Genome-wide Association Analysis Identifies a Susceptibility Locus for Pulmonary Arterial Hypertension

Nat Genet. 2013 May;45(5):518-21. doi: 10.1038/ng.2581. Epub 2013 Mar 17.

Abstract

Pulmonary arterial hypertension (PAH) is a rare, severe disease resulting from progressive obliteration of small-caliber pulmonary arteries by proliferating vascular cells. PAH can occur without recognized etiology (idiopathic PAH), be associated with a systemic disease or occur as a heritable form, with BMPR2 mutated in approximately 80% of familial and 15% of idiopathic PAH cases. We conducted a genome-wide association study (GWAS) based on 2 independent case-control studies for idiopathic and familial PAH (without BMPR2 mutations), including a total of 625 cases and 1,525 healthy individuals. We detected a significant association at the CBLN2 locus mapping to 18q22.3, with the risk allele conferring an odds ratio for PAH of 1.97 (1.59-2.45; P = 7.47 × 10(-10)). CBLN2 is expressed in the lung, and its expression is higher in explanted lungs from individuals with PAH and in endothelial cells cultured from explanted PAH lungs.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Case-Control Studies
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / pathology
  • Familial Primary Pulmonary Hypertension
  • Genetic Predisposition to Disease*
  • Genome, Human*
  • Genome-Wide Association Study*
  • Genotype
  • Humans
  • Hypertension, Pulmonary / genetics*
  • Immunoenzyme Techniques
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics*
  • Pulmonary Artery / metabolism
  • Pulmonary Artery / pathology
  • Quantitative Trait Loci*
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • RNA, Messenger