Whole Blood RNA Profiles Associated with Pulmonary Arterial Hypertension and Clinical Outcome

TY - JOUR

T1 - Whole Blood RNA Profiles Associated with Pulmonary Arterial Hypertension and Clinical Outcome

AU - Rhodes, Christopher J

AU - Otero-Núñez, Pablo

AU - Wharton, John

AU - Swietlik, Emilia M

AU - Kariotis, Sokratis

AU - Harbaum, Lars

AU - Dunning, Mark J

AU - Elinoff, Jason M

AU - Errington, Niamh

AU - Thomson, A A Roger

AU - Iremonger, James

AU - Coghlan, J Gerry

AU - Corris, Paul A

AU - Howard, Luke S

AU - Kiely, David G

AU - Church, Colin

AU - Pepke-Zaba, Joanna

AU - Toshner, Mark

AU - Wort, Stephen J

AU - Desai, Ankit A

AU - Humbert, Marc

AU - Nichols, William C

AU - Southgate, Laura

AU - Trégouët, David-Alexandre

AU - Trembath, Richard C

AU - Prokopenko, Inga

AU - Gräf, Stefan

AU - Morrell, Nicholas W

AU - Wang, Dennis

AU - Lawrie, Allan

AU - Wilkins, Martin R

PY - 2020/8/15

Y1 - 2020/8/15

N2 - Rationale: Idiopathic and heritable pulmonary arterial hypertension (PAH) are rare but comprise a genetically heterogeneous patient group. RNA sequencing linked to the underlying genetic architecture can be used to better understand the underlying pathology by identifying key signaling pathways and stratify patients more robustly according to clinical risk.Objectives: To use a three-stage design of RNA discovery, RNA validation and model construction, and model validation to define a set of PAH-associated RNAs and a single summarizing RNA model score. To define genes most likely to be involved in disease development, we performed Mendelian randomization (MR) analysis.Methods: RNA sequencing was performed on whole-blood samples from 359 patients with idiopathic, heritable, and drug-induced PAH and 72 age- and sex-matched healthy volunteers. The score was evaluated against disease severity markers including survival analysis using all-cause mortality from diagnosis. MR used known expression quantitative trait loci and summary statistics from a PAH genome-wide association study.Measurements and Main Results: We identified 507 genes with differential RNA expression in patients with PAH compared with control subjects. A model of 25 RNAs distinguished PAH with 87% accuracy (area under the curve 95% confidence interval: 0.791-0.945) in model validation. The RNA model score was associated with disease severity and long-term survival (P = 4.66 × 10-6) in PAH. MR detected an association between SMAD5 levels and PAH disease susceptibility (odds ratio, 0.317; 95% confidence interval, 0.129-0.776; P = 0.012).Conclusions: A whole-blood RNA signature of PAH, which includes RNAs relevant to disease pathogenesis, associates with disease severity and identifies patients with poor clinical outcomes. Genetic variants associated with lower SMAD5 expression may increase susceptibility to PAH.

AB - Rationale: Idiopathic and heritable pulmonary arterial hypertension (PAH) are rare but comprise a genetically heterogeneous patient group. RNA sequencing linked to the underlying genetic architecture can be used to better understand the underlying pathology by identifying key signaling pathways and stratify patients more robustly according to clinical risk.Objectives: To use a three-stage design of RNA discovery, RNA validation and model construction, and model validation to define a set of PAH-associated RNAs and a single summarizing RNA model score. To define genes most likely to be involved in disease development, we performed Mendelian randomization (MR) analysis.Methods: RNA sequencing was performed on whole-blood samples from 359 patients with idiopathic, heritable, and drug-induced PAH and 72 age- and sex-matched healthy volunteers. The score was evaluated against disease severity markers including survival analysis using all-cause mortality from diagnosis. MR used known expression quantitative trait loci and summary statistics from a PAH genome-wide association study.Measurements and Main Results: We identified 507 genes with differential RNA expression in patients with PAH compared with control subjects. A model of 25 RNAs distinguished PAH with 87% accuracy (area under the curve 95% confidence interval: 0.791-0.945) in model validation. The RNA model score was associated with disease severity and long-term survival (P = 4.66 × 10-6) in PAH. MR detected an association between SMAD5 levels and PAH disease susceptibility (odds ratio, 0.317; 95% confidence interval, 0.129-0.776; P = 0.012).Conclusions: A whole-blood RNA signature of PAH, which includes RNAs relevant to disease pathogenesis, associates with disease severity and identifies patients with poor clinical outcomes. Genetic variants associated with lower SMAD5 expression may increase susceptibility to PAH.

U2 - 10.1164/rccm.202003-0510OC

DO - 10.1164/rccm.202003-0510OC

M3 - SCORING: Journal article

C2 - 32352834

VL - 202

SP - 586

EP - 594

JO - AM J RESP CRIT CARE

JF - AM J RESP CRIT CARE

SN - 1073-449X

IS - 4

ER -