Understanding the genetic variations associated with chronic kidney disease represents an important step for drug development. Now, and in what they claim is one of the most comprehensive genome-wide association studies (GWAS) of its kind, researchers at the Perelman School of Medicine, University of Pennsylvania, have generated one of the clearest pictures to date of the genetic underpinnings of chronic kidney disease. The study identified 182 genes likely responsible for kidney function—many of which can be targeted with existing drugs—and 88 genes for hypertension. Additionally, the research team mapped the key cell types and mechanisms that are linked to disease. They say that the new results could help researchers identify potential treatment approaches, including the use of existing drugs.
“This is a key roadmap for understanding the mechanisms of chronic kidney disease,” said principal investigator Katalin Susztak, MD, PhD, a professor in the division of renal-electrolyte and hypertension at Penn, who led the research with lead author Xin Sheng, PhD, a postdoctoral fellow at Penn. “Fortunately, some of the genes we’ve identified for kidney disease can be targeted with existing drugs.”
Reporting their results in Nature Communications, Susztak and colleagues concluded, “Our study clarifies the mechanism of commonly used antihypertensive and renal-protective drugs and identifies drug repurposing opportunities for kidney disease.” Their paper is titled, “Mapping the genetic architecture of human traits to cell types in the kidney identifies mechanisms of disease and potential treatments.”
Chronic kidney disease impacts an estimated 850 million people worldwide, and is responsible for approximately 1 in 60 deaths, yet few treatments are available for the condition, and “new therapeutics are desperately needed,” the authors wrote. The disorder is also a growing economic burden. Total Medicare spending for patients with kidney failure reached $36.6 billion in 2018, accounting for about 7% of all Medicare paid claims costs, according to Centers for Disease Control and Prevention (CDC) figures.
Although diabetes and high blood pressure play key roles in chronic kidney disease development, the disease has a strong heritable component, and genetic factors are increasingly recognized to contribute to disease risk.
To better understand the genetic variations associated with kidney disease, researchers have turned to GWAS, which involve scanning DNA variations across the complete genome in hundreds of thousands of people. Existing genetic studies have identified hundreds of regions in the human genome that are associated with kidney disease, but these maps have not been able to pinpoint specific genes, cell types, and mechanisms. “Large population-based GWAS identified around 300 loci with statistically significant reproducible association with kidney function (estimated glomerular filtration rate, or eGFR),” the team noted. However, they pointed out, “The functional interpretation of GWAS is challenging due to the cell-type-dependent influences of genetic variants.”
Susztak commented, “The existing maps have indicated regions in the genome for kidney disease heritability, like an initial treasure map, but, until now, we did not know where the treasure chest was located or how it looked. Our goal was to find the exact location of the treasure and to open up the box to see what was inside.”
One key challenge in translating genetic maps to specific genes is that most of the genetic variants that can cause kidney disease alter how the genes are regulated. “… it is unclear in which cell types these variants are active and how they influence specific biological pathways,” the investigators noted. In addition, they stated, “ … more than 90% of lead-associated variants are found in the noncoding regions of the genome, complicating the precise identification of CKD risk target genes.”
To overcome existing challenges, the researchers collected 659 human kidney samples. After manually dissecting each tissue sample, they analyzed the expression of each gene and the genetic variation. The team next generated gene expression and regulation data for each human kidney cell type using a newly developed single cell sequencing method. This enabled the researchers to identify the key cell types where the genetic variant induces a faulty expression of genes. “… we generated a comprehensive multi-omic dataset and used orthogonal analytical approaches to annotate kidney-related phenotypes,” they wrote. Their results identified nearly 200 genes for kidney function, as well as more than 80 genes for hypertension.
Finally, the researchers clarified the mechanisms behind several existing kidney disease drugs—including angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB)—showing that they matched with the genes implicated in the disease. “Overall, our study highlights the critical role of the kidney in blood pressure regulation and raises the possibility that these variants might be useful for future precision therapeutic approaches, to understand differences in response to ACEi and ARBs,” they concluded.
“We have used these drugs for several decades, but now we know why they work so effectively,” Susztak said. “This study represents a very important milestone for the nephrology field and the millions of patients currently affected by chronic kidney disease.”