title: Genetic predictors of fibrin D-dimer levels in healthy adults.
abstract: 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.
  
  
  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
  Three genes were associated with fibrin D-dimer levels. Of these 3, the F3 association was the strongest, and has not been previously reported.
authors.affiliation: Department of Epidemiology, University of Washington, Seattle 98101, USA. nlsmith@u.washington.edu
authors.forename: Nicholas L
authors.initials: NL
authors.lastname: Smith
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Huffman
authors.forename: David P
authors.initials: DP
authors.lastname: Strachan
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.forename: Abbas
authors.initials: A
authors.lastname: Dehghan
authors.forename: Stella
authors.initials: S
authors.lastname: Trompet
authors.forename: Lorna M
authors.initials: LM
authors.lastname: Lopez
authors.forename: So-Youn
authors.initials: SY
authors.lastname: Shin
authors.forename: Jens
authors.initials: J
authors.lastname: Baumert
authors.forename: Veronique
authors.initials: V
authors.lastname: Vitart
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Bis
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Wild
authors.forename: Ann
authors.initials: A
authors.lastname: Rumley
authors.forename: Qiong
authors.initials: Q
authors.lastname: Yang
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: David J
authors.initials: DJ
authors.lastname: Stott
authors.forename: Gail
authors.initials: G
authors.lastname: Davies
authors.forename: Angela M
authors.initials: AM
authors.lastname: Carter
authors.forename: Barbara
authors.initials: B
authors.lastname: Thorand
authors.forename: Ozren
authors.initials: O
authors.lastname: Polašek
authors.forename: Barbara
authors.initials: B
authors.lastname: McKnight
authors.forename: Harry
authors.initials: H
authors.lastname: Campbell
authors.forename: Alicja R
authors.initials: AR
authors.lastname: Rudnicka
authors.forename: Ming-Huei
authors.initials: MH
authors.lastname: Chen
authors.forename: Brendan M
authors.initials: BM
authors.lastname: Buckley
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Harris
authors.forename: Annette
authors.initials: A
authors.lastname: Peters
authors.forename: Drazen
authors.initials: D
authors.lastname: Pulanic
authors.forename: Thomas
authors.initials: T
authors.lastname: Lumley
authors.forename: Anton J M
authors.initials: AJ
authors.lastname: de Craen
authors.forename: David C
authors.initials: DC
authors.lastname: Liewald
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.forename: Susan
authors.initials: S
authors.lastname: Campbell
authors.forename: Ian
authors.initials: I
authors.lastname: Ford
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Gow
authors.forename: Michelle
authors.initials: M
authors.lastname: Luciano
authors.forename: David J
authors.initials: DJ
authors.lastname: Porteous
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Guo
authors.forename: Naveed
authors.initials: N
authors.lastname: Sattar
authors.forename: Albert
authors.initials: A
authors.lastname: Tenesa
authors.forename: Mary
authors.initials: M
authors.lastname: Cushman
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
authors.forename: Peter M
authors.initials: PM
authors.lastname: Visscher
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.forename: Igor
authors.initials: I
authors.lastname: Rudan
authors.forename: Edwin G
authors.initials: EG
authors.lastname: Bovill
authors.forename: Alan F
authors.initials: AF
authors.lastname: Wright
authors.forename: Wendy L
authors.initials: WL
authors.lastname: McArdle
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Tofler
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Rudi G J
authors.initials: RG
authors.lastname: Westendorp
authors.forename: John M
authors.initials: JM
authors.lastname: Starr
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Grant
authors.forename: Mahir
authors.initials: M
authors.lastname: Karakas
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Hastie
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
authors.forename: James F
authors.initials: JF
authors.lastname: Wilson
authors.forename: Gordon D O
authors.initials: GD
authors.lastname: Lowe
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
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authors.initials: JC
authors.lastname: Witteman
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Deary
authors.forename: Nicole
authors.initials: N
authors.lastname: Soranzo
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Koenig
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayward
mesh_terms: D000328:Adult; D000368:Aged; D001777:Blood Coagulation / Q000235:genetics*; D005165:Factor V / Q000235:genetics*; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000235:genetics* / Q000378:metabolism; D005340:Fibrinogen / Q000235:genetics; D005820:Genetic Testing; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D012016:Reference Values; D013925:Thromboplastin / Q000235:genetics*; D044465:White People / Q000235:genetics / Q000706:statistics & numerical data
chemical_list: D005338:Fibrin Fibrinogen Degradation Products; C036309:fibrin fragment D; D005165:Factor V; D005340:Fibrinogen; D013925:Thromboplastin