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Team Uncovers New Variants Involved in Kidney Stone Risk

NEW YORK (GenomeWeb) – A study published online today in Nature Communications implicated a combination of common and rare variants in elevated kidney stone risk in the Icelandic population.

Researchers from Decode Genetics, the University of Iceland, and elsewhere did a genome-wide association study involving 5,419 Icelandic individuals with kidney stones — including nearly 2,200 individuals plagued by recurrent kidney stone problems — along with hundreds of thousands of unaffected controls from the same population.

That search picked up significant and suggestive ties to recurrent kidney stone risk in two genes, while the team's more in-depth look at variants in kidney-expressed genes led to two rare variants with ties to the condition.

The same set of SNPs seemed to coincide with metabolic features such as calcium levels in blood and other biochemical traits, hinting at potential contributors to kidney stone formation.

"In addition to discovering associations with kidney stones, we assessed the association of these variants to 13 biochemical traits involved in calcium-phosphate metabolism, purine metabolism, kidney function, acid-base, and ion homeostasis in a large population set," senior author Kari Stefansson, Decode Genetics founder and CEO and University of Iceland researcher, and colleagues noted.

Nearly 9 percent of Americans develop kidney stones at some stage in their lives, the team noted, and more than one-third of kidney stone sufferers experience resurgence of the condition within five years.

While it's known that higher-than-usual levels of calcium salts and other salts in the urine contribute to kidney stone risk, investigators are still teasing apart the environmental and genetic factors that contribute to kidney stone risk.

Prior GWAS have implicated signaling and/or biochemically-linked loci such as the cell-cell adhesion-related genes CLDN14 or the sodium-phosphate transporter-coding gene SLC34A1.

In an effort to find further variants contributing to kidney stone risk, the researchers considered genetic patterns in 5,419 Icelanders who appeared prone to kidney stones — a group that included 2,979 individuals genotyped with Illumina arrays and 2,440 genotyped relatives.

The team noted that a subset of the individuals — almost 2,200 — was classified as recurrent kidney stone formers.

The researchers looked at how common and rare variants stacked up in the kidney stone-prone group compared with those in 279,970 unaffected Icelandic controls, focusing on 28.3 million variants that were either directly genotyped or imputed with the help of whole-genome sequence data for more than 2,600 Icelanders and haplotype phasing patterns in nearly 99,000 members of the population.

In addition to verifying associations between kidney stones and variants in SLC34A1, CLDN14, and other genes, the team saw a significant overrepresentation of SNPs in and around the alkaline phosphatase enzyme gene ALPL in kidney stone sufferers. SNPs in the calcium sensing G-protein receptor gene CASR showed more tenuous ties to kidney stoner risk.

The strongest new association involved ALPL, a chromosome 1 gene expressed in the kidney's proximal tubules, which also appears to influence serum phosphate levels and levels of alkaline phosphatase in the blood.

When the researchers turned their attention to coding variants in genes previously earmarked for being preferentially expressed in kidney tissue, they found missense mutations in the already-identified SLC34A1 and in the epithelial calcium channel gene TRPV5.

Together, the study's author argued that the findings "emphasize the role of sequence variants in genes involved in calcium-phosphate homeostasis in kidney stone disease" and noted that the "pathophysiology underlying these associations requires further study."