In this study, we propose to perform the first genome-wide association study (GWAS) for Immunoglobulin A Nephropathy (IgAN, OMIM %161950), an understudied disease that is a major cause of kidney failure in the U.S. and worldwide. It is the most common cause of kidney failure among Asian populations, and the most common form of primary glomerulonephritis among young Caucasians. Similar to many immune mediated disorders, IgAN is a genetically complex trait and genetic basis for disease is not known. To perform a GWAS, we have assembled the largest international case/control cohort of IgAN. This study population consists of a Chinese cohort recruited from Beijing and Shanghai ( >2,000 biopsy-documented cases of IgAN and >2,000 healthy controls) and a Caucasian/European cohort recruited the North America and Europe (>2000 biopsydocumented cases and 2000 controls), with the recruitment ongoing at four study sites. Critically, all the samples for these studies are in hand. Initial genotyping of 551 cases and 441 controls from Beijing, China (Illumina 610quad chip). Analyses of the data demonstrated absence of significant stratification (?=1.005) and revealed genome-wide significant association of IgAN with the HLA-DQA2 locus (p=9x10-8). In addition, In addition, this modest-sized cohort revealed several suggestive associations on chromosomes 7q31 (p=7x10-6), 15q13 (p=8x10-6), 4q21 (p=2x10-5), and 3q26.2 (p=3x10-5), highlighting novel candidate genes for disease. In this project, we propose to complete the genotyping of the Beijing cohort (total of 1200 IgAN cases/1200 controls) to identify common variants with modest to large effects on disease. We will next replicate these findings in independent cohorts from Shanghai (750 cases/750 controls) and Caucasians from North America/Europe (2000 cases/2000 controls). These studies will provide insight into the pathogenesis of IgAN, providing novel opportunities for development of diagnostic and therapeutic tools for this major cause of kidney failure.
Immunoglobulin A Nephropathy (IgAN, OMIM %161950), an understudied disease that is a major cause of kidney failure in the U.S. and worldwide. These genetic studies will provide insight into the pathogenesis of IgAN, providing novel opportunities for development of diagnostic and therapeutic tools for this major cause of kidney failure.
|Kiryluk, Krzysztof; Li, Yifu; Sanna-Cherchi, Simone et al. (2012) Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis. PLoS Genet 8:e1002765|
|Gharavi, Ali G; Kiryluk, Krzysztof; Choi, Murim et al. (2011) Genome-wide association study identifies susceptibility loci for IgA nephropathy. Nat Genet 43:321-7|