A novel molecular signature for elevated tricuspid regurgitation velocity in sickle cell disease

Ankit A. Desai, Tong Zhou, Homaa Ahmad, Wei Zhang, Wenbo Mu, Sharon Trevino, Michael S. Wade, Nalini Raghavachari, Gregory J. Kato, Marlene H. Peters-Lawrence, Tejas Thiruvoipati, Kristin Turner, Nicole Artz, Yong Huang, Amit R. Patel, Jason X.J. Yuan, Victor R. Gordeuk, Roberto M. Lang, Joe G.N. Garcia, Roberto F. Machado

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Rationale: An increased tricuspid regurgitation jet velocity (TRV > 2.5 m/s) and pulmonary hypertension defined by right heart catheterization both independently confer increased mortality in sickle cell disease (SCD). Objectives: We explored the usefulness of peripheral blood mononuclear cell-derived gene signatures as biomarkers for an elevated TRV in SCD. Methods: Twenty-seven patientswith SCD underwent echocardiography and peripheral blood mononuclear cell isolation for expression profiling and 112 patients with SCD were genotyped for single-nucleotide polymorphisms. Measurements and Main Results: Genome-wide gene and miRNA expression profiles were correlated against TRV, yielding 631 transcripts and 12 miRNAs. Support vector machine analysis identified a 10-gene signature including GALNT13 (encoding polypeptide N-acetylgalactosaminyltransferase 13) that discriminates patients with and without increased TRV with 100% accuracy. This finding was then validated in a cohort of patients with SCD without (n = 10) and with pulmonary hypertension (n = 10,90%accuracy). Increased TRV-related miRNAs revealed strong in silico binding predictions of miR-301a to GALNT13 corroborated by microarray analyses demonstrating an inverse correlation between their expression. A genetic association study comparing patients with an elevated (n = 49) versus normal (n = 63) TRV revealed five significant single-nucleotide polymorphisms within GALNT13 (P < 0.005), four trans-acting (P < 2.1 × 10-7) and one cis-acting (P = 0.6 × 10-4) expression quantitative trait locus upstream of the adenosine-A2B receptor gene (ADORA2B). Conclusions: These studies validate the clinical usefulness of genomic signatures as potential biomarkers and highlight ADORA2B and GALNT13 as potential candidate genes in SCD-associated elevated TRV.

Original languageEnglish (US)
Pages (from-to)359-368
Number of pages10
JournalAmerican journal of respiratory and critical care medicine
Volume186
Issue number4
DOIs
StatePublished - Aug 15 2012
Externally publishedYes

Keywords

  • Candidate gene approach
  • Microarray
  • Pulmonary hypertension
  • eQTL

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Fingerprint Dive into the research topics of 'A novel molecular signature for elevated tricuspid regurgitation velocity in sickle cell disease'. Together they form a unique fingerprint.

  • Cite this

    Desai, A. A., Zhou, T., Ahmad, H., Zhang, W., Mu, W., Trevino, S., Wade, M. S., Raghavachari, N., Kato, G. J., Peters-Lawrence, M. H., Thiruvoipati, T., Turner, K., Artz, N., Huang, Y., Patel, A. R., Yuan, J. X. J., Gordeuk, V. R., Lang, R. M., Garcia, J. G. N., & Machado, R. F. (2012). A novel molecular signature for elevated tricuspid regurgitation velocity in sickle cell disease. American journal of respiratory and critical care medicine, 186(4), 359-368. https://doi.org/10.1164/rccm.201201-0057OC