IgA nephropathy (IgAN) is the most relevant for of glomerulonephritis in Europe. It occurs in early adulthood and leads to end stage renal disease in more than 25%of patients after 10 years from the onset of the disease. Thus, considering that young adults need periodic dialysis treatment that is very expensive, IgAN is a socio-economic problem for European countries. This disease is often a symptomatic in family members of IgAN patients. This project is devoted to develop a genomic DNA bank of IgAN patients and family members (WP1) for the identification of potential susceptibility chromosomal region (s) -conferring genotype to familial IgAN (WP2) and then for the identification of genetic marker (s) which individualize susceptibility-conferring genotype to the disease (WP3). The identified gene(s) will be used by the SME, involved in the project, for the development of the DNA kit for the diagnosis of familial IgAN (WP4).
A group of European scientists, specialists IgA Nephropathy (IgAN), constituted the IgAN Consortium:
1) and organized the first Biobank in the world through the recruitment of DNA samples from IgAN patients and family members following a common protocol;
2) DNA samples from 70 IgAN families, 63 IgAN suspected families, 158 trios, 1011 IgAN patients, and 1040 healthy subjects were collected from different European geographic areas. A web-site (www.igan.net) was organized to collect and share personal, genetic data and clinical findings of all subjects enrolled in the study taking care of subject's privacy. A section containing general information about the disease and project achievements was developed for public vision. Convenient and statistically productive genetic studies were performed. In the first stage, genome wide analysis supported linkage with the new chromosomal regions: 4q22.1-31.21, 7q33-36.3, 10p14, 10q26.11, 12q24.21, 17q21.32 and 21q21.1;
3) In the second stage genome scan study, additional markers for the areas of interest were analyzed in linked families. Studies are currently under way in order to restrict the linked regions. Our data provide suggestive evidence of genetic heterogeneity in familial IgAN. 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;
4) This is the first and largest to date family-based study which suggests an important role of IFN gamma in the development of the disease. No association was found with MBL2 gene polymorphisms;
5) Allelic and genotypic frequencies of MBL2 gene polymorphisms at position -550, -328, -221 and at codon 54 did not show any difference between patients and controls. A similar frequency distribution of these polymorphisms was also found in the subgroups of IgAN patients subdivided according to the clinical manifestations and the progression of the disease. 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 found in the study;
6) A genetic analysis of single nucleotide polymorphisms within the PDGF-B gene evidenced no association with development and progression of IgAN;
7) Direct sequencing of C1GALT1 gave us the possibility to identify, for the first time, two new SNPs -796T and -784G/T, whose submission is in progress;
8) A case-control association study was performed to investigate the role of C1GALT1 in the pathogenesis of IgAN;
9) The genotype 1365G/G was associated with development but not with the IgAN 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.
Funding SchemeCSC - Cost-sharing contracts
71013 San Giovanni Rotondo