Identification of genetic polymorphisms associated with risk for pulmonary hypertension in sickle cell disease

Blood. 2008 Jun 15;111(12):5721-6. doi: 10.1182/blood-2007-02-074849. Epub 2008 Jan 10.


Up to 30% of adult patients with sickle cell disease (SCD) will develop pulmonary hypertension (pHTN), a complication associated with significant morbidity and mortality. To identify genetic factors that contribute to risk for pHTN in SCD, we performed association analysis with 297 single nucleotide polymorphisms (SNPs) in 49 candidate genes in patients with sickle cell anemia (Hb SS) who had been screened for pHTN by echocardiography (n = 111). Evidence of association was primarily identified for genes in the TGFbeta superfamily, including activin A receptor, type II-like 1 (ACVRL1), bone morphogenetic protein receptor 2 (BMPR2), and bone morphogenetic protein 6 (BMP6). The association of pHTN with ACVRL1 and BMPR2 corroborates the previous association of these genes with primary pHTN. Moreover, genes in the TGFbeta pathway have been independently implicated in risk for several sickle cell complications, suggesting that this gene pathway is important in overall sickle cell pathophysiology. Genetic variation in the beta-1 adrenergic receptor (ADRB1) was also associated with pHTN in our dataset. A multiple regression model, which included age and baseline hemoglobin as covariates, retained SNPs in ACVRL1, BMP6, and ADRB1 as independently contributing to pHTN risk. These findings may offer new promise for identifying patients at risk for pHTN, developing new therapeutic targets, and reducing the occurrence of this life-threatening SCD complication.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Activin Receptors, Type II / genetics
  • Adult
  • Anemia, Sickle Cell / epidemiology*
  • Anemia, Sickle Cell / genetics*
  • Bone Morphogenetic Protein 6
  • Bone Morphogenetic Protein Receptors, Type II / genetics
  • Bone Morphogenetic Proteins / genetics
  • Female
  • Genetic Predisposition to Disease / epidemiology
  • Genotype
  • Humans
  • Hypertension, Pulmonary / epidemiology*
  • Hypertension, Pulmonary / genetics*
  • Logistic Models
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Receptors, Adrenergic, beta-1 / genetics
  • Risk Factors


  • BMP6 protein, human
  • Bone Morphogenetic Protein 6
  • Bone Morphogenetic Proteins
  • Receptors, Adrenergic, beta-1
  • ACVRL1 protein, human
  • Activin Receptors, Type II
  • BMPR2 protein, human
  • Bone Morphogenetic Protein Receptors, Type II