title: Synergistic heterozygosity for TGFbeta1 SNPs and BMPR2 mutations modulates the age at diagnosis and penetrance of familial pulmonary arterial hypertension.
abstract: OBJECTIVE
  We hypothesized that functional TGFbeta1 SNPs increase TGFbeta/BMP signaling imbalance in BMPR2 mutation heterozygotes to accelerate the age at diagnosis, increase the penetrance and SMAD2 expression in familial pulmonary arterial hypertension.
  
  
  METHODS
  Single nucleotide polymorphism genotypes of BMPR2 mutation heterozygotes, age at diagnosis, and penetrance of familial pulmonary arterial hypertension were compared and SMAD2 expression was studied in lung sections.
  
  
  RESULTS
  BMPR2 mutation heterozygotes with least active -509 or codon 10 TGFbeta1 SNPs had later mean age at diagnosis of familial pulmonary arterial hypertension (39.5 and 43.2 years) than those with more active genotypes (31.6 and 33.1 years, P = 0.03 and 0.02, respectively). Kaplan-Meier analysis also showed that those with the less active single nucleotide polymorphisms had later age at diagnosis. BMPR2 mutation heterozygotes with nonsense-mediated decay resistant BMPR2 mutations and the least, intermediate and most active -509 TGFbeta1 SNP genotypes had penetrances of 33, 72, and 80%, respectively (P = 0.003), whereas those with 0-1, 2, or 3-4 active single nucleotide polymorphism alleles had penetrances of 33, 72, and 75% (P = 0.005). The relative expression of TGFbeta1 dependent SMAD2 was increased in lung sections of those with familial pulmonary arterial hypertension compared with controls.
  
  
  CONCLUSIONS
  The TGFbeta1 SNPs studied modulate age at diagnosis and penetrance of familial pulmonary arterial hypertension in BMPR2 mutation heterozygotes, likely by affecting TGFbeta/BMP signaling imbalance. This modulation is an example of Synergistic Heterozygosity.
authors.affiliation: Divisions of Medical Genetics, Vanderbilt University School of Medicine, Nashville, Tennessee 27232-2578, USA. john.a.phillips@vanderbilt.edu
authors.forename: John A
authors.initials: JA
authors.lastname: Phillips
authors.forename: Justin S
authors.initials: JS
authors.lastname: Poling
authors.forename: Charles A
authors.initials: CA
authors.lastname: Phillips
authors.forename: Krista C
authors.initials: KC
authors.lastname: Stanton
authors.forename: Eric D
authors.initials: ED
authors.lastname: Austin
authors.forename: Joy D
authors.initials: JD
authors.lastname: Cogan
authors.forename: Lisa
authors.initials: L
authors.lastname: Wheeler
authors.forename: Chang
authors.initials: C
authors.lastname: Yu
authors.forename: John H
authors.initials: JH
authors.lastname: Newman
authors.forename: Harry C
authors.initials: HC
authors.lastname: Dietz
authors.forename: James E
authors.initials: JE
authors.lastname: Loyd
mesh_terms: D000328:Adult; D000367:Age Factors; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006801:Humans; D006976:Hypertension, Pulmonary / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009154:Mutation; D010375:Pedigree; D019683:Penetrance; D020641:Polymorphism, Single Nucleotide; D051899:Smad2 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism
chemical_list: C497782:SMAD2 protein, human; D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II