Two polymorphic gene loci associated with treprostinil dose in pulmonary arterial hypertension

Authors

Vasiliki Thomeas-McEwing, Department of Medicine, University of Chicago, Chicago, Illinois.
Mitchell A. Psotka, Inova Heart and Vascular Institute, Falls Church, Virginia.
Eric R. Gamazon, Department of Medicine, University of Chicago, Chicago, Illinois.
Paula Friedman, Department of Medicine, University of Chicago, Chicago, Illinois.
Anuar Konkashbaev, Department of Medicine, University of Chicago, Chicago, Illinois.
Michiaki Kubo, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
Yusuke Nakamura, Department of Medicine, University of Chicago, Chicago, Illinois.
Mark J. Ratain, Department of Medicine, University of Chicago, Chicago, Illinois.
Raymond L. Benza, Cardiovascular Institute, Allegheny General Hospital, Pittsburgh, Pennsylvania.
Nancy J. Cox, Department of Medicine, University of Chicago, Chicago, Illinois.
Mardi I. Gomberg-Maitland, Department of Medicine, University of Chicago, Chicago, Illinois.
Michael L. Maitland, Department of Medicine, University of Chicago, Chicago, Illinois.

Document Type

Journal Article

Publication Date

6-1-2022

Journal

Pharmacogenetics and genomics

Volume

32

Issue

4

DOI

10.1097/FPC.0000000000000463

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.

APA Citation

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.; and Maitland, Michael L., "Two polymorphic gene loci associated with treprostinil dose in pulmonary arterial hypertension" (2022). GW Authored Works. Paper 1227.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/1227

Department

Medicine