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Genotyping Study Turns Up Risk Variants for T2D-Related Kidney Complication in Chinese Population

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Chinese researchers reported in today's issue of the Journal of the American Medical Association that they have uncovered genetic variants linked to serious kidney complications in Chinese individuals with type 2 diabetes.

The researchers followed nearly 1,200 Chinese individuals with type 2 diabetes over several years, using genotyping to look for associations between a kidney complication called end-stage renal disease and 18 common SNPs in and around PRKCB1, a protein kinase C-beta signaling protein gene. Indeed, the team found a quartet of SNPs in this region that were associated with end-stage renal disease in Chinese patients with type 2 diabetes.

"Our consistent results … suggest that genetic variation in the PRKCB1 gene is an important determinant for the risk of developing DKD in Chinese patients with type 2 diabetes," corresponding author Ronald Ma, a medicine and therapeutics researcher at the Chinese University of Hong Kong, and his co-authors wrote.

Their models suggest the alleles might provides clues about which diabetes patients are at risk of kidney complications, with individuals carrying more of the risk alleles apparently at higher risk than those who have none or just one.

Some 94 million or more adults in China have type 2 diabetes, the researchers noted. And Chinese diabetics seem to be at higher risk of diabetes-related kidney problems and kidney failure than those from other populations, with past research finding that roughly one to three percent of Chinese diabetics develop diabetes related kidney problems.

Because diabetic kidney disease seems to have a strong — but largely uncharacterized — genetic component, Ma and his co-workers decided to look for common genetic variants linked to end-stage renal disease in Chinese diabetics, focusing on 18 SNPs in and around PRKCB1 — a gene previously linked to some diabetes complications and kidney-related processes in human and animal studies.

For the initial phase of the study, the team assessed the PRKCB1 SNPs in genomic DNA from 1,172 unrelated individuals with type 2 diabetes who had been recruited to the Hong Kong Diabetes Registry between 1995 and 1998. The samples were genotyped using the Sequenom MassArray platform at McGill University and the Genome Quebec Innovation Centre.

Of the 1,172 individuals tested, 7.7 percent went on to develop end-stage renal disease over a mean follow-up time of 7.9 years.

When they looked for variants linked to such kidney problems using genotype data, combined with information on Chinese population structure from HapMap, the researchers found that four of the SNPs were significantly associated with end-stage renal disease.

And the risk alleles seemed to have a cumulative influence on end-stage kidney disease risk: the researchers estimated that individuals with four risk alleles are about six times more likely to develop the kidney condition than those with none of the risk alleles or with a single risk allele.

The team subsequently verified the associations between end-stage renal disease and PRKCB1 SNPS in another 1,049 individuals who were recruited after 1998 and had been diagnosed with type 2 diabetes before the age of 45 years old.

Of these participants, 151 developed chronic kidney disease, though researchers noted that follow-up time was shorter than it had been in the initial cohort. Again, the presence of PRKCB1 variants seemed to up the risk of kidney troubles in an additive way.

More research is needed to untangle the functional consequence of the PRKCB1 variants, though the team's initial bioinformatics search hints that the SNPs identified in the current study might impact transcription of PRKCB1.

Based on its findings, combined with previously reported results from other groups, the team speculated that "the risk association of renal disease with PRKCB1 may be mediated by interacting pathways, including but not limited to hyperglycemia, and increased oxidative stress causing tubular damage and interstitial fibrosis."

Moreover, the researchers noted that the results in the Chinese population may also provide insights into the appropriate use of ruboxistaurin, a protein kinase C-beta inhibiting compound that is being tested for the treatment of other diabetes-related complications.

"Given the phenotypic and genetic heterogeneity of complex diseases such as [diabetic kidney disease], it would be of interest to examine the interaction between PRKCB1 genotype and clinical response to ruboxistaurin," Ma and his co-authors wrote.

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