title: Predicting venous thrombosis in women using a combination of genetic markers and clinical risk factors.
abstract: BACKGROUND
  Family history of venous thromboembolism (VTE) has been suggested to be more useful in risk assessment than thrombophilia testing.
  
  
  OBJECTIVE
  We investigated established genetic susceptibility variants for association with VTE and evaluated a genetic risk score in isolation and combined with known trigger factors, including family history of VTE.
  
  
  METHODS
  A total of 18 single nucleotide polymorphisms (SNPs) selected from the literature were genotyped in 2835 women participating in a Swedish nationwide case-control study (the ThromboEmbolism Hormone Study [TEHS]). Association with VTE was assessed by odds ratios (ORs) with 95% confidence interval (CI) using logistic regression. Clinical and genetic predictors that contributed significantly to the fit of the logistic regression model were included in the prediction models. SNP-SNP interactions were investigated and incorporated into the models if found significant. Risk scores were evaluated by calculating the area under the receiver-operating characteristics curve (AUC).
  
  
  RESULTS
  Seven SNPs (F5 rs6025, F2 rs1799963, ABO rs514659, FGG rs2066865, F11 rs2289252, PROC rs1799810 and KNG1 rs710446) with four SNP-SNP interactions contributed to the genetic risk score for VTE, with an AUC of 0.66 (95% CI, 0.64-0.68). After adding clinical risk factors, which included family history of VTE, the AUC reached 0.84 (95% CI, 0.82-0.85). The goodness of fit of the genetic and combined scores improved when significant SNP-SNP interaction terms were included.
  
  
  CONCLUSIONS
  Prediction of VTE in high-risk individuals was more accurate when a combination of clinical and genetic predictors with SNP-SNP interactions was included in a risk score.
authors.affiliation: Coagulation Unit, Hematology Centre, Karolinska University Hospital Solna, Stockholm, Sweden; Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet (KI), Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Bruzelius
authors.forename: M
authors.initials: M
authors.lastname: Bottai
authors.forename: M
authors.initials: M
authors.lastname: Sabater-Lleal
authors.forename: R J
authors.initials: RJ
authors.lastname: Strawbridge
authors.forename: A
authors.initials: A
authors.lastname: Bergendal
authors.forename: A
authors.initials: A
authors.lastname: Silveira
authors.forename: A
authors.initials: A
authors.lastname: Sundström
authors.forename: H
authors.initials: H
authors.lastname: Kieler
authors.forename: A
authors.initials: A
authors.lastname: Hamsten
authors.forename: J
authors.initials: J
authors.lastname: Odeberg
mesh_terms: D000328:Adult; D019540:Area Under Curve; D016022:Case-Control Studies; D005260:Female; D056726:Genetic Association Studies; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006801:Humans; D016015:Logistic Models; D008875:Middle Aged; D016017:Odds Ratio; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D012372:ROC Curve; D018570:Risk Assessment; D012307:Risk Factors; D012737:Sex Factors; D013548:Sweden / Q000453:epidemiology; D020246:Venous Thrombosis / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*
chemical_list: D005819:Genetic Markers
keywords: ROC curve; epidemiology; polymorphism, single nucleotide; venous thrombosis; women