Counting the number of times a string of letters appears in the genome could bring us closer to predicting kidney failure, suggests an international team of researchers1. They found that fewer copies of a gene which produces an important defense protein increases a person’s risk of developing a common form of kidney inflammation.
The findings could help explain why Chinese people are more susceptible to the condition known as immunoglobulin A nephropathy (IgAN). “Chinese populations have the highest prevalence of IgAN in the world,” says Jianjun Liu, who led the study at the A*STAR Genome Institute of Singapore. “IgAN is a leading cause of kidney disease in this population.”
Several genome-wide association studies have been conducted to identify single-nucleotide variations associated with the risk of developing IgAN. One of these large-scale fishing exercises recently identified a specific region on chromosome 8 linked to IgAN. “The contribution of this locus to the IgAN risk equals the sum of all the other genetic risk factors that have been discovered so far,” says Liu. He and his team wanted to explore this region further by quantifying patterns of repetition, known as copy number of variations, in a specific gene called DEFA1A3. The number of times a gene repeats can influence disease development and progression.
Using a sophisticated genomic mining technique, the researchers compared the number of DEFA1A3 genes present in DNA of more than one thousand individuals with IgAN, and a similar number of healthy individuals. They found that the IgAN patients had significantly fewer repetitions of the DEFA1A3 gene, which was associated with an increased risk of developing the disease. Variations in this gene number could also predict whether IgAN patients would progress to end-stage kidney disease. The DEFA1A3 gene encodes an essential anti-microbial compound called α-defensin, which is released by immune cells during inflammatory responses.
Liu and his colleagues replicated the analysis in a Caucasian population and found a similar trend: fewer copies of the α-defensin gene in individuals with IgAN. Interestingly, however, the reduced occurrence of a four-nucleotide deletion observed in the Chinese IgAN group, which correlated with IgAN risk, was not seen in the Caucasian group. “We believe this locus contributes to the difference in prevalence between Caucasian and Chinese populations,” says Liu. “However, more studies of this locus, particularly in the Caucasian population, will be needed to confirm and quantify this contribution.”
The α-defensin protein expressed in this region of the genome could offer potential targets for IgAN therapy, he adds.
The A*STAR-affiliated researchers contributing to this research are from the Genome Institute of Singapore