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

Abstract

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 ( alpha =0.50) and 2.56 ( alpha =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.

Genome-wide scan identifies a copy number variable region at 3p21.1 that influences the TLR9 expression levels in IgA nephropathy patients

“…We found 48 markers from PBAT that intersected 43 CNVs indentified by MSA within a distance of 500 kb (Supplementary Table 3). In particular, we confirmed again the involvement of the region on chromosome 17q12-22 identified in our GWLS 8 Table 4). Moreover, we performed a CNV analysis using the PennCNV model 27 and found 36 regions that overlap with the aberrations identified by MSA within a distance of 600 kb (Supplementary Table 4).…”

“…Many LGWS and GWAS in both familial and sporadic IgAN suggest that there is a strong genetic component in the disease. [7][8][9][10][11][12] However, most studies have not evaluated the contribution to this complex disorder of other forms of genetic variation, such as structural variations, mainly in the form of CNVs. 15 Indeed, CNVs have recently been shown to have an important role in complex disease phenotypes as psoriasis, 30 rheumatoid arthritis 31 and systemic lupus erythematosus.…”

“…?)dup, containing ankyrinrepeat and fibronectin type III domain gene, overlapped with the region found in linkage in our previous GWLS. 8 We also performed the CNV analysis in a family-based setting using the PBAT algorithm. 23 Only significant markers with a P-value o0.05 in familial IgAN patients were further considered for the analysis; these were annotated and matched with CNVs identified with MSA.…”

“…Three GWLS of familial IgAN have reported linkages at 2q36, 4q26-31, 6q22-23 and 17q12-22, but no disease genes were identified within these areas. [7][8][9] Three GWAS that allows hypothesis-free examination have been performed for IgAN, leading to the identification of susceptibility alleles in the major histocompatibility complex (MHC) region on chromosome 6p [10][11][12] and additional loci on chromosomes 1q32, 22q12, 17p13 and 8p23. So far, no genetic variants or genes underlying these loci have been identified as causative or affecting the pathology, plausibly because of the presence of genetic/environmental and locus heterogeneity and to contribution from noncoding susceptibility alleles such as point mutations or structural genomic variants within intronic or promoter regions.…”

A SPRY2 mutation leading to MAPK/ERK pathway inhibition is associated with an autosomal dominant form of IgA nephropathy

“…Association studies identified distinct loci on chromosomes 6p21, 8p23, 17p13, 22q12, 1q32. 6,7 On the other hand, classical linkage studies performed on AD families identified additional loci on chromosomes 2q36, 4q26-31, 6q22, 17q12-22, [8][9][10] lending further support to the complex etiology and broad genetic heterogeneity of the disease.…”