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

Recently, in cooperation with more than twenty institutions in China such as the Institute of Nephrology in Jinling Hospital, Nanjing University, as well as the Genome Institute of Singapore (GIS), the Institute of Nephrology in The First Affiliated Hospital of Sun Yat-sen University conducted the research of susceptibility genes for IgA Nephropathy (IgAN), revealing multiple new IgAN susceptibility genes. The research findings were published online by Nature Communications on June 1, 2015. Dr. Ming Li from the Institute of Nephrology of The First Affiliated Hospital of Sun Yat-sen University, Jia-Nee Foo from GIS and Jinquan Wang from Jinling Hospital, Nanjing University, are the co-first authors in this paper. Professor Xueqing Yu from Sun Yat-sen University and Professor Jianjun Liu from GIS are co-corresponding authors.

IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the world, accounting for around 20.0% to 45.3% of total primary glomerular diseases. Its clinical and pathological features are varied, and therapeutic response is different. Besides, its clinical outcomes are not identical. Some patients of IgAN only showed the symptom of benign hematuria, whose renal function would be stable throughout their life without any special intervention treatment. However, around 15% to 40% of them progressed to end-stage renal failure – uremia, and needed early intervention.

The pathogenesis of IgAN is not fully clarified yet. Efficient clinical treatment methods are still under exploration. Currently IgAN is considered as a multi-factorial complex disease, ineraction of genetic and environmental factors contributing greatly to it.

The Institute of Nephrology in The First Affiliated Hospital of Sun Yat-sen University has long been dedicated to the studies of IgAN genetics. It identified a number of susceptibility loci for IgAN in a two-stage genome-wide association study (GWAS) in 2012 (Nature Genetics, 2012). Based on this previous study, the present research worked on the GWAS data thoroughly, and recruited 8,313 cases of IgAN patients and 19,680 healthy people for comparison, finding out various susceptibility loci for IaAN in Han Chinese. Through referencing the data of the whole genome chip research from the GWAS session, increasing the sample amount of the control group, namely the healthy group, taking the 1000 genome project as a reference, applying gene imputation method to apply in-depth analysis to the GWAS data involving 3,792,949 single nucleotide polymorphism (SNP) loci, and applying large sample verification to the most significant 122 SNP loci, susceptibility locus (16p11.2) reported recently by researchers from Europe and the United States was validated. In the meantime, in the zone of the acknowledged susceptibility locus DEFA, three new SNP loci are independently correlated with IgAN. Besides, the results demonstrate that the mutation of susceptibility loci 3q27.3 and 11p11.2, and the mRNA expression in leukocytes are significantly correlated. What’s more, the results indicate that the allele frequency of susceptibility loci ST6GAL1, ACCS and DEFA are significantly correlated with the incidence of IgAN in different geographic areas. This research authenticates again that genetic susceptibility loci play an important role in the pathogenesis of IgAN.

Professor Xueqing Yu stated that along with further genetic research on IgAN, we would have a more comprehensive understanding of the maps of generic IgAN variation. Meanwhile, because the clinical manifestation, Pathological pattern, therapeutic response, and clinical outcomes of patients with IgAN are different, with genetic factors contributing to these differences, the susceptibility loci identified in the present research will help carry out translational research, and establish a sound foundation for future clinical application research. In the future, based on the information of susceptibility loci that we have found, it is possible that we screen the high-risk population for IgAN from general people in the community, and provide early intervention and prevention for them. In addition, among IgAN patients, based on the known genetic information, through large-scale sample analysis and long-time observation, and screening genes that are related with progression of disease, therapeutic response, and clinical prognosis, clinician can be guided to offer targeted treatment, improve the therapeutic effect, and reduce side-effects, to realize the real individualized treatment, which is the “precise medicine” being strongly advocated nowadays. Besides, through further research, we can look for virulence gene among susceptibility loci. Through relevant functional research, we can then provide new intervention targets for kidney disease treatment, and lay a solid foundation for the invention of medicines for these new targets.

The current research was funded by projects including the Key Program of National Natural Science Foundation of China (NSFC), Major State Basic Research Development Program of China (973 program), Key Program of Translational Research of the Department of Science and Technology in Guangdong Province, the Natural Science Project of Guangdong Province, and etc.

Reference:

1. Yu XQ*, Li M, Zhang H, Low HQ, Wei X, Wang JQ, Sun LD, Sim KS, Li Y, Foo JN, Wang W, Li ZJ, Yin XY, Tang XQ, Fan L, Chen J, Li RS, Wan JX, Liu ZS, Lou TQ, Zhu L, Huang XJ, Zhang XJ, Liu ZH, Liu JJ. A genome-wide association study in Han Chinese identifies multiple susceptibility loci for IgA nephropathy. Nat Genet. 2012; 44(2):178-82.

2. Li M, Fu J, Wang J, et al. Identification of new susceptibility loci for IgA nephropathy in Han Chinese. Nature Communications. 2015 doi:10.1038/ncomms8270