S-22-6: renal expression of micrornas and their association with blood pressure regulation - insights from small rna-sequencing of 493 human kidneys

The kidney is a critical regulator of blood pressure (BP) and a contributor to cardiovascular health. Recently, microRNAs (miRNAs) have emerged as potential mediators of genetic predisposition to cardiovascular and kidney disorders, yet their overall role in blood pressure control has not been fully characterised. We sought to identify and catalogue all renal miRNAs, investigate which of them are genetically regulated and assess whether their expression-modifying single nucleotide polymorphisms (SNPs) overlap with genetic variants associated with BP in previous genome-wide association studies (GWAS). We first characterised the entire renal miRNA transcriptome through de novo small RNA-sequencing of 493 human kidney samples. We then integrated these expression profiles with genotype information to perform expression quantitative trait loci (eQTL) analysis - the largest of its kind - and identify genetically regulated miRNAs and their regulatory SNPs. We then examined the extent to which miRNA-regulating variants overlapped with the curated list of BP-associated GWAS SNPs. We identified 1,459 mature miRNAs expressed in the human kidney, and the top 50 most highly expressed miRNAs accounted for 24.2% of the measured expression. We also discovered that 78% of miRNA genes expressed in the kidney were intragenic to other genes and 58% mapped to an intron of those genes. After correction for multiple testing, our eQTL analysis had identified 140 genetically regulated miRNAs in the kidney. They were controlled by 19,901 unique SNPs (eSNPs) with a total of 21,805 miRNA-eSNP pairs. Functional annotation of miRNA eSNPs demonstrated 2.54-fold enrichment for kidney enhancer regions and 1.69-fold enrichment for kidney promoters when compared to randomly selected SNPs. Through overlap with GWAS SNPs for systolic, diastolic and pulse pressures, we identified 8 kidney BP miRNA eSNPs responsible for the regulation of 9 mature miRNAs. Collectively, we generated a catalogue of miRNAs expressed in the human kidney, annotated novel kidney relevant miRNAs and their regulatory variants and discovered 9 renal microRNAs that may act as mediators of genetic predisposition to high BP.