Transcriptome Study of 2 Black Cohorts Reveals cis Long Noncoding RNAs Associated With Hypertension‐Related mRNAs

Abstract

Background Long noncoding RNAs (lncRNAs) have emerged as critical regulators of the expression of genes involved in cardiovascular diseases. This project aims to identify circulating lncRNAs associated with protein‐coding mRNAs differentially expressed between hypertensive and normotensive individuals and establish their link with hypertension. Methods and Results The analyses were conducted in 3 main steps: (1) an unbiased whole blood transcriptome‐wide analysis was conducted to identify and replicate protein‐coding genes differentially expressed by hypertension status in 497 and 179 Black individuals from the GENE‐FORECAST (Genomics, Environmental Factors and the Social Determinants of Cardiovascular Disease in African‐Americans Study) and MH‐GRID (Minority Health Genomics and Translational Research Bio‐Repository Database) studies, respectively. Subsequently, (2) proximal lncRNAs, termed cis lncRNA quantitative trait loci, associated with each mRNA were identified in the GENE‐FORECAST study and replicated in the MH‐GRID study. Finally, (3) the lncRNA quantitative trait loci were used as predictors in a random forest model to predict hypertension in both data sets. A total of 129 mRNAs were significantly differentially expressed between normotensive and hypertensive individuals in both data sets. The lncRNA‐mRNA association analysis revealed 249 cis lncRNA quantitative trait loci associated with 102 mRNAs, including VAMP2 (vesicle‐associated membrane protein 2), mitogen‐activated protein kinase kinase 3, CCAAT enhancer binding protein beta, and lymphocyte antigen 6 complex, locus E. The 249 lncRNA quantitative trait loci predicted hypertension with an area under the curve of 0.79 and 0.71 in GENE‐FORECAST and MH‐GRID studies, respectively. Conclusions This study leveraged a significant sample of Black individuals, a population facing a disproportionate burden of hypertension. The analyses unveiled a total of 271 lncRNA‐mRNA relationships involving mRNAs that play critical roles in vascular pathways relevant to blood pressure regulation. The compelling findings, consistent across 2 independent data sets, establish a reliable foundation for designing in vitro/in vivo experiments.