35 Genes Shape Risk to Chronic Kidney Disease

Understanding the genetic makeup of complex chronic diseases is a significant step toward developing advanced diagnostics and better treatment options. In that vein, an international team of investigators led by scientists at the University of Manchester put together an extensive genome-wide association study (GWAS) to identify the genetic factors that predispose people to chronic kidney disease (CKD).

Findings from the new study were published recently in Nature Communications through an article entitled “Molecular insights into genome-wide association studies of chronic kidney disease-defining traits.” The discovery is a major advance in the understanding of the significantly under-diagnosed disorder which, if left undetected, can lead to failing kidneys that need dialysis or kidney transplantation.

The identification of 35 kidney genes is an important step forward to the future development of new diagnostic tests and treatments for the disease that affects around one in ten adults.

“Chronic kidney disease is known for its strong genetic component, noted senior study investigator Maciej Tomaszewski, Ph.D., a professor at the University of Manchester. “Our limited knowledge of its exact genetic mechanisms partly explains why progress in the development of new diagnostic tests and treatments of chronic kidney disease has been so slow.

In the current study, the researchers examined 280 kidney transcriptomes and 9958 gene expression profiles that were obtained from 44 non-renal tissues. From this, the team was able to uncover gene expression partners (eGenes) for 88.9% of chronic kidney disease-defining traits loci.

“The findings were made possible by using a state-of-the-art technology known as next-generation RNA sequencing applied to one of the largest ever collections of human kidneys,” Dr. Tomaszewski explained. “We hope that some of the kidney genes we discovered may become attractive targets for the development of future diagnostics and treatment for patients with chronic kidney disease.”

Additionally, the international team of researchers utilized epigenomic chromatin segmentation analysis and variant effect prediction to annotate the functional consequences to 74% of chronic kidney disease loci. “Our colocalization analysis and Mendelian randomization in >130,000 subjects demonstrate causal effects of three eGenes (NAT8B, CASP9, and MUC1) on estimated glomerular filtration rate,” the authors wrote. “We identify a common alternative splice variant in MUC1 (a gene responsible for a rare Mendelian form of kidney disease) and observe increased renal expression of a specific MUC1 mRNA isoform as a plausible molecular mechanism of the GWAS association signal.”

“One of the genes – mucin-1 – is especially interesting,” remarked study investigator Adrian Woolf, Ph.D., a professor at Manchester Children’s Hospital and The Universality of Manchester. “It makes a sticky protein called mucin that coats urinary tubes inside the kidney. Mutations of this gene have already been found in rare families with inherited kidney failure.”

Co-study investigator Fadi Charchar, Ph.D., a professor at Federation University Australia added, “We hope that early prediction by genetic testing even before the development of symptoms will in the future be the first line of defense against one of the world’s top killers. Early detection followed by treatment using kidney-protective medication or avoidance of drugs which can damage the kidneys is the key to healthier kidneys later in life.”

The investigators were encouraged by their findings, but remain cautious to draw any broad conclusions yet, as there is still considerable work that remains to be done in identifying potential diagnostic or therapeutic interventions that can be derived from this data.

We refer to CKD as a silent killer because it is common for it to have little or no symptoms until the consequences of the disease have taken hold. The findings of this research are hugely important as they bring us a step closer to being able to understand, diagnose earlier, and prevent kidney disease,” concluded Elaine Davies, director of research operations at Kidney Research UK, who was not directly involved with the study.