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Development of a genomic dna bank of iga nephropathy (igan) patients and family members. new trends in genetics for the early diagnosis of familial igan

Exploitable results

Immunoglobulin A Nephropathy (IgAN), also known as Berger's Disease, is the most frequent primary glomerulonephritis worldwide and one of the leading cause of end-stage kidney disease (ESKD) requiring dialysis or transplantation. It occurs in early adulthood in sporadic or familial form. The onset is characterized by gross hematuria concomitant with upper respiratory tract infections or persistent microscopic hematuria, usually with a normal renal function associated or not with proteinuria. Such insidious clinical onset has to be supported by a renal biopsy showing a specific histological pattern. A slow progression (10-20 years) toward ESKD is the common course. This project aimed to develop a DNA bio-bank of IgAN patients and family members in order to identify potential genetic markers contributing to the onset and progression of this complex disease. The IgAN Consortium, gathering the leading European scientists in the field, was set up. So far, DNA samples from more than 70 IgAN families, 240 trios, 1300 IgAN patients and 2400 healthy controls have been collected throughout Europe in the first organized bio-bank in the world. A related website (www.igan.net) is available to share demographic, genetic and clinical data within the Consortium and it also contains open sections with general information about the disease and project achievements with published papers. The investigators found that familial IgAN has an increased risk of ESKD and a linkage-based approach to study this form has identified significant loci on chromosomes 6q22-23, 4q26-31 and 17q12-22. Studies are currently under way in order to restrict the linked regions. Familial and case-control association studies with candidate gene polymorphisms have been performed obtaining interesting results. A family based association study evidenced an association of IgAN with 13-CA repeat intron 1 IFN gamma allele while no association was found with MBL2 gene polymorphisms. No difference in the ACE I/D and AGT M235T gene polymorphisms distribution between IgAN patients and controls and between patients with stable and those with deteriorating renal function was shown. A genetic analysis of single nucleotide polymorphisms (SNPs) within the PDGF-B gene evidenced no association with development and progression of IgAN while it has been shown that IgAN patients exhibit high systemic level of PDGF-DD. The haplotype -116C/-51G of the podocin NPHS2 promoter was found more frequent in IgAN patients than in controls. A case-control association study was performed to investigate the role of galactosyltransferase core-1 beta3-galactosyltransferase-1 (C1GalT1) in the pathogenesis of IgAN. The genotype 1365G/G was associated with the onset but not with the progression. Moreover, a reduced expression of C1GalT1 in homozygous subjects for 1365 G/G genotype was observed. The results of this study suggest that C1GalT1 plays a possible role as a pathogenetic factor for IgAN. Direct sequencing of C1GalT1 enabled us to identify, for the first time, two new SNPs -796T and -784G/T. No evidence for its chaperon 'cosmc' has been found. Microarray analysis carried out on peripheral blood leukocytes and renal tissue samples is ongoing. Differences in gene expression between IgAN patients and healthy controls as well as in the same patients during gross hematuria episodes and microhematuria will be highlighted. A study of the regulatory microRNA of IgAN patients has also been undertaken. The robust piece of evidence provided by this project has not only contributed to define the genetic and genomic aspect of this glomerulonephritis but also prompted future directions. A genome-wide association scan, as the next step to cover the genetic spectrum of such complex disease, would benefit from a systems biology approach in order to maximize the impact of the large amount of data generated by the applied high-throughput technology.

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