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 Machado

Research output: Contribution to journalArticle

24 Citations (Scopus)

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

Fingerprint

Tricuspid Valve Insufficiency
Sickle Cell Anemia
MicroRNAs
Pulmonary Hypertension
Genes
Single Nucleotide Polymorphism
Blood Cells
Adenosine A2B Receptors
Biomarkers
Cell Separation
Quantitative Trait Loci
Genetic Association Studies
Microarray Analysis
Cardiac Catheterization
Transcriptome
Computer Simulation
Echocardiography
Genome
Mortality

Keywords

  • Candidate gene approach
  • eQTL
  • Microarray
  • Pulmonary hypertension

ASJC Scopus subject areas

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

Cite this

A novel molecular signature for elevated tricuspid regurgitation velocity in sickle cell disease. / Desai, Ankit A.; Zhou, Tong; Ahmad, Homaa; Zhang, Wei; Mu, Wenbo; Trevino, Sharon; Wade, Michael S.; Raghavachari, Nalini; Kato, Gregory J.; Peters-Lawrence, Marlene H.; Thiruvoipati, Tejas; Turner, Kristin; Artz, Nicole; Huang, Yong; Patel, Amit R.; Yuan, Jason X.J.; Gordeuk, Victor R.; Lang, Roberto M.; Garcia, Joe G.N.; Machado, Roberto.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 186, No. 4, 15.08.2012, p. 359-368.

Research output: Contribution to journalArticle

Desai, AA, Zhou, T, Ahmad, H, Zhang, W, Mu, W, Trevino, S, Wade, MS, Raghavachari, N, Kato, GJ, Peters-Lawrence, MH, Thiruvoipati, T, Turner, K, Artz, N, Huang, Y, Patel, AR, Yuan, JXJ, Gordeuk, VR, Lang, RM, Garcia, JGN & Machado, R 2012, 'A novel molecular signature for elevated tricuspid regurgitation velocity in sickle cell disease', American Journal of Respiratory and Critical Care Medicine, vol. 186, no. 4, pp. 359-368. https://doi.org/10.1164/rccm.201201-0057OC
Desai, Ankit A. ; Zhou, Tong ; Ahmad, Homaa ; Zhang, Wei ; Mu, Wenbo ; Trevino, Sharon ; Wade, Michael S. ; Raghavachari, Nalini ; Kato, Gregory J. ; Peters-Lawrence, Marlene H. ; Thiruvoipati, Tejas ; Turner, Kristin ; Artz, Nicole ; Huang, Yong ; Patel, Amit R. ; Yuan, Jason X.J. ; Gordeuk, Victor R. ; Lang, Roberto M. ; Garcia, Joe G.N. ; Machado, Roberto. / A novel molecular signature for elevated tricuspid regurgitation velocity in sickle cell disease. In: American Journal of Respiratory and Critical Care Medicine. 2012 ; Vol. 186, No. 4. pp. 359-368.
@article{ea2cd283d993433183676a8f03ffb4c8,
title = "A novel molecular signature for elevated tricuspid regurgitation velocity in sickle cell disease",
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.",
keywords = "Candidate gene approach, eQTL, Microarray, Pulmonary hypertension",
author = "Desai, {Ankit A.} and Tong Zhou and Homaa Ahmad and Wei Zhang and Wenbo Mu and Sharon Trevino and Wade, {Michael S.} and Nalini Raghavachari and Kato, {Gregory J.} and Peters-Lawrence, {Marlene H.} and Tejas Thiruvoipati and Kristin Turner and Nicole Artz and Yong Huang and Patel, {Amit R.} and Yuan, {Jason X.J.} and Gordeuk, {Victor R.} and Lang, {Roberto M.} and Garcia, {Joe G.N.} and Roberto Machado",
year = "2012",
month = "8",
day = "15",
doi = "10.1164/rccm.201201-0057OC",
language = "English (US)",
volume = "186",
pages = "359--368",
journal = "American Journal of Respiratory and Critical Care Medicine",
issn = "1073-449X",
publisher = "American Thoracic Society",
number = "4",

}

TY - JOUR

T1 - A novel molecular signature for elevated tricuspid regurgitation velocity in sickle cell disease

AU - Desai, Ankit A.

AU - Zhou, Tong

AU - Ahmad, Homaa

AU - Zhang, Wei

AU - Mu, Wenbo

AU - Trevino, Sharon

AU - Wade, Michael S.

AU - Raghavachari, Nalini

AU - Kato, Gregory J.

AU - Peters-Lawrence, Marlene H.

AU - Thiruvoipati, Tejas

AU - Turner, Kristin

AU - Artz, Nicole

AU - Huang, Yong

AU - Patel, Amit R.

AU - Yuan, Jason X.J.

AU - Gordeuk, Victor R.

AU - Lang, Roberto M.

AU - Garcia, Joe G.N.

AU - Machado, Roberto

PY - 2012/8/15

Y1 - 2012/8/15

N2 - 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.

AB - 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.

KW - Candidate gene approach

KW - eQTL

KW - Microarray

KW - Pulmonary hypertension

UR - http://www.scopus.com/inward/record.url?scp=84865300397&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84865300397&partnerID=8YFLogxK

U2 - 10.1164/rccm.201201-0057OC

DO - 10.1164/rccm.201201-0057OC

M3 - Article

C2 - 22679008

AN - SCOPUS:84865300397

VL - 186

SP - 359

EP - 368

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

SN - 1073-449X

IS - 4

ER -