Chronic thromboembolic pulmonary hypertension (CTEPH) is an important and severe consequence of pulmonary embolism (PE), resulting from failure of thrombus resolution. Identifying genetic risk factors for CTEPH would provide important insights into pathobiology and might allow risk-stratification following PE. A genome-wide association study (GWAS) was performed in 1250 CTEPH patients, 1492 healthy controls and ~7 million single-nucleotide polymorphisms to identify novel disease loci.

The ABO locus was identified as the most significant common variant genetic association with CTEPH in both a discovery and validation cohort. The A1 subgroup of ABO was enriched in CTEPH and this may result in multiple functional consequences including variation in plasma von Willebrand factor (VWF) levels.

Abnormalities in haemostasis are implicated in CTEPH pathobiology, including elevated levels of VWF, which is cleaved by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). The ADAMTS13-VWF axis was investigated in 208 CTEPH patients including its relationship to ABO blood groups and ADAMTS13 genetic variants.

Plasma ADAMTS13 levels are markedly reduced in CTEPH. This is independent of pulmonary hypertension, disease severity or systemic inflammation. Plasma VWF levels were confirmed to be markedly increased in CTEPH. These findings implicate dysregulation of the ADAMTS13-VWF axis in CTEPH pathobiology.