Two polymorphic gene loci associated with treprostinil dose in pulmonary arterial hypertension. Issue 4 (7th April 2022)

• Record Type: Journal Article
• Authors: Thomeas-McEwing, Vasiliki; Psotka, Mitchell A.; Gamazon, Eric R.; Friedman, Paula; Konkashbaev, Anuar; Kubo, Michiaki; Nakamura, Yusuke; Ratain, Mark J.; Benza, Raymond L.; Cox, Nancy J.; Gomberg-Maitland, Mardi I.; Maitland, Michael L.
• Is Part Of: Pharmaocogenetics and genomics. Volume 32:Issue 4(2022)
• Page Start: 144
• Page End: 151
• Publication Date: 2022-04-07
• Subjects: calcium-calmodulin-dependent protein kinase type 2 -- genome-wide association study -- pharmacogenetics -- phosphoribosylformylglycinamide synthetase -- prostaglandins -- pulmonary arterial hypertension; Pharmacogenetics -- Periodicals; Pharmacogenomics -- Periodicals; Genetic toxicology -- Periodicals; Biomedical genetics -- Periodicals; 615.7
• DOI: 10.1097/FPC.0000000000000463
• Languages: English
• ISSNs: 1744-6872

Abstract

Abstract : Objective: Prostacyclin infusion for pulmonary arterial hypertension (PAH) is an effective therapy with varied dosing requirements and clinical response. The major aim of this study was to determine new biologically-based predictors of prostacyclin treatment response heterogeneity. Methods: Ninety-eight patients with hemodynamically defined PAH at two academic medical centers volunteered for registry studies. A stable dose of treprostinil was the quantitative phenotype for the genome-wide association study (GWAS). Candidate genes with the largest effect sizes and strongest statistical associations were further characterized with in silico and in-vitro assays to confirm mechanistic hypotheses. The clinical significance of these candidate predictors was assessed for mechanistically consistent physiologic effects in an independent cohort of patients. Results: GWAS identified three loci for association with P < 10 -6 . All three loci had clinically significant effect sizes. Specific single-nucleotide polymorphisms (SNPs) at two of the loci: rs11078738 in phosphoribosylformylglycinamidine synthase and rs10023113 in CAMK2D encoded sequence changes with clear predicted consequences. Production of the primary mediator of prostacyclin-induced vasodilation, cyclic AMP, was reduced in human cell lines by the missense variant rs11078738 (p.L621P). Located in the promoter of CAMK2D, the allele of rs10023113 associated with a higher treprostinil dose has higher ventricular transcription of CAMK2δ. At initial diagnostic catheterization in a separate cohort of patients, the same allele of rs10023113 was associated with elevated right mean atrial and ventricular diastolic pressures. Conclusions: The quantitative phenotype of stable treprostinil dose identified two gene loci associated with pharmacodynamic response and right ventricular function in PAH worth further investigation.