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Decode-Led Study Suggests Kidney Disease Risk Variant Influences Other Age-Related Processes

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – A genetic variant previously linked to chronic kidney disease risk also appears to have a role in age-associated changes in kidney function and the onset of interrelated conditions, according to a study appearing in PLoS Genetics online last night by researchers from Iceland and the Netherlands.

Through its genome-wide association study of more than 3,200 Icelandic individuals with chronic kidney disease and nearly 39,000 healthy control individuals, also from Iceland, the Decode Genetics-led team verified a prior association between a genetic locus in and around the UMOD gene, which codes for a protein found in mammalian urine, and kidney disease.

The researchers subsequent experiments revealed that a UMOD associated with chronic kidney disease in Icelandic populations is also linked to levels of the kidney function marker serum creatinine — particularly in older Icelandic individuals — and may influence kidney response to conditions frequently affecting those with kidney disease.

"This SNP is now a validated risk factor for kidney disease, but we have also shown how it can be made even more meaningful if looked at in the context of age and broader health history," senior author Kari Stefansson, executive chairman and president of research for Decode Genetics, who is also affiliated with the University of Iceland, said in a statement, noting that the variant seems to modulate how kidneys adapt to age and environmental insults.

Stefansson and his team used the Illumina HumanHap300 array or the Illumina HumanHapCNV370 array to assess 2,903 individuals from Iceland with chronic kidney disease and 35,818 unaffected controls. Between the variants that overlapped on both chips and other SNPs imputed from HapMap CEU samples, the team looked at 2.5 million SNPs per individual.

The team also did a similar genotyping on 22,256 Icelanders for whom they had serum creatinine concentration data.

In the process, the researchers detected chronic kidney disease-associated SNPs in linkage disequilibrium on chromosome 16 — a locus implicated in a 2009 GWAS of kidney function and disease.

Their follow-up work showed that a SNP called rs4293393 tagged this signal and showed a nominally significant association with kidney disease in another 300 affected and 2,964 control individuals from Iceland.

The rs4293393 SNP falls upstream of UMOD, a gene coding for a mammalian kidney protein called uromodulin that's found in urine from healthy individuals, the researchers noted.

The team also saw links between the variant and serum creatinine levels in their discovery group and in a validation cohort that included 2,379 Icelandic individuals. And, they reported, the strength of this association increased with age in the Icelandic population.

On the other hand, they noted, rs4293393 was not associated with serum creatinine levels in 1,819 health Dutch individuals — a population with very different serum creatinine levels overall than those observed in the Icelandic population.

Additional experiments indicate that the variant signals decreased kidney stone risk in both the Icelandic and Dutch populations.

Given its apparent ties to kidney disease and aging in Icelandic individuals, the researchers decided to test whether the UMOD variant was associated with conditions that frequently co-occur with chronic kidney disease in older individuals, such as high blood pressure and type 2 diabetes.

Findings from those experiments hinted that the variant's association with serum creatinine concentration is stronger in individuals with comorbid conditions such as high blood pressure or type 2 diabetes, though it shows only weak association with risk of hypertension itself.

Together, the team argued, the findings suggest that variants in and around UMOD are related to changes in the kidney that occur with age, along with an individual's response to conditions that often accompany kidney disease in older individuals.

"Our observations indicate that UMOD is important for maintaining kidney function with advancing age and exposure to risk factors that are associated with aging, such as [hypertension], [type 2 diabetes mellitus], and cardiovascular disease," they concluded.

"We believe this mechanism may be a fruitful subject for further research aimed at preventing and treating kidney disease," Stefansson said in a statement.

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