Synergistic heterozygosity for TGFβ1 SNPs and BMPR2 mutations modulates the age at diagnosis and penetrance of familial pulmonary arterial hypertension

PurposeWe hypothesized that functional TGFβ1 SNPs increase TGFβ/BMP signaling imbalance in BMPR2 mutation heterozygotes to accelerate the age at diagnosis, increase the penetrance and SMAD2 expression in familial pulmonary arterial hypertension.MethodsSingle 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.ResultsBMPR2 mutation heterozygotes with least active -509 or codon 10 TGFβ1 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 TGFβ1 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 TGFβ1 dependent SMAD2 was increased in lung sections of those with familial pulmonary arterial hypertension compared with controls.ConclusionsThe TGFβ1 SNPs studied modulate age at diagnosis and penetrance of familial pulmonary arterial hypertension in BMPR2 mutation heterozygotes, likely by affecting TGFβ/BMP signaling imbalance. This modulation is an example of Synergistic Heterozygosity.