Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
21502573
TITLE
Genetic predictors of fibrin D-dimer levels in healthy adults.
ABSTRACT
BACKGROUND NlmCategory: BACKGROUND
Fibrin fragment D-dimer, one of several peptides produced when crosslinked fibrin is degraded by plasmin, is the most widely used clinical marker of activated blood coagulation. To identity genetic loci influencing D-dimer levels, we performed the first large-scale, genome-wide association search.
METHODS AND RESULTS NlmCategory: RESULTS
A genome-wide investigation of the genomic correlates of plasma D-dimer levels was conducted among 21 052 European-ancestry adults. Plasma levels of D-dimer were measured independently in each of 13 cohorts. Each study analyzed the association between ≈2.6 million genotyped and imputed variants across the 22 autosomal chromosomes and natural-log–transformed D-dimer levels using linear regression in additive genetic models adjusted for age and sex. Among all variants, 74 exceeded the genome-wide significance threshold and marked 3 regions. At 1p22, rs12029080 (P=6.4×10(-52)) was 46.0 kb upstream from F3, coagulation factor III (tissue factor). At 1q24, rs6687813 (P=2.4×10(-14)) was 79.7 kb downstream of F5, coagulation factor V. At 4q32, rs13109457 (P=2.9×10(-18)) was located between 2 fibrinogen genes: 10.4 kb downstream from FGG and 3.0 kb upstream from FGA. Variants were associated with a 0.099-, 0.096-, and 0.061-unit difference, respectively, in natural-log–transformed D-dimer and together accounted for 1.8% of the total variance. When adjusted for nonsynonymous substitutions in F5 and FGA loci known to be associated with D-dimer levels, there was no evidence of an additional association at either locus.
CONCLUSIONS NlmCategory: CONCLUSIONS
Three genes were associated with fibrin D-dimer levels. Of these 3, the F3 association was the strongest, and has not been previously reported.
DATE PUBLISHED
2011 May 3
HISTORY
PUBSTATUS PUBSTATUSDATE
aheadofprint 2011/04/18
entrez 2011/04/20 06:00
pubmed 2011/04/20 06:00
medline 2011/07/14 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Smith NL Smith Nicholas L NL Department of Epidemiology, University of Washington, Seattle 98101, USA. nlsmith@u.washington.edu
Huffman JE Huffman Jennifer E JE
Strachan DP Strachan David P DP
Huang J Huang Jie J
Dehghan A Dehghan Abbas A
Trompet S Trompet Stella S
Lopez LM Lopez Lorna M LM
Shin SY Shin So-Youn SY
Baumert J Baumert Jens J
Vitart V Vitart Veronique V
Bis JC Bis Joshua C JC
Wild SH Wild Sarah H SH
Rumley A Rumley Ann A
Yang Q Yang Qiong Q
Uitterlinden AG Uitterlinden Andre G AG
Stott DJ Stott David J DJ
Davies G Davies Gail G
Carter AM Carter Angela M AM
Thorand B Thorand Barbara B
Polašek O Polašek Ozren O
McKnight B McKnight Barbara B
Campbell H Campbell Harry H
Rudnicka AR Rudnicka Alicja R AR
Chen MH Chen Ming-Huei MH
Buckley BM Buckley Brendan M BM
Harris SE Harris Sarah E SE
Peters A Peters Annette A
Pulanic D Pulanic Drazen D
Lumley T Lumley Thomas T
de Craen AJ de Craen Anton J M AJ
Liewald DC Liewald David C DC
Gieger C Gieger Christian C
Campbell S Campbell Susan S
Ford I Ford Ian I
Gow AJ Gow Alan J AJ
Luciano M Luciano Michelle M
Porteous DJ Porteous David J DJ
Guo X Guo Xiuqing X
Sattar N Sattar Naveed N
Tenesa A Tenesa Albert A
Cushman M Cushman Mary M
Slagboom PE Slagboom P Eline PE
Visscher PM Visscher Peter M PM
Spector TD Spector Tim D TD
Illig T Illig Thomas T
Rudan I Rudan Igor I
Bovill EG Bovill Edwin G EG
Wright AF Wright Alan F AF
McArdle WL McArdle Wendy L WL
Tofler G Tofler Geoffrey G
Hofman A Hofman Albert A
Westendorp RG Westendorp Rudi G J RG
Starr JM Starr John M JM
Grant PJ Grant Peter J PJ
Karakas M Karakas Mahir M
Hastie ND Hastie Nicholas D ND
Psaty BM Psaty Bruce M BM
Wilson JF Wilson James F JF
Lowe GD Lowe Gordon D O GD
O'Donnell CJ O'Donnell Christopher J CJ
Witteman JC Witteman Jacqueline C M JC
Jukema JW Jukema J Wouter JW
Deary IJ Deary Ian J IJ
Soranzo N Soranzo Nicole N
Koenig W Koenig Wolfgang W
Hayward C Hayward Caroline C
INVESTIGATORS
JOURNAL
VOLUME: 123
ISSUE: 17
TITLE: Circulation
ISOABBREVIATION: Circulation
YEAR: 2011
MONTH: May
DAY: 3
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1524-4539
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Circulation
COUNTRY: United States
ISSNLINKING: 0009-7322
NLMUNIQUEID: 0147763
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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GRANTS
GRANTID AGENCY COUNTRY
068545 Wellcome Trust United Kingdom
068545/Z/02 Wellcome Trust United Kingdom
076113/B/04/Z Wellcome Trust United Kingdom
079895 Wellcome Trust United Kingdom
079996 Wellcome Trust United Kingdom
091746 Wellcome Trust United Kingdom
091746/Z/ Wellcome Trust United Kingdom
BB/F019394/1 Biotechnology and Biological Sciences Research Council United Kingdom
CZB/4/276 Chief Scientist Office United Kingdom
CZB/4/505 Chief Scientist Office United Kingdom
CZB/4/710 Chief Scientist Office United Kingdom
DK063491 NIDDK NIH HHS United States
ETM/55 Chief Scientist Office United Kingdom
G0000934 Medical Research Council United Kingdom
G0700704 Medical Research Council United Kingdom
HL073410 NHLBI NIH HHS United States
HL095080 NHLBI NIH HHS United States
K24 DK080140 NIDDK NIH HHS United States
M01-RR00425 NCRR NIH HHS United States
MC_PC_U127561128 Medical Research Council United Kingdom
MC_QA137934 Medical Research Council United Kingdom
MC_U127561128 Medical Research Council United Kingdom
N01-HC-15103 NHLBI NIH HHS United States
N01-HC-25195 NHLBI NIH HHS United States
N01-HC-35129 NHLBI NIH HHS United States
N01-HC-45133 NHLBI NIH HHS United States
N01-HC-55222 NHLBI NIH HHS United States
N01-HC-75150 NHLBI NIH HHS United States
N01-HC-85079 NHLBI NIH HHS United States
N01-HC-85086 NHLBI NIH HHS United States
N02-HL-6-4278 NHLBI NIH HHS United States
R01 HL 087652 NHLBI NIH HHS United States
SAG09977 Biotechnology and Biological Sciences Research Council United Kingdom
U.1275.00.001(61128) Medical Research Council United Kingdom
U01 DK062418 NIDDK NIH HHS United States
U01 HL080295 NHLBI NIH HHS United States
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Adult
Aged
Blood Coagulation genetics
European Continental Ancestry Group statistics & numerical data
Factor V genetics
Female genetics
Fibrin Fibrinogen Degradation Products metabolism
Fibrinogen genetics
Genetic Testing genetics
Genome-Wide Association Study genetics
Humans genetics
Male genetics
Middle Aged genetics
Reference Values genetics
Thromboplastin genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 Fibrin Fibrinogen Degradation Products
0 fibrin fragment D
9001-24-5 Factor V
9001-32-5 Fibrinogen
9035-58-9 Thromboplastin
OTHER ID's
OTHERID SOURCE
PMC3095913 NLM
UKMS35274 NLM
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