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

IF 1.7 3区 医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Vasiliki Thomeas-McEwing, Mitchell A Psotka, Eric R Gamazon, Paula Friedman, Anuar Konkashbaev, Michiaki Kubo, Yusuke Nakamura, Mark J Ratain, Raymond L Benza, Nancy J Cox, Mardi I Gomberg-Maitland, Michael L Maitland
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引用次数: 2

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.

肺动脉高压患者中与曲前列地尼剂量相关的两个多态性基因位点。
目的:前列环素输注治疗肺动脉高压(PAH)是一种有效的治疗方法,具有不同的剂量要求和临床反应。本研究的主要目的是确定新的基于生物学的预测因素,预测前列环素治疗反应的异质性。方法:两个学术医学中心的98例血液动力学定义的多环芳烃患者自愿参加登记研究。稳定剂量的treprostiil是全基因组关联研究(GWAS)的定量表型。具有最大效应量和最强统计关联的候选基因通过计算机和体外分析进一步表征,以确认机制假设。这些候选预测因子的临床意义在一个独立的患者队列中被评估为机械一致的生理效应。结果:GWAS鉴定出3个与P相关的基因位点。结论:稳定剂量曲前列地尼的定量表型鉴定出两个与PAH的药效学反应和右心室功能相关的基因位点,值得进一步研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Pharmacogenetics and genomics
Pharmacogenetics and genomics 医学-生物工程与应用微生物
CiteScore
3.20
自引率
3.80%
发文量
47
审稿时长
3 months
期刊介绍: ​​​​Pharmacogenetics and Genomics is devoted to the rapid publication of research papers, brief review articles and short communications on genetic determinants in response to drugs and other chemicals in humans and animals. The Journal brings together papers from the entire spectrum of biomedical research and science, including biochemistry, bioinformatics, clinical pharmacology, clinical pharmacy, epidemiology, genetics, genomics, molecular biology, pharmacology, pharmaceutical sciences, and toxicology. Under a single cover, the Journal provides a forum for all aspects of the genetics and genomics of host response to exogenous chemicals: from the gene to the clinic.
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