title: Mutations and polymorphisms in hemoglobin genes and the risk of pulmonary hypertension and death in sickle cell disease.
abstract: Pulmonary hypertension is a common complication of sickle cell disease (SCD) and a risk factor for early death. Hemolysis may participate in its pathogenesis by limiting nitric oxide (NO) bioavailability and producing vasculopathy. We hypothesized that hemoglobin mutations that diminish hemolysis in SCD would influence pulmonary hypertension susceptibility. Surprisingly, coincident alpha-thalassemia (Odds Ratio [OR]=0.95, 95% CI=0.46-1.94, P=NS) was not associated with pulmonary hypertension susceptibility in homozygous SCD. However, pulmonary hypertension cases were less likely to have hemoglobin SC (OR=0.18, 95% confidence interval [CI]=0.06-0.51, P=0.0005) or Sbeta(+) thalassemia (OR=0.25, 95% CI=0.06-1.16, P=0.10). These compound heterozygotes may be protected from pulmonary hypertension because of reduced levels of intravascular hemolysis, but develop this complication at a lower rate possibly due to the presence of non-hemolytic risk factors such as renal dysfunction, iron overload and advancing age. Despite this protective association, patients with SC who did develop pulmonary hypertension remained at significant risk for death during 49 months of follow-up (Hazard Ratio=8.20, P=0.0057).
authors.affiliation: Vascular Medicine Branch, NHLBI, NIH, Bethesda, Maryland 20892-1476, USA. jamesta@mail.nih.gov
authors.forename: James G
authors.initials: JG
authors.lastname: Taylor
authors.forename: Diana
authors.initials: D
authors.lastname: Ackah
authors.forename: Crystal
authors.initials: C
authors.lastname: Cobb
authors.forename: Nick
authors.initials: N
authors.lastname: Orr
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Percy
authors.forename: Vandana
authors.initials: V
authors.lastname: Sachdev
authors.forename: Roberto
authors.initials: R
authors.lastname: Machado
authors.forename: Oswaldo
authors.initials: O
authors.lastname: Castro
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Kato
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gladwin
mesh_terms: D000328:Adult; D017677:Age Distribution; D000483:Alleles; D000755:Anemia, Sickle Cell / Q000150:complications / Q000235:genetics* / Q000401:mortality* / Q000503:physiopathology; D002851:Chromatography, High Pressure Liquid; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D015331:Cohort Studies; D005189:False Positive Reactions; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006239:Haplotypes; D006454:Hemoglobins / Q000235:genetics*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology; D008297:Male; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*; D012307:Risk Factors; D015996:Survival Rate; D017085:alpha-Thalassemia / Q000150:complications
chemical_list: D005819:Genetic Markers; D006454:Hemoglobins