Genetic imputation of kidney transcriptome, proteome and multi-omics illuminates new blood pressure and hypertension targets.

Genetic mechanisms of blood pressure (BP) regulation remain poorly defined. Using kidney-specific epigenomic annotations and 3D genome information we generated and validated gene expression prediction models for the purpose of transcriptome-wide association studies in 700 human kidneys. We identified 889 kidney genes associated with BP of which 399 were prioritised as contributors to BP regulation. Imputation of kidney proteome and microRNAome uncovered 97 renal proteins and 11 miRNAs associated with BP. Integration with plasma proteomics and metabolomics illuminated circulating levels of myo-inositol, 4-guanidinobutanoate and angiotensinogen as downstream effectors of several kidney BP genes (SLC5A11, AGMAT, AGT, respectively). We showed that genetically determined reduction in renal expression may mimic the effects of rare loss-of-function variants on kidney mRNA/protein and lead to an increase in BP (e.g., ENPEP). We demonstrated a strong correlation (r = 0.81) in expression of protein-coding genes between cells harvested from urine and the kidney highlighting a diagnostic potential of urinary cell transcriptomics. We uncovered adenylyl cyclase activators as a repurposing opportunity for hypertension and illustrated examples of BP-elevating effects of anticancer drugs (e.g. tubulin polymerisation inhibitors). Collectively, our studies provide new biological insights into genetic regulation of BP with potential to drive clinical translation in hypertension.

Contributions of obesity to kidney health and disease: insights from Mendelian randomization and the human kidney transcriptomics.

AIMS: Obesity and kidney diseases are common complex disorders with an increasing clinical and economic impact on healthcare around the globe. Our objective was to examine if modifiable anthropometric obesity indices show putatively causal association with kidney health and disease and highlight biological mechanisms of potential relevance to the association between obesity and the kidney. METHODS AND RESULTS: We performed observational, one-sample, two-sample Mendelian randomization (MR) and multivariable MR studies in ∼300 000 participants of white-British ancestry from UK Biobank and participants of predominantly European ancestry from genome-wide association studies. The MR analyses revealed that increasing values of genetically predicted body mass index and waist circumference were causally associated with biochemical indices of renal function, kidney health index (a composite renal outcome derived from blood biochemistry, urine analysis, and International Classification of Disease-based kidney disease diagnoses), and both acute and chronic kidney diseases of different aetiologies including hypertensive renal disease and diabetic nephropathy. Approximately 13-16% and 21-26% of the potentially causal effect of obesity indices on kidney health were mediated by blood pressure and type 2 diabetes, respectively. A total of 61 pathways mapping primarily onto transcriptional/translational regulation, innate and adaptive immunity, and extracellular matrix and metabolism were associated with obesity measures in gene set enrichment analysis in up to 467 kidney transcriptomes. CONCLUSIONS: Our data show that a putatively causal association of obesity with renal health is largely independent of blood pressure and type 2 diabetes and uncover the signatures of obesity on the transcriptome of human kidney.