Although not generally considered a hereditary disease, IgA nephropathy (IgAN) ethnic variation in prevalence and familial clustering, along with subclinical renal abnormalities among relatives of IgAN cases, have suggested an undefined genetic component. IgAN may occur in a sporadic or a familial form according to the clinical evidence that one or more subjects belonging to the same family are affected by biopsy-proven IgAN. However, the heterogeneity of IgAN phenotype is more consistent with the combined effects of variation at multiple interacting genes and the environment. We propose to investigate genetic factors possibly involved in the development of IgAN. We utilized two main strategies in order to select genes. The first is candidate gene approach by function: we evaluated C1GALT1, C1GALT1C1, FCAR, TFRC, ST6GALNAC2, TLR4. The second approach was to analyze candidate genes in genomic regions demonstrated to be in linkage with familiar cases of IgAN (chr 4q26-31 and 17q12-22). Public databases were queried to obtain the available gene maps for 4q26-31 and 17q12-22 chromosomal linked regions and the information on the expression pattern of these genes in tissue and organs. There were 99 and 522 genes in the two regions, respectively. We have carefully analyzed the known genes one by one and evaluated their activities. If these genes seem to have a relevance in the pathogenesis of the disease, then these are to be considered candidates. We evaluated TRPC3, IL21, CFI, ENPEP, NPNT located on chr 4q26-31 and CCL2, CCL3, CCL5, CCL7, CCR7, CD300LG, HNF1B, TBX21, B4GALNT2, GRN, ITGA3, ITGB3, ITGA2B located on chr 17q12-22. Within these genes, we carefully selected 192 single nucleotide polymorphisms (SNPs). SNPs are individual variations in genome sequence; they are organized into DNA blocks called haplotypes, and these haplotype blocks are inherited without recombination over many generations. Tag and functional SNPs have been chosen to further narrow the linked chromosomal regions. We are analyzing the 192 selected SNPs with the Illumina Veracode technology, a multiplex recent testing method based on digitally encoded microbeads. We collected 443 DNA samples of Italian patients affected by IgAN and 470 DNA samples of Italian healthy individuals as controls in order to perform a case-control association study. Allele, genotype and haplotype frequencies could then be compared to assess the potential role of each gene and SNPs in the pathogenesis of IgAN. The logistic univariate and multivariate analysis could allow the evaluation of the development risk of the disease and the improvement of new strategies in order to reduce disease risk factors.
Role of genetic polymorphisms in the pathogenesis of IgAN
BERTINETTO, FRANCESCA;GARINO, Elena;MATULLO, Giuseppe;AMOROSO, Antonio
2009-01-01
Abstract
Although not generally considered a hereditary disease, IgA nephropathy (IgAN) ethnic variation in prevalence and familial clustering, along with subclinical renal abnormalities among relatives of IgAN cases, have suggested an undefined genetic component. IgAN may occur in a sporadic or a familial form according to the clinical evidence that one or more subjects belonging to the same family are affected by biopsy-proven IgAN. However, the heterogeneity of IgAN phenotype is more consistent with the combined effects of variation at multiple interacting genes and the environment. We propose to investigate genetic factors possibly involved in the development of IgAN. We utilized two main strategies in order to select genes. The first is candidate gene approach by function: we evaluated C1GALT1, C1GALT1C1, FCAR, TFRC, ST6GALNAC2, TLR4. The second approach was to analyze candidate genes in genomic regions demonstrated to be in linkage with familiar cases of IgAN (chr 4q26-31 and 17q12-22). Public databases were queried to obtain the available gene maps for 4q26-31 and 17q12-22 chromosomal linked regions and the information on the expression pattern of these genes in tissue and organs. There were 99 and 522 genes in the two regions, respectively. We have carefully analyzed the known genes one by one and evaluated their activities. If these genes seem to have a relevance in the pathogenesis of the disease, then these are to be considered candidates. We evaluated TRPC3, IL21, CFI, ENPEP, NPNT located on chr 4q26-31 and CCL2, CCL3, CCL5, CCL7, CCR7, CD300LG, HNF1B, TBX21, B4GALNT2, GRN, ITGA3, ITGB3, ITGA2B located on chr 17q12-22. Within these genes, we carefully selected 192 single nucleotide polymorphisms (SNPs). SNPs are individual variations in genome sequence; they are organized into DNA blocks called haplotypes, and these haplotype blocks are inherited without recombination over many generations. Tag and functional SNPs have been chosen to further narrow the linked chromosomal regions. We are analyzing the 192 selected SNPs with the Illumina Veracode technology, a multiplex recent testing method based on digitally encoded microbeads. We collected 443 DNA samples of Italian patients affected by IgAN and 470 DNA samples of Italian healthy individuals as controls in order to perform a case-control association study. Allele, genotype and haplotype frequencies could then be compared to assess the potential role of each gene and SNPs in the pathogenesis of IgAN. The logistic univariate and multivariate analysis could allow the evaluation of the development risk of the disease and the improvement of new strategies in order to reduce disease risk factors.
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