Kidneys at risk

It is estimated that nearly a third of all diabetic patients may be at risk for diabetic nephropathy, a renal disorder that progresses slowly but can inflict severe and irreversible kidney damage.

“In Japan, more than 16,000 patients with diabetic nephropathy enter dialysis therapy per year, and these individuals account for 43% of all new [Japanese] cases requiring renal replacement therapy,” explains Shiro Maeda of the RIKEN Center for Genomic Medicine in Yokohama.

There is considerable evidence suggesting the existence of genetic risk factors for diabetic nephropathy, but efforts to directly identify candidate genes have been undermined by limited understanding of disease pathology. In such situations, genome-wide association studies, in which large populations are subjected to genetic analysis in order to identify single-nucleotide genomic variants potentially ‘linked’ to a condition of interest, offer a powerful alternative for disease gene discovery.

Maeda’s group recently launched such a study in partnership with a team of researchers from around the world, and their data have fingered a single nucleotide change in the gene encoding the enzyme acetyl-coenzyme A carboxylase beta (ACACB) as a significant risk factor for diabetic nephropathy among both Japanese and European populations1. This genetic variation was located within a non-protein-coding, regulatory segment of the gene, and appears to boost expression levels relative to the standard ACACB variant.

Strikingly, although type I and type II diabetes patients are both at risk for diabetic nephropathy, the polymorphism identified by Maeda and colleagues only showed significant association for patients with type II diabetes, which arises when individuals acquire resistance to the hormone insulin. “I think our report is the first to provide evidence suggesting the existence of diabetic nephropathy genes specific to patients with type 2 diabetes,” Maeda says. “However, this finding should be evaluated further.”

The gene ACACB is involved in the metabolism of fatty acids, which is in keeping with previous findings that have linked defects in this process with kidney disease. Nevertheless, as the first genetic factor to be explicitly linked to diabetic nephropathy, Maeda points out that considerably more research will be required to clarify the pathological role of ACACB and to uncover other potential accomplices.

“We will examine possible mechanisms by which ACACB contributes to development and progression of diabetic nephropathy using cultured human kidney cells or genetically engineered mice,” he says, “and we are also performing a larger-scale genome-wide association study to identify additional susceptibility genes.”

The corresponding author for this highlight is based at the Laboratory for Endocrinology and Metabolism, RIKEN Center for Genomic Medicine

Journal information

1. Maeda, S., Kobayashi, M., Araki, S., Babazono, T., Freedman, B.I., Bostrom, M.A., Cooke, J.N., Toyoda, M., Umezono, T., Tarnow, L. et al. A single nucleotide polymorphism within the acetyl-coenzyme A carboxylase beta gene is associated with proteinuria in patients with type 2 diabetes. PLoS Genetics 6, e1000842 (2010)