hronic thromboembolic pulmonary hypertension (CTEPH) due to unresolved pulmonary embolism is a potentially correctable pulmonary hypertension (PH) by pulmonary thromboendarterectomy. [1][2][3] The incidence of this disease has been estimated as 0.1-0.5% in patients surviving acute pulmonary embolism. 1,2 However, it was recently reported that the incidence of this disease is in fact relatively high (3.8% at 2 years after acute pulmonary embolism). 4 In addition, a recent study based on mailed questionnaires in Japan revealed 169 new cases of acute pulmonary embolism and 17 new cases of CTEPH within 2 months, suggesting that the ratio of CTEPH to acute pulmonary thromboembolism (10.1%) might be high in Japan. 5 Without surgery the prognosis of CTEPH is thought to be poor, and the survival rate at 5 years is 30% in patients with mean pulmonary arterial pressure (Ppa) higher than 40 mmHg. 6 The precise mechanism of the progression of PH remains undefined. Although the extent of vascular obstruction is a major determinant, hemodynamic progression may involve recurrent thromboembolism or in situ thrombosis as well as pulmonary vascular remodeling. 2 The renin-angiotensin system plays a fundamental role in the onset and/or progression of a variety of cardiovascular diseases, 7-12 including venous thromboembolism. 13,14 Angiotensin-converting enzyme (ACE) plays an important role in systemic vascular remodeling and also endothelial dysfunction. 12,15,16 As well as its involvement in the development of cardiovascular diseases, the ACE gene has also been considered a candidate for contributing to the development of exercise-induced PH in chronic obstructive pulmonary disease (COPD) patients in Japan. 17 The ACE gene contains a polymorphism based on the presence (insertion, I) or absence (deletion, D) within intron 16 of a 287-basepair nonsense DNA domain, resulting in 3 genotypes (II, DI, DD). 18 The D allele is associated with increased circulating and cellular concentrations of ACE, which could be related to increased cardiovascular risk including venous thromboembolism. 7,12,13,19 In addition, increased expression of ACE has been reported in primary and secondary plexiform PH, 20 and ACE inhibition therapy delays pulmonary vascular neointimal formation. 21 The ACE genotype may contribute to vascular remodeling in distal pulmonary arteries even in CTEPH.We hypothesized that ACE-I/D polymorphism might be related to CTEPH susceptibility, severity of the disease, and its outcome. Methods SubjectsThe patient group comprised 95 consecutive patients with

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)¼5.07, 95% confidence interval (CI)¼2.52-10.19, P¼0.00000075, corrected P-value (Pc)¼0.00014), IKBL-p*03 (OR¼2.33, 95% CI¼1.49-3.66, P¼0.00017, Pc¼0.033) and B*5201 (OR¼2.47, 95% CI¼1.56-3.90, P¼0.000086, Pc¼0.016), 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.