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Genetic Heterogeneity in Italian Families with IgA Nephropathy: Suggestive Linkage for Two Novel IgA Nephropathy Loci

2006; Elsevier BV; Volume: 79; Issue: 6 Linguagem: Inglês

10.1086/510135

1537-6605

Luigi Bisceglia, Giuseppina Cerullo, Paola Forabosco, Diletta Domenica Torres, Francesco Scolari, Michele Di Perna, Marina Foramitti, Antonio Amoroso, Sara Bertok, Jürgen Floege, Peter R. Mertens, Klaus Zerres, Efstathios Alexopoulos, Dimitrios Kirmizis, Ermelinda Mazzucco, Leopoldo Zelante, Francesco Paolo Schena,

Systemic Lupus Erythematosus Research

IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide, but its etiologic mechanisms are still poorly understood. Different prevalences among ethnic groups and familial aggregation, together with an increased familial risk, suggest important genetic influences on its pathogenesis. A locus for familial IgAN, called “IGAN1,” on chromosome 6q22-23 has been described, without the identification of any responsible gene. The partners of the European IgAN Consortium organized a second genomewide scan in 22 new informative Italian multiplex families. A total of 186 subjects (59 affected and 127 unaffected) were genotyped and were included in a two-stage genomewide linkage analysis. The regions 4q26-31 and 17q12-22 exhibited the strongest evidence of linkage by nonparametric analysis (best P=.0025 and .0045, respectively). These localizations were also supported by multipoint parametric analysis, in which peak LOD scores of 1.83 (α=0.50) and 2.56 (α=0.65) were obtained using the affected-only dominant model, and by allowance for the presence of genetic heterogeneity. Our results provide further evidence for genetic heterogeneity among families with IgAN. Evidence of linkage to multiple chromosomal regions is consistent with both an oligo/polygenic and a multiple-susceptibility-gene model for familial IgAN, with small or moderate effects in determining the pathological phenotype. Although we identified new candidate regions, replication studies are required to confirm the genetic contribution to familial IgAN. IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide, but its etiologic mechanisms are still poorly understood. Different prevalences among ethnic groups and familial aggregation, together with an increased familial risk, suggest important genetic influences on its pathogenesis. A locus for familial IgAN, called “IGAN1,” on chromosome 6q22-23 has been described, without the identification of any responsible gene. The partners of the European IgAN Consortium organized a second genomewide scan in 22 new informative Italian multiplex families. A total of 186 subjects (59 affected and 127 unaffected) were genotyped and were included in a two-stage genomewide linkage analysis. The regions 4q26-31 and 17q12-22 exhibited the strongest evidence of linkage by nonparametric analysis (best P=.0025 and .0045, respectively). These localizations were also supported by multipoint parametric analysis, in which peak LOD scores of 1.83 (α=0.50) and 2.56 (α=0.65) were obtained using the affected-only dominant model, and by allowance for the presence of genetic heterogeneity. Our results provide further evidence for genetic heterogeneity among families with IgAN. Evidence of linkage to multiple chromosomal regions is consistent with both an oligo/polygenic and a multiple-susceptibility-gene model for familial IgAN, with small or moderate effects in determining the pathological phenotype. Although we identified new candidate regions, replication studies are required to confirm the genetic contribution to familial IgAN. IgA nephropathy (IgAN [MIM 161950]) is the most common form of primary glomerulonephritis worldwide. The diagnosis is based on the occurrence of mesangial IgA deposits in the glomeruli in the presence of recurrent episodes of intrainfectious macroscopic hematuria or persistent microscopic hematuria and/or proteinuria. Abnormal deglycosylated IgA1 synthesis, selective mesangial IgA1 deposition with ensuing mesangial cell proliferation, and extracellular matrix expansion lead to renal fibrosis, with molecular mechanisms still poorly understood. Approximately 20%–50% of patients older than 30 years develop end-stage renal disease within 20 years after the onset of the disease.1Schena FP Coppo R IgA nephropathies.in: Davison AM Cameron JS Grünfeld JP Ponticelli C Ritz E Winearls CG van T Persele C Oxford textbook of clinical nephrology. 3rd ed. Oxford University Press, Oxford2005: 469-501Google Scholar IgAN may occur in a sporadic or familial form. Familial IgAN was first described in two families with HLA-identical brothers.2Tolkoff-Rubin NE Cosimi AB Fuller T Rublin RH Colvin RB IgA nephropathy in HLA-identical siblings.Transplantation. 1978; 26: 430-433Crossref PubMed Scopus (87) Google Scholar, 3Sabatier JC Ducret F Colon S Genin C Berthoux FC Intercapillary glomerulonephritis with IgA deposits in 2 HLA identical brothers.J Urol Nephrol Paris. 1978; 84: 672-675PubMed Google Scholar After these reports were published, nuclear families with IgAN were reported worldwide.4Levy M Multiplex families in IgA nephropathy.Contrib Nephrol. 1993; 104: 46-53Crossref PubMed Google Scholar, 5Li PK Burns AP So AK Lai KN Rees AJ Familial IgA nephropathy: a study of HLA class II allogenotypes in a Chinese kindred.Am J Kidney Dis. 1992; 20: 458-462Abstract Full Text PDF PubMed Google Scholar, 6Scolari F Amoroso A Savoldi S Familial clustering of IgA nephropathy: further evidence in an Italian population.Am J Kidney Dis. 1999; 33: 857-865Abstract Full Text Full Text PDF PubMed Google Scholar, 7Kabasakal C Keskinoglu A Mir S Basdemir G IgA nephropathy occurring in two siblings of three families.Turk J Pediatr. 1997; 39: 395-401PubMed Google Scholar The familial clustering and the striking ethnic variation in prevalence are suggestive of an important genetic component in the pathogenesis of the disease. IgAN does not exhibit basic Mendelian segregation patterns, although an increased risk of the disease was observed in close relatives of the probands.8Schena FP Cerullo G Rossini M Lanzilotta SG D’Altri C Manno C Increased risk of end-stage renal disease in familial IgA nephropathy.J Am Soc Nephrol. 2002; 13: 453-460Crossref PubMed Google Scholar In an attempt to identify genes that underlie this disease, an initial genomewide scan was performed with 30 multiplex families with IgAN, of which 24 were from Italy. This study identified the IGAN1 locus on 6q22-23, in linkage with IgAN. It yielded a significant LOD score of 5.6 in 60% of the linked families, with the assumption of an autosomal dominant mode of inheritance with incomplete penetrance.9Gharavi AG Yan Y Scolari F Schena FP Frasca GM Ghiggeri GM Cooper K Amoroso A Viola BF Battini G Caridi G Canova C Farhi A Subramanian V Nelson-Williams C Woodford S Julian BA Wyatt RJ Lifton RP IgA nephropathy, the most common cause of glomerulonephritis, is linked to 6q22-23.Nat Genet. 2000; 26: 354-357Crossref PubMed Scopus (270) Google Scholar Since that first study, the partners of the European IgAN Consortium have recruited new informative families to better elucidate the genetic determination of the disease.10Schena FP Cerullo G Torres DD Scolari F Foramitti M Amoroso A Pirrulli D Floege J Mertens PR Zerres K Alexopoulos E Kirmizis D Zelante L Bisceglia L Ghiggeri GM Frasca GM European IgA Nephropathy Consortium The IgA Nephropathy Biobank: an important starting point for the genetic dissection of a complex trait.BMC Nephrol. 2005; 6: 14Crossref PubMed Scopus (0) Google Scholar The current study is a second-generation genomewide scan to search for regions involved in IgAN susceptibility, performed in a completely independent subset of 22 Italian multiplex families with IgAN. Recruitment strategies and criteria for diagnosis have been reported elsewhere and are freely available on the European IgAN Consortium Web site.10Schena FP Cerullo G Torres DD Scolari F Foramitti M Amoroso A Pirrulli D Floege J Mertens PR Zerres K Alexopoulos E Kirmizis D Zelante L Bisceglia L Ghiggeri GM Frasca GM European IgA Nephropathy Consortium The IgA Nephropathy Biobank: an important starting point for the genetic dissection of a complex trait.BMC Nephrol. 2005; 6: 14Crossref PubMed Scopus (0) Google Scholar Written informed consent was obtained from all participating patients and relatives before they entered the study. They were interviewed, and all personal and relevant clinical and laboratory data were recorded and stored in the IgAN Consortium database. At the time of the interview, a blood sample was collected for DNA extraction, and a urinalysis was performed for all family members. Recurrent episodes of macroscopic hematuria were considered an indication for kidney biopsy. After urinalysis, relatives with microscopic hematuria and negative results of urine culture underwent Addis count with contrast phase microscopy and renal ultrasonography and were checked systematically once a year. Individuals with secondary forms of IgAN (systemic lupus erythematosus [MIM 152700], mixed cryoglobulinemia [MIM 123550], and chronic hepatitis) were excluded. Familial IgAN was diagnosed when at least two family members had biopsy-proven IgAN. The study plan was approved by the local ethics committees. This study included 59 affected (37 male and 22 female) and 127 unaffected (52 male and 75 female) subjects. The unaffected subjects were probands’ first-, second-, and third-degree relatives aged >18 years. The number of patients affected with IgAN ranged from two to four subjects in each family. Macrohematuria, microhematuria, and renal insufficiency at onset were present in 18, 19, and 6 patients with IgAN, respectively. No documentation was available for the others. Mean (±SD) age at renal biopsy was 29.6 ± 13 years, serum creatinine level was 1.15 ± 0.5 mg/dl, daily proteinuria was 1.1 ± 1.2 g, and creatinine clearance was 93.3 ± 30 ml/min. These clinical characteristics were available for 48 patients with IgAN and were missing for 11. All renal biopsy specimens were classified, according to Lee’s classification, as “mild” (grade 1–2, n=14), “moderate” (grade 3, n=11), or “severe” (grade 4–5, n=7) histologic lesions. These findings were missing for 16 patients because diagnosis of IgAN was made in other hospitals using a different histological classification, and the biopsy samples were no longer available for review. Hypertension was present in 15 (31%) of the patients. The mean duration of follow-up was 12 ± 8.5 years, and 16 patients (33.3%) reached end-stage kidney disease. DNA was extracted from whole-blood samples with the use of commercial kits (Genomix [Talent] and Blood and Cells Culture Midi DNA kit [Qiagen]). A two-stage genomewide scan was performed. In the first stage, 382 highly polymorphic markers along the 22 autosomal chromosomes, at ∼10 cM density, were typed in a subset of 16 informative families; interesting regions were subsequently investigated in the whole sample of 22 families. The pedigrees of the families analyzed can be visualized in the Registry–Clinical Finding Search Page of the European IgAN Consortium Web site. Microsatellite markers included in the ABI PRISM Linkage Mapping Set v2.5-MD10 were analyzed using the ABI Prism 3100 capillary electrophoresis apparatus (Applied Biosystems). GeneScan 3.7 and Genotyper 3.7 NT software were used for genotyping. Additional microsatellite markers, available in the Marshfield genetic map and the University of California–Santa Cruz (UCSC) draft of the human genome, were genotyped to increase the resolution of the genetic map in the fine mapping of the identified candidate regions. The inheritance of each marker in all pedigrees was tested by PedCheck for inconsistencies due to null alleles, mistyping, nonpaternity, or other errors, and repeat genotyping was performed as necessary.11O’Connell JR Weeks DE PedCheck: a program for identification of genotype incompatibilities in linkage analysis.Am J Hum Genet. 1998; 63: 259-266Abstract Full Text Full Text PDF PubMed Scopus (1822) Google Scholar All marker alleles were considered to have equal frequency. Maximum-likelihood–based (LOD score) methods of linkage analysis were used, with the assumption of an autosomal dominant mode of inheritance, with disease-allele frequency of 0.001 and estimated penetrance of 75%. The phenocopy rate was set at 0.01. Multipoint NPL (NPLall statistic), parametric LOD score, and heterogeneity LOD score (HLOD) were calculated using Genehunter12Kruglyak L Daly MJ Reeve-Daly MP Lander ES Parametric and nonparametric linkage analysis: a unified multipoint approach.Am J Hum Genet. 1996; 58: 1347-1363PubMed Google Scholar in the first stage of the analysis and Simwalk213Sobel E Lange K Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker sharing statistics.Am J Hum Genet. 1996; 58: 1323-1337PubMed Google Scholar in the second, since some of the families included in the second stage were too large to be analyzed with the exact method implemented in Genehunter. The proportion of families linked (α) was allowed to vary until the HLOD was maximized. Recent studies demonstrate that, although the estimated value of α is problematic when this method is used, the HLOD score remains a powerful method for detection of linkage in the presence of heterogeneity.14Greenberg DA Abreu PC Determining trait locus position from multipoint analysis: accuracy and power of three different statistics.Genet Epidemiol. 2001; 21: 299-314Crossref PubMed Scopus (58) Google Scholar, 15Hodge SE Vieland VJ Greenberg DA HLODs remain powerful tools for detection of linkage in the presence of genetic heterogeneity.Am J Hum Genet. 2002; 70: 556-559Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Parametric LOD scores were also evaluated using an affected-only strategy—that is, by assuming all unaffected individuals as phenotypically unknown, since they may not provide reliable information on the underlying disease-locus genotype for a complex disease. First of all, we tested whether the families with IgAN were linked to the previous locus IGAN1 on 6q22-23. We analyzed the markers D6S287, D6S1702, D6S1690, D6S1705, D6S1040, and D6S262, which span a 9.5-cM region overlapping the locus IGAN1. Multipoint parametric analysis yielded in the region maximum HLOD scores of 0.42 (α=0.20) and 1.05 (α=0.45) for the affected-only approach, whereas multipoint nonparametric analysis yielded P=.01. The overall results obtained from the first-stage genomewide scan are represented in figure 1 and table 1. Four loci yielding multipoint HLOD ⩾1 and NPL P≤.05 were identified. The region 4q22.1-31.2 yielded maximum HLOD 1.19 (α=0.35) and nonparametric LOD 1.68 (P=.0445). The multipoint curves identified a 56-cM interval bounded by markers D4S2964 and D4S424. The region 7q33-36.3, spanning 43 cM between D7S640 and D7S2465, yielded maximum HLOD 1.19 (α=0.25) and nonparametric LOD 1.73 (P=.0388). The 38-cM region 10p13-15.3, bounded by D10S249 and D10S1653, yielded maximum HLOD 1.39 (α=0.15) and nonparametric LOD 2.34 (P=.0093). The region 17q11.2-23.3 yielded maximum HLOD 1.00 (α=0.40) and nonparametric LOD 2.63 (P=.0040). The multipoint curves identified a 39-cM interval bounded by D17S1857 and D17S944. Other loci showing only multipoint HLOD ⩾1 or NPL P≤.05 were not further investigated. In particular, the 44-cM region 2q24.3-35, between D2S2330 and D2S2382, yielded HLOD 1.13 (α=0.20); the 37-cM region 8q21.3-24.21, between D8S270 and D8S284, yielded NPL 1.8 (P=.0319); the 41-cM region 10q23.33-26.2, between D10S185 and D10S217, yielded HLOD 1.08 (α=0.44); the 53-cM region 12q23.3-24.33, between D12S78 and D12S1723, yielded nonparametric LOD 1.97 (P=.0286); and the 42-cM region 15q13.2-22.3, between D15S165 and D15S153, yielded nonparametric LOD 1.71 (P=.0412). The analysis of the four regions identified in stage I was then extended to six other new collected families with IgAN. In the final sample of 22 families, only chromosomes 4 and 17 provided HLOD scores >1 and P values <.05 for the multipoint NPLall statistic of Simwalk2 (table 2). In particular, the NPL P value of .0059 and the HLOD of 3.80 were obtained at D17S1868 when an affected-only approach was used. The highest evidence in the chromosome 4 region was reached at D4S402, with an NPL P value of .0454 and an HLOD of 1.05 (α=0.45). These chromosomal regions were considered a high priority for fine-mapping analysis.Table 1First-Stage Genomewide Scan Results Obtained by Analyzing 16 Multiplex Families with IgAN: Most-Relevant Regions Identified by Parametric Linkage and NPL AnalysesLinkage Analysis ResultsCandidate IntervalMarkerDistance from p-ter (cM)Chromosome LocationHLODaData were obtained by assuming an autosomal dominant model of inheritance with incomplete penetrance (75%). (α)Nonparametric LOD (P)ChromosomalMarker (Distance)D4S4021244q26…1.68 (.0445)4q22.1-31.2…D4S15751324q281.19 (.35)……D4S2964–D4S424 (56 cM)D7S6611557q34…1.73 (.0388)7q33-36.3…D7S7981687q36.31.19 (.25)……D7S640–D7S2465 (43 cM)D10S16534010p131.39 (.15)…10p13-15.3…D10S1891910p14…2.34 (.0093)…D10S249–D10S1653 (38 cM)D17S7985317q11.21.00 (.40)…17q11.2-23.3…D17S18686417q21.32…2.63 (.0040)…D17S1857–D17S944 (39 cM)D2S3252042q33.31.13 (.20)…2q24.3-35D2S2330–D2S2382 (44 cM)D8S17841068q22.3…1.8 (.0319)8q21.3-24.21D8S6270–D8S284 (37 cM)D10S169313710q26.111.08 (.44)…10q23.33-26.2D10S185–D10S217 (41 cM)D12S7912512q24.21…1.97 (.0286)12q23.3-24.33D12S78–D12S1723 (53 cM)D15S1175115q21.3…1.71 (.0412)15q13.2-22.3D15S165–D15S153 (42 cM)a Data were obtained by assuming an autosomal dominant model of inheritance with incomplete penetrance (75%). Open table in a new tab Table 2Results from Parametric Linkage and NPL Analyses Performed in 22 Families with IgAN in the Regions Identified in Stage IChromosomeMarker IntervalRegion Span (cM)Peak MarkerHLODaHLOD scores were calculated by assuming the dominant model, described in the text, and by using an affected-only approach. (α)NPL P4D4S2964–D4S42491.3–147.4D4S4021.05 (.45).04547D7S640–D7S2465146.9–191.1D7S7981.02 (.40)NSbNS = not significant.10D10S249–D10S1653.0–40.1…<1NSbNS = not significant.17D17S798–D17S94445.0–90.0D17S18683.80 (1.0).0059a HLOD scores were calculated by assuming the dominant model, described in the text, and by using an affected-only approach.b NS = not significant. Open table in a new tab Fifteen additional markers were genotyped between D4S1572 and D4S424 (∼36 cM), with a final average spacing of ∼2 cM between markers; five additional markers were genotyped between D17S798 and D17S944 (∼30 cM), with a final average spacing of ∼3.7 cM. The strongest evidence, shown in table 3, was observed on 17q12-22, where HLOD 2.56 (α=0.65) was obtained at D17S944 with use of the affected-only model, and the peak NPL P value of .0045 was observed at D17S943, located ∼12 cM from D17S944. NPL P values <.05 were observed in the whole 30-cM region. The analysis of the region 4q26-31 yielded the maximum HLOD 1.83 (α=0.50) and NPL P=.0025 at D4S2965; NPL P values <.05 were obtained in an ∼32-cM region spanning from D4S1513 to D4S424 (table 3). The pedigrees of the larger families with genotypes and reconstructed haplotypes are represented in figure 2.Table 3Results from the Fine-Mapping Analysis of the Regions 4q26-31 and 17q12-22, with Parametric Linkage and NPL AnalysesPeak MarkerRegionRegion Span (cM)HLODaHLOD scores were calculated by assuming the dominant model, described in the text, and by using an affected-only approach. (α)NPL PD4S29654q26-31117.0–147.01.83 (.50).0025D17S94317q12-2257.0–90.0….0045D17S94417q12-2257.0–90.02.56 (.65)…a HLOD scores were calculated by assuming the dominant model, described in the text, and by using an affected-only approach. Open table in a new tab Our data show that, besides IGAN1, the existence of at least two other loci candidates contain causative and/or susceptibility genes for familial IgAN. Although the families in our data set were similar from a clinical and demographic point of view, these results and those obtained for locus IGAN1 strongly pointed to genetic heterogeneity in familial IgAN. The evidence of IgAN linked to multiple chromosomal regions is consistent with both an oligo/polygenic and a multiple-susceptibility-gene model for familial IgAN, all having a small or moderate effect in determining the pathological phenotype, as observed in complex diseases. Despite the success of linkage studies in defining regions of the genome containing important disease loci, the process is slow, and it is difficult to convert this information into genes and responsible DNA variants. The gene(s) associated with onset and/or progression of IgAN lying in the IGAN1 locus has not yet been identified. A genomewide scan in a novel murine model identified a susceptibility locus on chromosome 10 in a region syntenic to human IGAN1.16Suzuki H Suzuki Y Yamanaka T Hirose S Nishimura H Toei J Horikoshi S Tomino Y Genome-wide scan in a novel IgA nephropathy model identifies a susceptibility locus on murine chromosome 10, in a region syntenic to human IGAN1 on chromosome 6q22-23.J Am Soc Nephrol. 2005; 16: 1289-1299Crossref PubMed Scopus (68) Google Scholar However, this animal model does not fully resemble human IgAN, since hematuria is completely absent, and there are fundamental differences between the human and murine IgA system. The association of IGAN1 with mesangioproliferative glomerular injury with IgA deposition emerges from this study. Our overall linkage analysis also suggests to search for the critical genes among the 199 and 347 genes mapped in the regions 4q26-31 and 17q12-22, respectively. We carefully analyzed these genes and identified the following potential candidate genes of major interest located in 4q26-31: transient receptor potential channel 3 (TRPC3 [MIM 602345]), interleukin-2 (IL-2 [MIM 147680]), and interleukin-21 (IL-21 [MIM 605384]), which could be largely involved in the unbalanced T-helper 1/T-helper 2 immune response observed in patients with IgAN.17Lim CS Zheng S Kim YS Ahn C Han JS Kim S Lee JS Chae DW Koo JR Chun RW Noh JW Th1/Th2 predominance and proinflammatory cytokines determine the clinicopathological severity of IgA nephropathy.Nephrol Dial Transplant. 2001; 16: 269-275Crossref PubMed Google Scholar, 18Ebihara I Hirayama K Yamamoto S Muro K Yamagata K Koyama A Th2 predominance at the single-cell level in patients with IgA nephropathy.Nephrol Dial Transplant. 2001; 16: 1783-1789Crossref PubMed Scopus (35) Google Scholar, 19Schena FP Cerullo G Torres DD Scolari F Foramitti M Amoroso A Pirulli D Floege J Mertens PR Zerres K Alexopoulos E Kirmizis D Zelante L Bisceglia L Role of interferon-gamma gene polymorphisms in susceptibility to IgA nephropathy: a family-based association study.Eur J Hum Genet. 2006; 14: 488-496Crossref PubMed Scopus (0) Google Scholar These genes should be investigated, to assess their role in the pathogenesis of IgAN. Moreover, a recently published paper has evidenced an altered gene-expression pattern in leukocytes of patients with IgAN, through an Affimetrix GeneChip microarray experiment.20Preston GA Waga I Alcorta DA Sasai H Munger WE Sullivan P Phillips B Jennette JC Falk RJ Gene expression profiles of circulating leukocytes correlate with renal disease activity in IgA nephropathy.Kidney Int. 2004; 65: 420-430Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar Among the genes with increased expression, we identified some candidate genes mapped in 17q12-22 and 6q22-23. The histone deacetylase 5 (HD5 [MIM 605315]) and granulin (GRN [MIM 138945]) genes on 17q12-22 could be involved in immune-response deregulation. The serine/threonine protein kinase (SGK [MIM 602958]) gene, localized on chromosome 6q23, could induce extracellular matrix expansion, which leads to renal fibrosis. The vanin 3 (VNN3 [MIM 606592]) gene, localized on 6q23, could be implicated in abnormal deglycosylated IgA1 synthesis, which represents another important pathogenic factor for IgAN.21Novak J Tomana M Matousovic K Brown R Hall S Novak L Julian BA Wyatt RJ Mestecky J IgA1-containing immune complexes in IgA nephropathy differentially affect proliferation of mesangial cells.Kidney Int. 2005; 67: 504-513Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar Our data suggest that newly found loci trigger or participate in familial IgAN and that gene-gene and gene-environment interactions may play an important role in the development of this disease. Although we identified new candidate regions, replication studies are required to confirm the genetic contribution in familial IgAN. It is common to describe IgAN as a single disease, but the present limited understanding of the etiology and pathogenesis of IgAN does not yet provide evidence for such a view. Mesangial IgA deposition and subsequent injury may eventually turn out to represent a final common pathway of the glomerular response to a wide range of causative and pathogenic processes. The major task in dissecting this complex disorder is not only to shed light on its pathogenesis but also to provide potential targets for treatment, screening, and prevention and to increase the understanding of why some patients do not respond to currently available treatments whereas others do. We are grateful to the patients and relatives for their cooperation in this study. We thank Mariella Mastrolonardo for her editorial assistance. This project was supported by grants from the 5th European Framework Programme (QLG1-CT-2000-00464), the Ministero dell’Istruzione, Università e Ricerca (PRIN 2001-067748 and FIRB 2001-RBNE013JYM), the Ministero della Salute (RC2006), and Centro di Eccellenza Genomica in Campo Biomedico ed Agrario. The European IgAN Consortium partners thank the Italian renal units that contributed to the diagnosis of IgAN in families and the collection of DNA samples: Pediatric Nephrology, Perugia Hospital (S. Maffei); Nephrology and Dialysis Unit, Bambino Gesù Children's Research Hospital, Roma (F. Emma); Renal Unit, University of Foggia (L. Gesualdo); Renal Unit, Martina Franca (A. L. Marangi); Renal Unit, Santa Maria degli Angeli Hospital, Putignano (M. Giannattasio); Renal Unit, Ospedale Riuniti, Ancona, (G. M. Frascà); and Laboratory on Pathophysiology of Uremia, G. Gaslini Children's Hospital, Genova (G. M. Ghiggeri).