A novel molecular signature for elevated tricuspid regurgitation velocity in sickle cell disease.
Research paper by
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
9th Jun 2012
9th Jun 2012
American journal of respiratory and critical care medicine
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).We explored the usefulness of peripheral blood mononuclear cell-derived gene signatures as biomarkers for an elevated TRV in SCD.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.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).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.