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New Chronic Kidney Disease Pathways Emerge From Integrated Tissue-Specific Genetic Analysis

NEW YORK (GenomeWeb) – Digging into genetic risk variants and related gene regulatory and expression profiles in kidney tissue can help in finding potential drug targets for chronic kidney disease (CKD), new research suggests.

Researchers from the University of Pennsylvania, the University of Miami, and Boehringer Ingelheim Pharmaceuticals brought together genome-wide association study, expression quantitative trait locus (eQTL), RNA sequence, single-cell sequence, and regulatory mapping information for human kidney glomerular and tubular tissue. The analysis, described online yesterday in Nature Medicine, led them to a core network influencing proximal renal tubule expression and endolysosomal pathways in the kidney.

"We combined compartment-specific transcriptome, genome, epigenome, and single-cell sequencing data to identify new genes, cell types, and mechanisms contributing to the CKD pathophysiology," senior author Katalin Susztak, a genetics, renal electrolyte and hypertension researcher at UPenn, and her co-authors wrote.

At the heart of this network, the team saw a TGF-beta pathway adaptor protein called DAB2 that appeared to contribute to CKD in mouse model experiments. Along with DAB2, the analysis uncovered another 26 suspected candidate CKD genes, though the authors noted that there is a ways to go to translate such findings into new treatments.

"We are just starting to find which molecules have gone astray to cause disease in order to develop drugs to counteract overactive molecules that cause damage to healthy tissue," Susztak said in a statement.

Dozens of genetic loci have been implicated in kidney disease in past genome-wide association studies, the team explained. While some of these variants appear to influence nearby genes, the group reasoned that causal CKD pathways could be uncovered with a combination of GWAS, eQTL, sequence, and other clues.

"In the past, many GWAS efforts have identified sequence variants for CKD, but the biological basis of these variants was poorly understood," Susztak said. "We need to do more with all of the information we have sitting in GWAS databases to identify the genes, cells, and molecular pathways responsible for CKD."

Using microdissection, the researchers separated hundreds of human kidney samples into tubule and glomerulus compartments before sequencing the RNA of 121 tubule and 119 glomerulus samples with Illumina instruments. From there, they looked for eQTLs impacting the expression of nearby genes, identifying so-called eVariants that regulate the expression of hundreds of target genes (known as eGenes) within each kidney compartment and thousands more eGenes shared across compartments.

The team bolstered these eGene sets with insights from the GTEx project and went on to search for overlap between eQTLs in the tubules or glomeruli and other kidney compartments and for variants implicated in kidney disease through GWAS.

The authors noted that "compared to previous eQTL studies of whole-kidney tissue samples, the compartment-based eQTL analysis could identify a larger number of causal genes for CKD," leading them to 27 candidate genes.

The team's kidney compartment eQTL insights, combined with available single-cell RNA sequence data from mouse kidneys, also indicated that proximal tubule epithelial cells in the kidney are particularly prone to express genes from the endolysosomal pathway and other apparent GWAS target genes.

The researchers focused in on DAB2, a core gene showing altered expression in kidney tubule tissue when a CKD-associated variant called rs11959928 was present. For example, they found that mice that were missing the gene had lower levels of kidney damage after exposure to kidney-damaging folic acid — an effect that appeared to be mediated by differences in DAB2 activity in kidney tubule cells.

"Our data delivered new biological insight by the identification of DAB2 as a kidney-disease-causing gene and the additional 26 putative candidate genes," the authors concluded.