Researchers discover strong genetic risk factor for IgA nephropathy

Discovery opens up possibilities for new potential therapeutic target for the disease and related renal dysfunction

An international research collaboration has discovered a strong genetic risk factor for IgA nephropathy (IgAN) - the most common inflammatory kidney disease worldwide - and related renal dysfunction. Published in Science Translational Medicine, the discovery has advanced the researchers' understanding of IgAN.

The prevalence of IgAN is higher in Asia than Western countries, and 15-40% of the patients will eventually progress to end-stage renal diseases within 20 years of the disease onset. Despite its global prevalence, IgAN's pathogenesis is not well understood. By investigating copy number variations (CNVs) of the alpha-defensin gene in Chinese patients with IgAN and healthy controls as well as a Caucasian cohort with IgAN, the researchers found that a low copy number of the alpha-defensin gene increases the risk of IgAN, and the CNV of alpha-defensin gene can explain the 4.96% of disease risk.

In addition, the researchers also found that the low copy number of the alpha-defensin gene also increases the risk of renal dysfunction in IgAN patients and shows negative correlations with serum IgA1 and galactose-deficient IgA1. This is the first study that demonstrates the vital role of alpha-defensin gene in IgAN development and related renal dysfunction, suggesting the gene to be a potential therapeutic target for this important kidney disease.

This collaboration was led by Prof Liu Jianjun, Deputy Director for Research Programmes and Senior Group Leader of Human Genetics at A*STAR's Genome Institute of Singapore (GIS), and Prof Yu Xueqing, Professor of Medicine and Director of the Institute of Nephrology at the First Affiliated Hospital of Sun Yat-sen University (SYSU), and the current President of the Chinese Society of Nephrology. To date, the collaborative research team from GIS and SYSU have already discovered five novel genetic risk loci for IgAN.

"As a major source of genetic variation, CNVs have long been suggested to play important roles in disease development, but only a few specific CNVs have demonstrated convincing evidence. This CNV contributes more genetic risk to IgAN than the cumulative effect of all the other loci we have discovered. So, this discovery is truly exciting," said Prof Liu.

Prof Yu added:

IgAN is the most common primary glomerulonephritis worldwide. However, no disease-specific treatment agents have been developed yet, due to the unknown pathogenesis of IgAN. Our findings revealed the important role of alpha-defensin gene in the development and renal progression of IgAN. It will help in exploring the specific intervention target for IgAN, and provide a solid work for the future development of disease specific targeted drugs.

GIS Executive Director Prof Ng Huck Hui said:

The positive correlation between alpha-defensin gene and risk for IgAN identified in this study is a significant discovery. The translation of these findings have the potential to be beneficial to IgAN patients worldwide.

"This paper provides important insights into the genetics and root causes of the world's most common primary disease of the kidney glomerulus, IgAN. The identification of a copy number variant as a genetic mechanism of disease is novel and the discovery of altered activity of alpha-defensins in IgAN pathogenesis suggests potential new avenues for therapy," said Prof Thomas Coffman, Dean of the Duke-NUS Medical School.

"The discovery of IgAN susceptibility gene, alpha-defensin, is a major breakthrough in the fight against the disease. It will pave the way for identifying individuals at high risk for IgAN. It may also reveal new treatment target (i.e. its protein product - human neutrophil peptides) to prevent the onset and progression of IgAN," said Dr Lim Su Chi, Clinical Director, Clinical Research Unit at the Khoo Teck Puat Hospital.