Pharmacogenomics in the Management of Pulmonary Arterial Hypertension: Current Perspectives

Pulmonary arterial hypertension (PAH) is a rare disease with heterogeneous causes that can lead to right ventricular (RV) failure and death if left untreated. There are currently 10 medications representative of five unique pharmacologic classes that are approved for treatment. These have led to significant improvements in overall clinical outcome. However, substantial variability in dosing requirements and treatment response is evident, leading to suboptimal outcome for many patients. Furthermore, dosing is empiric and iterative and can lead to delays in meeting treatment goals and burdensome adverse effects. Pharmacogenomic (PGx) associations have been reported with certain PAH medications, such as treprostinil and bosentan, and can explain some of the variability in response. Relevant genes associated with treprostinil include , and and are the genes encoding the major metabolizing liver enzymes for treprostinil, and reduced function variants (*2, *3) with were associated with lower treatment persistence. Additionally, a higher activity score was associated with a significantly less risk of treatment discontinuation. Other genes of interest that have been explored with treprostinil include , which is associated with right ventricular dysfunction and significantly higher dose requirements. Similarly, is associated with lower concentrations of cyclic adenosine monophosphate and significantly higher dose requirements. Genes of interest with the endothelin receptor antagonist (ERA) class include and . A genetic variant in (rs11157866) was linked to a significantly increased rate of clinical improvement with ERAs. The *2 variant with (encoding for the major metabolizing enzyme for bosentan) was significantly associated with a higher risk for elevations in hepatic aminotransferases and liver injury. In summary, this article reviews the relevant pharmacogenes that have been associated to date with dosing and outcome among patients who received PAH medications.