Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, nineteen associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biologic pathways.

Abstract-The kidney has long been invoked in the etiology of essential hypertension. This could involve alterations in expression of specific genes and microRNAs (miRNAs). The aim of the present study was to identify, at the transcriptome-wide level, mRNAs and miRNAs that were differentially expressed between kidneys of 15 untreated hypertensive and 7 normotensive white male subjects of white European ancestry. By microarray technology we found 14 genes and 11 miRNAs that were differentially expressed in the medulla. We then selected and confirmed by real-time quantitative PCR expression differences for NR4A1, NR4A2, NR4A3, PER1, and SIK1 mRNAs and for the miRNAs hsa-miR-638 and hsa-let-7c. Luciferase reporter gene experiments in human kidney (HEK293) cells confirmed the predicted binding of hsa-let-7c to the 3Ј untranslated region of NR4A2 mRNA. In the renal cortex we found differential expression of 46 genes and 13 miRNAs. We then confirmed expression differences for AIFM1, AMBP, APOE, CD36, EFNB1, NDUFAF1, PRDX5, REN, RENBP, SLC13A1, STX4,. Functional experiments in HEK293 cells demonstrated that hsa-miR-663 can bind to the REN and APOE 3Ј untranslated regions and can regulate REN and APOE mRNA levels, whereas hsa-miR-181a regulated REN and AIFM1 mRNA. Our data demonstrated for the first time that miRNAs can regulate renin expression. The observed downregulation of 2 miRNAs in hypertension could explain the elevation in intrarenal renin mRNA. Renin, CD36, and other mRNAs, as well as miRNAs and associated pathways identified in the present study, provide novel insights into hypertension etiology. (Hypertension. 2011;58:1093-1098.) • Online Data SupplementKey Words: microarrays Ⅲ microRNAs Ⅲ renin angiotensin system Ⅲ kidney Ⅲ hypertension S olving the molecular etiology of essential hypertension has been challenging. 1 Studies of selected blood pressure (BP) genes and large genome-wide association studies have identified only a handful of gene variants of small effect sizes. The interplay between genetic and environmental factors that contributes to the heterogeneity of hypertension has made the identification of causative alleles, genes, and transcripts difficult. 1 A further impediment has been the difficulty in obtaining suitable human tissue samples other than blood.Guyton and colleagues 2,3 theorized that hypertension is caused by a primary defect in the kidney. This idea has gained support from rare monogenic forms of hypertension, in which single mutations in genes responsible for renal sodium reabsorption 4 result in BP elevation. 3 MicroRNAs (miRNAs) are important for physiological and pathophysiological processes in various diseases. 5 These 18 to 30 nucleotides noncoding RNAs regulate the expression and translation of half of protein-coding mRNAs in humans by binding to target sites in the 3Ј untranslated region (UTR) to destabilize them or impede translation. 5 If miRNAs modulate mRNAs for BP genes, they could form the basis for novel antihypertensive therapies. 6,7 Knowledge of effects of miRNAs ...