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


OBJECTIVE
We explored the usefulness of peripheral blood mononuclear cell-derived gene signatures as biomarkers for an elevated TRV in SCD.


METHODS
Twenty-seven patients with SCD underwent echocardiography and peripheral blood mononuclear cell isolation for expression profiling and 112 patients with SCD were genotyped for single-nucleotide polymorphisms.


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.
Institute for Personalized Respiratory Medicine,University of Illinois at Chicago, Chicago, IL 60612, USA.
Ankit A
AA
Desai
Tong
T
Zhou
Homaa
H
Ahmad
Wei
W
Zhang
Wenbo
W
Mu
Sharon
S
Trevino
Michael S
MS
Wade
Nalini
N
Raghavachari
Gregory J
GJ
Kato
Marlene H
MH
Peters-Lawrence
Tejas
T
Thiruvoipati
Kristin
K
Turner
Nicole
N
Artz
Yong
Y
Huang
Amit R
AR
Patel
Jason X-J
JX
Yuan
Victor R
VR
Gordeuk
Roberto M
RM
Lang
Joe G N
JG
Garcia
Roberto F
RF
Machado
D000328:Adult; D000755:Anemia, Sickle Cell / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology*; D006328:Cardiac Catheterization; D015331:Cohort Studies; D015150:Echocardiography, Doppler / Q000379:methods; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005819:Genetic Markers / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D006976:Hypertension, Pulmonary / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology; D008297:Male; D046228:Microarray Analysis / Q000379:methods; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011651:Pulmonary Artery / Q000000981:diagnostic imaging / Q000503:physiopathology; D043704:Receptor, Adenosine A2B / Q000235:genetics*; D015203:Reproducibility of Results; D060388:Support Vector Machine; D014262:Tricuspid Valve Insufficiency / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology*; D000097763:Polypeptide N-acetylgalactosaminyltransferase
D005819:Genetic Markers; D017350:N-Acetylgalactosaminyltransferases; D043704:Receptor, Adenosine A2B; D000097763:Polypeptide N-acetylgalactosaminyltransferase