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Functional Genetic Variations in BMPR2 and Other Signaling Pathways Modify Clinical Expression of Familial Pulmonary Arterial Hypertension

Eric Austin


John Phillips III

Joy Cogan

K. S. Stanton

C. A. Phillips

C. Yu

Lisa Wheeler

John Newman


James E. Loyd

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Conference: 2008 International PHA Conference and Scientific Sessions

Release Date: 06.20.2008

Presentation Type: Abstracts

Austin E.D., Phillips J.A. III, Cogan J.D., Stanton K.S., Phillips C.A., Yu C., Wheeler L.A., Newman J.H., Loyd J.E.

Vanderbilt University Medical Center, Nashville, TN, USA

BACKGROUND: Familial pulmonary arterial hypertension (FPAH) results from autosomal dominant inheritance of mutations in the bone morphogenetic protein receptor II (BMPR2) gene.  Variable expressivity suggests that genetic modifiers govern disease expression.  We hypothesized that nonsense-mediated decay (NMD) of BMPR2mRNAs and common functional genetic polymorphisms in signaling pathways related to the bone morphogenetic protein pathway modulate the age at diagnosis (AAD).

METHODS We studied 54 unrelated affected subjects, each with a BMPR2 mutation.  Mutations were analyzed for nonsense-mediated decay (NMD) activity, and DNAs were genotyped for functional polymorphisms in metabolic pathways suspected to interact with the BMPR2 pathway.  NMD active mutations were designated haploinsufficient (HI), and NMD absent mutations designated as potentially dominant negative (DN).

RESULTS: Affected subjects with a potentially DN mutation had a 12 year younger AAD, while those with 2 or more alleles of the Transforming Growth Factor β Pathway polymorphisms studied (TGFβ1 C-509T and TGFβ1 codon 10 (T29C)) had an 11 year younger AAD.  Those with potentially DN mutations plus ≥2 active TGFβ1 SNP alleles had a 15 year younger AAD.  In addition, subjects with a potentially DN BMPR2 mutation and the more active TGFβ1SNP alleles had a 4.8-fold higher risk of a younger AAD when controlling for polymorphisms associated with diminished nitric oxide production.

CONCLUSIONS: NMD status and genetic polymorphisms in signaling pathways related to BMPR2 modulate disease expression in BMPR2 mutation carriers.  Potentially DN mutations cause an earlier age at diagnosis than HI mutations, perhaps via a more deleterious effect on BMPR2 expression.  Polymorphisms that increase TGFβ pathway activity amplify this effect.