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Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium.

TitleNovel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium.
Publication TypeJournal Article
Year of Publication2010
AuthorsSmith NL, Chen M-H, Dehghan A, Strachan DP, Basu S, Soranzo N, Hayward C, Rudan I, Sabater-Lleal M, Bis JC, de Maat MPM, Rumley A, Kong X, Yang Q, Williams FMK, Vitart V, Campbell H, Malarstig A, Wiggins KL, van Duijn CM, McArdle WL, Pankow JS, Johnson AD, Silveira A, McKnight B, Uitterlinden AG, Aleksic N, Meigs JB, Peters A, Koenig W, Cushman M, Kathiresan S, Rotter JI, Bovill EG, Hofman A, Boerwinkle E, Tofler GH, Peden JF, Psaty BM, Leebeek F, Folsom AR, Larson MG, Spector TD, Wright AF, Wilson JF, Hamsten A, Lumley T, Witteman JCM, Tang W, O'Donnell CJ
Corporate AuthorsWellcome Trust Case Control Consortium;
JournalCirculation
Volume121
Issue12
Pagination1382-92
Date Published2010 Mar 30
ISSN1524-4539
KeywordsAdult, Factor VII, Factor VIII, Female, Genome-Wide Association Study, Hemostasis, Humans, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Thrombosis, von Willebrand Factor
Abstract

BACKGROUND: Plasma levels of coagulation factors VII (FVII), VIII (FVIII), and von Willebrand factor (vWF) influence risk of hemorrhage and thrombosis. We conducted genome-wide association studies to identify new loci associated with plasma levels.

METHODS AND RESULTS: The setting of the study included 5 community-based studies for discovery comprising 23 608 European-ancestry participants: Atherosclerosis Risk In Communities Study, Cardiovascular Health Study, British 1958 Birth Cohort, Framingham Heart Study, and Rotterdam Study. All subjects had genome-wide single-nucleotide polymorphism (SNP) scans and at least 1 phenotype measured: FVII activity/antigen, FVIII activity, and vWF antigen. Each study used its genotype data to impute to HapMap SNPs and independently conducted association analyses of hemostasis measures using an additive genetic model. Study findings were combined by meta-analysis. Replication was conducted in 7604 participants not in the discovery cohort. For FVII, 305 SNPs exceeded the genome-wide significance threshold of 5.0x10(-8) and comprised 5 loci on 5 chromosomes: 2p23 (smallest P value 6.2x10(-24)), 4q25 (3.6x10(-12)), 11q12 (2.0x10(-10)), 13q34 (9.0x10(-259)), and 20q11.2 (5.7x10(-37)). Loci were within or near genes, including 4 new candidate genes and F7 (13q34). For vWF, 400 SNPs exceeded the threshold and marked 8 loci on 6 chromosomes: 6q24 (1.2x10(-22)), 8p21 (1.3x10(-16)), 9q34 (

CONCLUSIONS: New genetic associations were discovered outside previously known biological pathways and may point to novel prevention and treatment targets of hemostasis disorders.

DOI10.1161/CIRCULATIONAHA.109.869156
Alternate JournalCirculation
PubMed ID20231535
PubMed Central IDPMC2861278
Grant ListN01HC55020 / HL / NHLBI NIH HHS / United States
M01-RR00425 / RR / NCRR NIH HHS / United States
N02-HL-6-4278 / HL / NHLBI NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
N01 HC055022 / HC / NHLBI NIH HHS / United States
HL073410 / HL / NHLBI NIH HHS / United States
CZB/4/710 / / Chief Scientist Office / United Kingdom
N01 HC085086 / HC / NHLBI NIH HHS / United States
R01 HL095080 / HL / NHLBI NIH HHS / United States
R01-HL-086694 / HL / NHLBI NIH HHS / United States
N01HC55018 / HL / NHLBI NIH HHS / United States
N01 HC085081 / HC / NHLBI NIH HHS / United States
U01 HL080295-04 / HL / NHLBI NIH HHS / United States
R01 HL087652-03 / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
UL1-RR-025005 / RR / NCRR NIH HHS / United States
G0000934 / / Medical Research Council / United Kingdom
U01 HL080295 / HL / NHLBI NIH HHS / United States
N01 HC075150 / HC / NHLBI NIH HHS / United States
N01-HC-55022 / HC / NHLBI NIH HHS / United States
N01-HC-85081 / HC / NHLBI NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
MC_U127561128 / / Medical Research Council / United Kingdom
R01-HL-087641 / HL / NHLBI NIH HHS / United States
N01 HC015103 / HC / NHLBI NIH HHS / United States
N01-HC-55016 / HC / NHLBI NIH HHS / United States
N01 HC085083 / HC / NHLBI NIH HHS / United States
N01 HC055018 / HC / NHLBI NIH HHS / United States
N01 HC025195 / HC / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
N02 HL64278 / HL / NHLBI NIH HHS / United States
N01 HC085085 / HC / NHLBI NIH HHS / United States
/ / Department of Health / United Kingdom
R01 HL087652 / HL / NHLBI NIH HHS / United States
HHSN268200625226C / / PHS HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
N01HC55022 / HL / NHLBI NIH HHS / United States
K24 DK080140-03 / DK / NIDDK NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
N01-HC-55021 / HC / NHLBI NIH HHS / United States
N01-HC-85086 / HC / NHLBI NIH HHS / United States
N01HC55015 / HL / NHLBI NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
G20234/2 / / Biotechnology and Biological Sciences Research Council / United Kingdom
R01 DK033651 / DK / NIDDK NIH HHS / United States
N01 HC085082 / HC / NHLBI NIH HHS / United States
N01-HC-85082 / HC / NHLBI NIH HHS / United States
R01-HL-59367 / HL / NHLBI NIH HHS / United States
N01 HC055019 / HC / NHLBI NIH HHS / United States
R01 HL087641-03 / HL / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
N01 HC085080 / HC / NHLBI NIH HHS / United States
N01-HC-55019 / HC / NHLBI NIH HHS / United States
N01-HC-55015 / HC / NHLBI NIH HHS / United States
N01 HC055222 / HC / NHLBI NIH HHS / United States
R01 HL 087652 / HL / NHLBI NIH HHS / United States
N01-HC-55222 / HC / NHLBI NIH HHS / United States
068545 / / Wellcome Trust / United Kingdom
P30 DK063491-07 / DK / NIDDK NIH HHS / United States
K24 DK080140 / DK / NIDDK NIH HHS / United States
N01-HC-85083 / HC / NHLBI NIH HHS / United States
N01-HC-75150 / HC / NHLBI NIH HHS / United States
R01 HL086694-03 / HL / NHLBI NIH HHS / United States
079996 / / Wellcome Trust / United Kingdom
N01-HC-55020 / HC / NHLBI NIH HHS / United States
N01-HC-85080 / HC / NHLBI NIH HHS / United States
N01HC55016 / HL / NHLBI NIH HHS / United States
G0000934(68341) / / Medical Research Council / United Kingdom
091746 / / Wellcome Trust / United Kingdom
M01 RR000425-39 / RR / NCRR NIH HHS / United States
N01 HC055015 / HC / NHLBI NIH HHS / United States
N01 HC055021 / HC / NHLBI NIH HHS / United States
M01 RR000425 / RR / NCRR NIH HHS / United States
R01 HL073410-05A2 / HL / NHLBI NIH HHS / United States
HL095080 / HL / NHLBI NIH HHS / United States
N01 HC085084 / HC / NHLBI NIH HHS / United States
G20234 / / Biotechnology and Biological Sciences Research Council / United Kingdom
U01 HG004402-02S1 / HG / NHGRI NIH HHS / United States
N01HC55019 / HL / NHLBI NIH HHS / United States
N01HC75150 / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
DK063491 / DK / NIDDK NIH HHS / United States
N01-HC-85079 / HC / NHLBI NIH HHS / United States
/ / Wellcome Trust / United Kingdom
R01 HL059367-09 / HL / NHLBI NIH HHS / United States
N01 HC055020 / HC / NHLBI NIH HHS / United States
068545/Z/02 / / Wellcome Trust / United Kingdom
MC_QA137934 / / Medical Research Council / United Kingdom
N01HC85079 / HL / NHLBI NIH HHS / United States
N01 HC085079 / HC / NHLBI NIH HHS / United States
R01 HL095080-02 / HL / NHLBI NIH HHS / United States
N01-HC-55018 / HC / NHLBI NIH HHS / United States
N01HC55021 / HL / NHLBI NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
U01-HG-004402 / HG / NHGRI NIH HHS / United States
R01 HL073410 / HL / NHLBI NIH HHS / United States
N01 HC045133 / HC / NHLBI NIH HHS / United States
UL1 RR025005-02 / RR / NCRR NIH HHS / United States
N01 HC035129 / HC / NHLBI NIH HHS / United States
N01 HC055016 / HC / NHLBI NIH HHS / United States