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

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.