title: Prothrombotic genetic risk factors are associated with an increased risk of liver fibrosis in the general population: The Rotterdam Study.
abstract: OBJECTIVE
  The coagulation system is known to be involved in fibrogenesis in patients with liver disease. We investigated whether common genetic prothrombotic risk factors are associated with an increased risk of fibrosis in the general population.
  
  
  METHODS
  This investigation was part of the Rotterdam Study, an ongoing, population-based cohort study. Liver stiffness (LS) was measured using transient elastography (Fibroscan) and associated with single nucleotide polymorphisms determining blood group type and presence of the Factor V Leiden (FVL) mutation or prothrombin G20210A gene variant.
  
  
  RESULTS
  Reliable LS measurements and genetic data were obtained from 1055 Caucasian participants. LS ⩾8.0 kPa, suggestive of clinically relevant fibrosis, was observed in 101 subjects (9.6%). Presence of FVL or prothrombin G20210A was independently associated with an increased risk of LS ⩾8.0 kPa (OR 2.09, 95%CI 1.07-4.07, p=0.03). Combination of blood group type non-O and the FVL mutation or prothrombin G20210A variant resulted in an even higher risk of LS ⩾8.0 kPa (OR 3.36, 95%CI 1.50-7.56, p=0.003). Presence of the FVL mutation or prothrombin G20210A variant in participants with blood group non-O was associated with a predicted probability of 14.3% (7.7-23.8) of LS ⩾8.0 kPa.
  
  
  CONCLUSIONS
  Participants carrying the FVL mutation or prothrombin G20210A variant have an increased risk of clinically relevant liver fibrosis, which is even higher in blood group type non-O carriers. The fact that genetic prothrombotic risk factors are associated with an increased risk of liver fibrosis suggests that coagulation plays an important role in fibrogenesis in the general population.
authors.affiliation: Dept. of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
authors.forename: Elisabeth P C
authors.initials: EP
authors.lastname: Plompen
authors.affiliation: Dept. of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
authors.forename: Sarwa
authors.initials: S
authors.lastname: Darwish Murad
authors.affiliation: Dept. of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands; Dept. of Public Health, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
authors.forename: Bettina E
authors.initials: BE
authors.lastname: Hansen
authors.affiliation: Dept. of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
authors.forename: Daan W
authors.initials: DW
authors.lastname: Loth
authors.affiliation: Dept. of Gastroenterology and Hepatology, University Hospital Ghent, Ghent, Belgium.
authors.forename: Jeoffrey N L
authors.initials: JN
authors.lastname: Schouten
authors.affiliation: Dept. of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
authors.forename: Pavel
authors.initials: P
authors.lastname: Taimr
authors.affiliation: Dept. of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Dept. of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands; Dept. of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Dept. of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands; Dept. of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
authors.forename: Bruno H
authors.initials: BH
authors.lastname: Stricker
authors.affiliation: Dept. of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands; Toronto Centre for Liver Disease, Toronto Western and General Hospital, University Health Network, Toronto, Ontario, Canada.
authors.forename: Harry L A
authors.initials: HL
authors.lastname: Janssen
authors.affiliation: Dept. of Hematology, Erasmus MC University Medical Center, Rotterdam, The Netherlands. Electronic address: f.leebeek@erasmusmc.nl.
authors.forename: Frank W G
authors.initials: FW
authors.lastname: Leebeek
mesh_terms: D020016:Activated Protein C Resistance / Q000150:complications / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D001789:Blood Group Antigens / Q000235:genetics; D015331:Cohort Studies; D054459:Elasticity Imaging Techniques; D005165:Factor V / Q000235:genetics; D005260:Female; D006801:Humans; D008103:Liver Cirrhosis / Q000097:blood / Q000209:etiology* / Q000235:genetics*; D008297:Male; D009426:Netherlands; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D011516:Prothrombin / Q000235:genetics; D012307:Risk Factors; D019851:Thrombophilia / Q000150:complications / Q000235:genetics; D013927:Thrombosis / Q000097:blood / Q000150:complications* / Q000235:genetics*
chemical_list: D001789:Blood Group Antigens; C095381:factor V Leiden; D005165:Factor V; D011516:Prothrombin
keywords: General population; Genetics; Liver fibrosis; Prothrombotic risk factors; Thrombophilia