NHLBI GO-ESP Family Studies: Pulmonary Arterial Hypertension

The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO. Pulmonary arterial hypertension (PAH) is a progressive disease characterized by widespread occlusion of the smallest arteries of the lungs. Pulmonary vascular obstruction leads to increased pulmonary vascular resistance, which subsequently causes heart failure with mean survival of 3 years. PAH occurs at all ages and affects women more than twice as frequently as men. Sporadic Idiopathic pulmonary arterial hypertension (IPAH), comprises 94% of what was formerly known as primary pulmonary hypertension, and is clinically and pathologically indistinguishable from familial PAH (FPAH). Most FPAH is due to mutation in BMPR2, including more than 120 families in the US. Our goal here is to find other genes that are a basis for FPAH, so we selected for exome sequencing 5 families among 40 who do not have mutation in BMPR2, or other known genes (ACVRL1, SMAD8, ENG) that rarely are the basis for FPAH.]]>
Inclusion: Bloodline member in a family with Pulmonary Arterial Hypertension (2 or more cases) Cardiac catheterization shows pulmonary hypertension (mean PA pressure >25mmHg at rest) No evidence of significant heart disease, including left ventricular or valvular heart disease No evidence of significant lung disease, including interstitial or obstructive lung disease No evidence of pulmonary embolism or obstruction of large pulmonary vessels No evidence of other diseases known to be associated with pulmonary hypertension, including connective tissue diseases, cirrhosis, HIV, antiphospholipid antibody syndrome, appetite suppressant use Exclusion: Failure to meet all inclusion criteria ]]>
We have studied FPAH continuously since 1980 when we analyzed prior published reports and described a new FPAH family in Tennessee, who has to date 30 women and 8 men with FPAH. We collected families for 15 years, and used this resource to link chromosome 2q31 PPH in 1997, and also to identify heterozygous mutation in BMPR2 as responsible in 2000. BMPR2 mutation is responsible for 75% of FPAH and our collaboration follows over 120 families in the U.S. with different BMPR2 mutations. The pathogenetic mechanisms by which BMPR2 mutations cause PAH disease are not yet fully understood, and variable age of onset and decreased penetrance are prominent features of BMPR2 related FPAH which confound genetic counseling. We have excluded BMPR2 as the basis in another 40 families with FPAH, and we seek here to identify the genes responsible by exome sequencing in patients from 5 families of this subgroup.]]>