Distinct Platelet Ribonucleic Acid Signatures in Patients with Pulmonary Hypertension

A Josien Smits, Mohammad Arkani, Sjors G J G In 't Veld, Anna E Huis In 't Veld, Nik Sol, Joanne A Groeneveldt, Liza Botros, Natalia J Braams, Samara Ma Jansen, Jip Ramaker, Kenn Zwaan, Edward Post, Esther J Nossent, Anco Boonstra, Frances S de Man, Anton Vonk Noordegraaf, Jose Gomez-Arroyo, Myron G Best, Tom Wurdinger, Harm Jan Bogaard

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)

Abstract

Rationale: Pulmonary hypertension encompasses progressive disorders leading to right ventricular dysfunction and early death. Late detection is an important cause of poor clinical outcomes. However, biomarkers that accurately predict the presence of pulmonary hypertension are currently lacking. Objectives: In this study, we provide evidence that blood platelets contain a distinctive ribonucleic acid (RNA) profile that may be exploited for the detection of pulmonary hypertension. Methods: Blood platelet RNA was isolated prospectively from 177 prevalent patients with different subtypes of pulmonary hypertension as well as 195 control subjects clinically not suspected of pulmonary hypertension. Sequencing libraries were created using SMARTer (Switching Mechanism at 5' end of RNA Template) copy desoxyribonucleic acid amplification and sequenced on the Illumina High Throughput Sequencing platform. RNA-sequencing reads were mapped to the human reference genome, and intron-spanning spliced RNA reads were selected. Differential spliced RNA panels were calculated by analysis of variance statistics. A particle swarm optimization-enhanced classification algorithm was built employing a development (n = 213 samples) and independent validation series (n = 159 samples). Results: We detected a total of 4,014 different RNAs in blood platelets from patients with pulmonary hypertension (n = 177) and asymptomatic control subjects (n = 195). Gene ontology analysis revealed enhanced RNA concentrations for genes related to RNA processing, translation, and mitochondrial function. A particle swarm optimization-selected RNA panel of 408 distinctive differentially spliced RNAs mediated detection of pulmonary hypertension with 93% sensitivity, 62% specificity, 77% accuracy, 0.89 (95% confidence interval, 0.83-0.93) area under the curve, and a negative predictive value of 91% in the independent validation series. The prediction score was independent of age, sex, smoking, pulmonary hypertension subtype, and the use of pulmonary hypertension-specific medication or anticoagulants. Conclusions: A platelet RNA panel may accurately discriminate patients with pulmonary hypertension from asymptomatic control subjects. In the light of current diagnostic delays, this study is the starting point for further development and evaluation of a platelet RNA-based blood test to ultimately improve early diagnosis and clinical outcomes in patients with pulmonary hypertension.

Original languageEnglish
Pages (from-to)1650-1660
Number of pages11
JournalAnnals of the American Thoracic Society
Volume19
Issue number10
Early online date10 May 2022
DOIs
Publication statusPublished - 1 Oct 2022

Keywords

  • biomarkers
  • blood platelets
  • hypertension
  • pulmonary

Cite this