HLA-DPB1 and NFKBIL1 may confer the susceptibility to chronic thromboembolic pulmonary hypertension in the absence of deep vein thrombosis

J Hum Genet. 2009 Feb;54(2):108-14. doi: 10.1038/jhg.2008.15. Epub 2009 Jan 23.


Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by pulmonary hypertension caused by thromboembolism of the pulmonary artery. Etiology of CTEPH may be heterogeneous and is largely unknown, but genetic factors are considered to be involved in the etiology. It has been reported that deep vein thrombosis (DVT) and/or coagulation factor variants are predisposing factors to CTEPH. However, more than half of the CTEPH patients, especially the Japanese, do not have prior DVT or coagulation abnormality, suggesting that there should be other risk factors for CTEPH. Moreover, there are several reports on the association between CTEPH and human leukocyte antigen (HLA). To further clarify the HLA-linked gene(s) controlling the susceptibility to CTEPH, 160 patients (99 without DVT and 61 with DVT) and 380 healthy controls were analyzed for polymorphisms in 15 microsatellite markers and 5 genes in the HLA region. We found a strong association of HLA markers with the DVT-negative CTEPH, DPB1(*)0202 (odds ratio (OR)=5.07, 95% confidence interval (CI)=2.52-10.19, P=0.00000075, corrected P-value (Pc)=0.00014), IKBL-p(*)03 (OR=2.33, 95% CI=1.49-3.66, P=0.00017, Pc=0.033) and B(*)5201 (OR=2.47, 95% CI=1.56-3.90, P=0.000086, Pc=0.016), whereas no significant association was observed for the DVT-positive CTEPH. The comparison of clinical characteristics of patients stratified by the presence of susceptibility genes implied that the DPB1 gene controlled the severity of the vascular lesion, whereas the IKBL gene (NFKBIL1) was associated with a relatively mild phenotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adult
  • Alleles
  • Demography
  • Female
  • Genetic Predisposition to Disease*
  • HLA-DP Antigens / genetics*
  • HLA-DP beta-Chains
  • Histocompatibility Antigens Class II / genetics*
  • Humans
  • Hypertension, Pulmonary / complications*
  • Hypertension, Pulmonary / genetics*
  • Linkage Disequilibrium / genetics
  • Male
  • Microsatellite Repeats / genetics
  • Middle Aged
  • Thromboembolism / complications*
  • Thromboembolism / genetics
  • Venous Thrombosis / complications
  • Venous Thrombosis / genetics*


  • Adaptor Proteins, Signal Transducing
  • HLA-DP Antigens
  • HLA-DP beta-Chains
  • HLA-DPB1 antigen
  • Histocompatibility Antigens Class II
  • NFKBIL1 protein, human