Genome-wide association analysis identifies a susceptibility locus for pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a rare and devastating disease, resulting from progressive obliteration of small caliber pulmonary arteries by proliferating vascular cells, and leading to cardiac failure, with an untreated mean survival of less than three years 1,2. PAH can complicate other pathological conditions, or can occur in the context of genetic mutations causing heritable PAH, or can be considered as idiopathic (iPAH), which represents approximately 40% of all PAH 3,4. Low penetrance dominant BMPR2 mutations are found in ~70% of familial PAH (fPAH), and in ~15% of iPAH which are thereafter considered as heritable PAH 5,6. We conducted a Genome-Wide Association Study (GWAS) based on two independent case-control studies for iPAH and fPAH (without BMPR2 mutations) totaling 625 patients and 1,525 healthy individuals, to identify novel genetic factors associated with iPAH and fPAH (i/fPAH) in the absence of BMPR2 mutations. A genome wide significant association was detected at the CBLN2 locus mapping to 18q22.3, the risk allele being associated with an odds ratio for i/fPAH of 1.97 [1.59 – 2.45] (P = 7.47 x 10−10). CBLN2 is expressed in the lung, particularly in pulmonary vascular endothelial cells, and its expression is increased in explanted lungs from PAH patients and in endothelial cells cultured from explanted PAH lungs.

Critical Genomic Networks and Vasoreactive Variants in Idiopathic Pulmonary Arterial Hypertension

“…More recently this technique has been used to identify de novo GVs associated with pulmonary vascular disease (15,(17)(18)(19). In addition, analytic techniques applied to WES data can identify the presence of polygenic disease (20,21), which is particularly useful when conditions are not clinically known to be heritable.…”

Endothelin-1 Pathway Polymorphisms and Outcomes in Pulmonary Arterial Hypertension

“…Our results offer hope that this paradigm may soon change, with genotyping providing a tool for guiding front-line treatment decisions. Although another GWAS in PAH is currently available, its focus was on association not outcome (82). In light of this, further studies, both to prospectively validate our findings in patients treated with ERAs and to expand this approach to patients treated with other PAH therapy, are warranted to advance treatment toward a personalized medicine approach.…”

Genetic Insights into Pulmonary Arterial Hypertension. Application of Whole-Exome Sequencing to the Study of Pathogenic Mechanisms

“…Interestingly, the prior negative study by West and colleagues (14) also used an auto-CPAP intervention. A few studies suggest that auto-CPAP may not be as effective as fixed CPAP in improving cardiometabolic outcomes (17,18), perhaps as a result of greater sympathetic activation (19,20). Although the precise mechanisms for differential effects of auto versus fixed CPAP are not known, it is possible that sleep fragmentation and mild obstructive respiratory events may persist with auto-CPAP, particularly at lower pressure settings.…”

“…Recently, Germain and colleagues first conducted a two-stage genome-wide association study of patients with IPAH and heritable PAH without detectable BMPR2 mutations and identified the CBLN2 locus associated with IPAH and heritable PAH (17). As with many other complex diseases, there are likely rare (,5% of the population) variants that exist in the pathogenesis of PAH that are not captured by genome-wide association studies, but could have a larger effect size while not being causative.…”