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Research Teams ID Genetic Variants Linked to Kidney Function, Disease

By Andrea Anderson

NEW YORK (GenomeWeb News) – In a pair of papers published online in Nature Genetics yesterday, two research teams reported that they have identified genetic variants associated with both normal kidney function and chronic kidney disease.

In the first of these, an international research team performed a meta-analysis on data from more than 67,000 individuals of European ancestry to track down almost two dozen new loci that appeared to be associated with kidney function or disease. Through validation testing using information on nearly 23,000 more individuals, the researchers verified that 20 of the loci are associated with either kidney function in general or with the production of — or signaling by — creatinine, a commonly used marker for kidney function.

Now, researchers hope that follow-up studies will help to tease apart the functional role of these variants in kidney function and disease, co-corresponding author Caroline Fox, a researcher at the National Heart, Lung, and Blood Institute, told GenomeWeb Daily News.

Chronic kidney disease, which affects more than a tenth of Europeans and North Americans, can increase the risk of developing a range of other diseases — from end-stage renal disease to heart disease. But while it's known that conditions such as hypertension and diabetes can increase the likelihood of developing chronic kidney disease, there is still a great deal to be learned about the genetics behind kidney disease and even normal kidney function.

In a previous study, Fox and her colleagues found variants in three genes — UMOD, SHROOM3, and STC1 — that appear to affect kidney function. Meanwhile, past research has turned up an association between a gene called MYH9 and end-stage kidney disease in African American individuals.

For the current study, the researchers used a meta-analysis approach to try to find even more variants linked to kidney function and disease, assessing data for 67,093 individuals of European ancestry from 20 studies. Most of these individuals were recruited through population-based studies done by the CKDGen consortium.

The team turned up 28 loci — 23 new and five previously identified loci — that had genome-wide significant associations with one of the kidney-related traits of interest.

In their follow-up assessment of another 22,982 individuals of European descent, the researchers verified that 13 of the 23 new loci were associated with kidney function (specifically glomerular filtration rate), influencing both creatinine levels as well as levels of a second kidney function marker called cystatin c. The team confirmed that another seven of the loci were associated with creatinine metabolism.

Interestingly, the researchers noted, some of these SNPs fell in and around genes involved in kidney-related processes such as nephrogenesis, glomerular filtration, angiogenesis, metabolism, and other kidney-related processes. In addition several loci appear to correspond to chronic kidney disease.

Even so, Fox explained, more studies — such as research in animals and sequencing experiments — are needed to explore the functional consequences of the specific variants detected.

In another paper in Nature Genetics, a research team led by investigators in the UK used a GWAS approach to first find loci linked to serum creatinine levels. They then tested these variants for associations with other kidney related processes. In the process, that team found four associated loci that overlapped with those detected by Fox and her colleagues.

"It was very nice to see that they identified four loci and we identified these four as well," Fox said.

For that study, researchers assessed data for 23,812 individuals of European descent genotyped on several array platforms as part of nine different studies, looking for loci associated with creatinine levels.

The team identified 109 such SNPs at five loci — four of which had not been identified previously, while the fifth contained a strongly associated SNP that falls in the previously identified SHROOM3 gene.

When they tested the top four SNPs for association with other kidney-related process, including glomerular filtration rate and cystatin c levels, the researchers found that two were associated the kidney function and disease in general, while the other two were associated with glomerular filtration rate alone — consistent with findings from the other study.

"Our findings of common genetic variants associated with creatinine, cystatin c and [chronic kidney disease] provide insight into the metabolic, solute and drug transport mechanisms underlying kidney function and [chronic kidney disease]," the authors concluded. "Further evaluation of these pathways may enable biomarker discovery and the development of new strategies to protect kidney function and prevent [chronic kidney disease]."

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