Source: The First Affiliated Hospital
Written by: The First Affiliated Hospital
Edited by: Wang Dongmei

Chronic kidney disease (CKD) is a prominent public health issue in China. Among CKD, IgA nephropathy (IgAN) is the most common primary glomerulonephritis and the major cause of ESRD (end stage renal disease) in Chinese population. However, the pathogenesis of IgAN has so far been unclear; leaving patients no precisely targeted therapy. Researchers from The First Affiliated Hospital of Sun Yat-sen University, collaborating with Genome Institute of Singapore, University of Nottingham and University of Leicester, discovered from a study of 3,105 cases strong associations between α-defensin copy number variations and IgAN, and indicated the potential of α-defensin copy number variations being novel prognostic markers and therapeutic targets. The research findings were published online by Science Translational Medicine on June 29, 2016. Professor Xueqing Yu from The First Affiliated Hospital of Sun Yat-sen University and Professor Jianjun Liu from Genome Institute of Singapore are co-corresponding authors.

The research was led by Professor Xueqing Yu, who excels in both clinical practice and scientific research as regards nephrology. Multiple research conducted or led by him is at the frontier of international field. The authoritative medical journal, The Lancet, published this year his profile entitled “Xueqing Yu: a driving force in Chinese nephrology”, which is one of the few articles The Lancet has issued about Chinese medical pioneers. Recently, Prof. Yu and his team have delivered multiple findings from the genetic studies of IgAN. They identified five susceptible loci for IgAN through GWAS in 2012 (Nature Genetics, 2012), including two Han Chinese specific susceptible loci 8p23.1 and 17p13. Then they discovered another three new susceptible loci through the expanded 4-stage GWAS in 2015 (Nature Communications, 2015). These findings expand our understanding of the genetic susceptibility to IgAN, and provide some new biological perception of the underlying molecular mechanisms of IgAN.

Building on these studies, researchers enrolled another1189 Han Chinese IgAN patients and 1187 healthy controls, and further investigated gene copy number variations within the previously reported susceptible loci. They discovered that low copy number of α-defensincould increase the risk of the development and renal dysfunction of IgAN. They then validated the consistent association effect of α-defensin copy number variations in European IgAN cohort (531 cases and 198 controls). In addition, these copy number variations were also negative correlated with both serum levels of IgA1 and proportions of galactose-deficient IgA1. The research confirmed that α-defensin copy number variations matter a great deal in the development and progression of IgAN, suggesting the potential of α-defensin being a specific intervention target for IgAN.

Professor Xueqing Yu stated that along with further genetic research on IgAN, the team would have a more comprehensive understanding of genetic variations in IgAN, discovering more common variations, rare variations and structural variations that related to IgAN, and exploring the genetic variations that associated with clinicopathologic phenotypes, treatment responses and clinical outcomes in IgAN patients. The copy number variations identified in previous research may be a potential novel bio-marker and therapeutic target for IgAN, facilitating translational medicine research and corner-stoning future clinical application research. In the future, the team will construct disease predicting models using those genetic variations identified to screen high-risk population for IgAN among general population, and to screen the patients with poor prognosis from general IgAN patients. Then the clinicians can be guided to offer targeted interventions and treatments, ultimately realizing the precise intervention and treatment.

2016 PhD graduate Zhen Ai from The First Affiliated Hospital of Sun Yat-sen University is the first author of this paper, Dr. Ming Li and PhD candidate Wenting Liu are co-first authors. PhD students under Prof. Yu’s mentoring have published multiple high-level papers in CSN series journals, exhibiting the academic excellence, solid research foundation and sustainable development potential of this nephrology team.

The current research is funded by grants including the National Natural Science Foundation of China (NSFC), Guangdong Department of Science and Technology Translational Medicine Center grant, and the Natural Science Project of Guangdong Province, and etc.

Link to the paper: http://stm.sciencemag.org/content/8/345/345ra88