Novel loci interacting epistatically with bone morphogenetic protein receptor 2 cause familial pulmonary arterial hypertension.

Background: Familial pulmonary arterial hypertension (FPAH) is a rare, autosomal-dominant, inherited disease with low penetrance. Mutations in the bone morphogenetic protein receptor 2 (BMPR2) have been identified in at least 70% of FPAH patients. However, the lifetime penetrance of these BMPR2 mutations is 10% to 20%, suggesting that genetic and/or environmental modifiers are required for disease expression. Our goal in this study was to identify genetic loci that may influence FPAH expression in BMPR2 mutation carriers.

Methods: We performed a genome-wide linkage scan in 15 FPAH families segregating for BMPR2 mutations. We used a dense single-nucleotide polymorphism (SNP) array and a novel multi-scan linkage procedure that provides increased power and precision for the localization of linked loci.

Results: We observed linkage evidence in four regions: 3q22 ([median log of the odds (LOD) = 3.43]), 3p12 (median LOD) = 2.35), 2p22 (median LOD = 2.21), and 13q21 (median LOD = 2.09). When used in conjunction with the non-parametric bootstrap, our approach yields high-resolution to identify candidate gene regions containing putative BMPR2-interacting genes. Imputation of the disease model by LOD-score maximization indicates that the 3q22 locus alone predicts most FPAH cases in BMPR2 mutation carriers, providing strong evidence that BMPR2 and the 3q22 locus interact epistatically.

Conclusions: Our findings suggest that genotypes at loci in the newly identified regions, especially at 3q22, could improve FPAH risk prediction in FPAH families. We also suggest other targets for therapeutic intervention.