A genome-wide association study of venous thromboembolism identifies risk variants in chromosomes 1q24.2 and 9q

Details

• Alternative Title:
  J Thromb Haemost
• Personal Author:
  Heit, John A. ; Armasu, Sebastian M. ; Asmann, Yan W. ; Cunningham, Julie M. ; Matsumoto, Martha E. ; Petterson, Tanya M. ; de Andrade, Mariza
• Description:
  Objectives
  
  To identify venous thromboembolism (VTE) disease-susceptibility genes.
  
  Patients/Methods
  
  We performed in silico genome wide association (GWAS) analyses using genotype data imputed to ~2.5 million single nucleotide polymorphisms (SNPs) from adults with objectively-diagnosed VTE (n=1503), and controls frequency-matched on age and sex (n=1459; discovery population). SNPs exceeding genome-wide significance were replicated in a separate population (VTE cases, n=1407; controls, n=1418). Genes associated with VTE were resequenced.
  
  Results
  
  Seven SNPs exceeded genome-wide significance (P < 5 × 10-8); four on chromosome 1q24.2 (F5 rs6025 [Factor V Leiden], BLZF1 rs7538157, NME7 rs16861990 and SLC19A2 rs2038024) and three on chromosome 9q34.2 (ABO rs2519093 [ABO intron 1], rs495828, rs8176719 [ABO blood type O allele]). The replication study confirmed a significant association of F5, NME7, and ABO with VTE. However, F5 was the main signal on 1q24.2 as only ABO SNPs remained significantly associated with VTE after adjusting for F5 rs6025. This 1q24.2 region was shown to be inherited as a haplotype block. ABO resequencing identified 15 novel single nucleotide variations (SNV) in ABO intron 6 and the ABO 3’ UTR that were strongly associated with VTE (P < 10-4) and belonged to three distinct linkage disequilibrium (LD) blocks; none were in LD with ABO rs8176719 or rs2519093. Our sample size provided 80% power to detect odds ratios=2.0 and 1.51 for minor allele frequencies=0.05 and 0.5, respectively (α=1 × 10-8; 1% VTE prevalence).
  
  Conclusions
  
  Aside from F5 rs6025, ABO rs8176719 and rs2519093, and F2 rs1799963, additional common and high VTE-risk SNPs among whites are unlikely.
  
  
• Subjects:
  ABO Blood-Group System Case-Control Studies Chromosomes, Human, Pair 1 Chromosomes, Human, Pair 9 Computer Simulation Factor V Gene Frequency Genetic Predisposition To Disease Genome-Wide Association Study Haplotypes Humans Linkage Disequilibrium Logistic Models Minnesota Models, Genetic Odds Ratio Polymorphism, Single Nucleotide Prevalence Prothrombin Risk Assessment Risk Factors Venous Thromboembolism White People

  More +
• Keywords:
  Deep Vein Thrombosis Epidemiology Genetics Genome-wide Scan Pulmonary Embolism Venous Thromboembolism
• Source:
  J Thromb Haemost. 2012; 10(8):1521-1531
• Pubmed ID:
  22672568
• Pubmed Central ID:
  PMC3419811
• Document Type:
  Journal Article
• Funding:
  U01 DD000235/DD/NCBDD CDC HHSUnited States/ ; R01 HL083141/HL/NHLBI NIH HHSUnited States/ ; AG0346760/AG/NIA NIH HHSUnited States/ ; R01 HL066216/HL/NHLBI NIH HHSUnited States/ ; DD000235/DD/NCBDD CDC HHSUnited States/ ; CA92153/CA/NCI NIH HHSUnited States/ ; R01 CA092153/CA/NCI NIH HHSUnited States/ ; HL66216/HL/NHLBI NIH HHSUnited States/ ; HL83141/HL/NHLBI NIH HHSUnited States/ ; HG04735/HG/NHGRI NIH HHSUnited States/ ; U01 HG004735/HG/NHGRI NIH HHSUnited States/
• Volume:
  10
• Issue:
  8
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:2268338b8a2b89009dcdaf40c183e1aa0cc7cddfe7aae917014277893026cf43
• Download URL:
  https://stacks.cdc.gov/view/cdc/33416/cdc_33416_DS1.pdf
• File Type:
  [PDF - 1.03 MB ]