait variation and links to common complex disease
. Cell
. 2016
;167
(5
):1415
-1429.e19
.63.
Kichaev
G
, Bhatia
G
, Loh
P-R
, et al. Leveraging polygenic functional enrichment to improve GWAS power
. Am J Hum Genet
. 2019
;104
(1
):65
-75
.64.
Vuckovic
D
, Bao
EL
, Akbari
P
, et al. The polygenic and monogenic basis of blood traits and diseases
. Cell
. 2020
;182
(5
):1214
-1231.e11
.65.
Zhang
L
, Prak
L
, Rayon-Estrada
V
, et al. ZFP36L2 is required for self-renewal of early burst-forming unit erythroid progenitors
. Nature
. 2013
;499
(7456
):92
-96
.66.
Makita
S
, Takatori
H
, Nakajima
H
. Post-transcriptional regulation of immune responses and inflammatory diseases by RNA-binding ZFP36 family proteins
. Front Immunol
. 2021
;12
:711633
.67.
Lai
WS
, Carballo
E
, Strum
JR
, Kennington
EA
, Phillips
RS
, Blackshear
PJ
. Evidence that tristetraprolin binds to AU-rich elements and promotes the deadenylation and destabilization of tumor necrosis factor alpha mRNA
. Mol Cell Biol
. 1999
;19
(6
):4311
-4323
.68.
Page
MJ
, Bester
J
, Pretorius
E
. The inflammatory effects of TNF-α and complement component 3 on coagulation
. Sci Rep
. 2018
;8
(1
):1812
.69.
Makita
S
, Takatori
H
, Iwata
A
, et al. RNA-binding protein ZFP36L2 downregulates helios expression and suppresses the function of regulatory T cells
. Front Immunol
. 2020
;11
:1291
.70.
Parra-Izquierdo
I
, Lakshmanan
HHS
, Melrose
AR
, et al. The toll-like receptor 2 ligand Pam2CSK4 activates platelet nuclear factor-∖kappaB and Bruton’s tyrosine kinase signaling to promote platelet-endothelial cell interactions
. Front Immunol
. 2021
;12
:729951
.71.
Fore
F
, Indriputri
C
, Mamutse
J
, Nugraha
J
. TLR10 and its unique anti-inflammatory properties and potential use as a target in therapeutics
. Immune Netw
. 2020
;20
(3
):e21
.72.
Oosting
M
, Cheng
S-C
, Bolscher
JM
, et al. Human TLR10 is an anti-inflammatory pattern-recognition receptor
. Proc Natl Acad Sci U S A
. 2014
;111
(42
):E4478
-E4484
.73.
Li
S
, Wang
L
, Sun
S
, Wu
Q
. Hepsin: a multifunctional transmembrane serine protease in pathobiology
. FEBS J
. 2021
;288
(18
):5252
-5264
.74.
Kazama
Y
, Hamamoto
T
, Foster
DC
, Kisiel
W
. Hepsin, a putative membrane-associated serine protease, activates human factor VII and initiates a pathway of blood coagulation on the cell surface leading to thrombin formation
. J Biol Chem
. 1995
;270
(1
):66
-72
.75.
Khandekar
G
, Iyer
N
, Jagadeeswaran
P
. Prostasin and hepatocyte growth factor B in factor VIIa generation: serine protease knockdowns in zebrafish
. Res Pract Thromb Haemost
. 2020
;4
(7
):1150
-1157
.76.
Li
S
, Peng
J
, Wang
H
, et al. Hepsin enhances liver metabolism and inhibits adipocyte browning in mice
. Proc Natl Acad Sci U S A
. 2020
;117
(22
):12359
-12367
.77.
Yu
IS
, Chen
HJ
, Lee
YS
, et al. Mice deficient in hepsin, a serine protease, exhibit normal embryogenesis and unchanged hepatocyte regeneration ability
. Thromb Haemost
. 2000
;84
(5
):865
-870
.78.
Wu
Q
, Yu
D
, Post
J
, Halks-Miller
M
, Sadler
JE
, Morser
J
. Generation and characterization of mice deficient in hepsin, a hepatic transmembrane serine protease
. J Clin Invest
. 1998
;101
(2
):321
-326
.79.
Maimaris
G
, Christodoulou
A
, Santama
N
, Lederer
CW
. Regulation of ER composition and extent, and putative action in protein networks by ER/NE protein TMEM147
. Int J Mol Sci
. 2021
;22
(19
):10231
.80.
Hahn
J
, Bressler
J
, Domingo-Relloso
A
, et al. DNA methylation analysis identifies novel genetic loci associated with circulating fibrinogen levels in blood
. J Thromb Haemost
. 2023
. 21(5):1135-1147.81.
Casini
A
, Undas
A
, Palla
R
, Thachil
J
, de Moerloose
P
; Subcommittee on Factor XIII and Fibrinogen
. Diagnosis and classification of congenital fibrinogen disorders: communication from the SSC of the ISTH
. J Thromb Haemost
. 2018
;16
(9
):1887
-1890
.82.
Korte
W
, Poon
M-C
, Iorio
A
, Makris
M
. Thrombosis in inherited fibrinogen disorders
. Transfus Med Hemother
. 2017
;44
(2
):70
-76
.83.
Uitte de Willige
S
, Standeven
KF
, Philippou
H
, Ariëns
RAS
. The pleiotropic role of the fibrinogen gamma’ chain in hemostasis
. Blood
. 2009
;114
(19
):3994
-4001
.84.
Vedder
D
, Gerritsen
M
, Meijers
JCM
, Nurmohamed
MT
. Coagulation in gout: is there a link with disease activity?
. Clin Rheumatol
. 2022
;41
(6
):1809
-1815
.85.
Wu
Y
, Chu
C
, Song
P
, Yang
Y
, Lin
C
, Xu
Q
. Plasma D-dimer is a promising indicator for the treatment of acute gouty attack
. Ann Clin Lab Sci
. 2018
;48
(4
):435
-439
.2024
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