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Multiple rare genetic variants co-segregating with familial IgA nephropathy all act within a single immune-related network.

ABSTRACT: BACKGROUND:IgA nephropathy (IgAN) is a common complex disease with a strong genetic involvement. We aimed to identify novel, rare, highly penetrant risk variants combining family-based linkage analysis with whole-exome sequencing (WES). METHODS:Linkage analysis of 16 kindreds of South Italian ancestry was performed using an 'affected-only' strategy. Eight most informative trios composed of two familial cases and an intrafamilial control were selected for WES. High-priority variants in linked regions were identified and validated using Sanger sequencing. Custom TaqMan assays were designed and carried out in the 16 kindreds and an independent cohort of 240 IgAN patients and 113 control subjects. RESULTS:We found suggestive linkage signals in 12 loci. After sequential filtering and validation of WES data, we identified 24 private or extremely rare (MAF <0.0003) linked variants segregating with IgAN status. These were present within coding or regulatory regions of 23 genes that merged into a common functional network. The genes were interconnected by AKT, CTNNB1, NFKB, MYC and UBC, key modulators of WNT/?-catenin and PI3K/Akt pathways, which are implicated in IgAN pathogenesis. Overlaying publicly available expression data, genes/proteins with expression notably altered in IgAN were included in this immune-related network. In particular, the network included the glucocorticoid receptor gene, NR3C1, which is the target of corticosteroid therapy routinely used in the treatment of IgAN. CONCLUSION:Our findings suggest that disease susceptibility could be influenced by multiple rare variants acting in a common network that could provide the starting point for the identification of potential drug targets for personalized therapy.

SUBMITTER: Cox SN

PROVIDER: S-EPMC5297991 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Multiple rare genetic variants co-segregating with familial IgA nephropathy all act within a single immune-related network.

Cox S N SN Pesce F F El-Sayed Moustafa J S JS Sallustio F F Serino G G Kkoufou C C Giampetruzzi A A Ancona N N Falchi M M Schena F P FP

Journal of internal medicine 20161011 2

<h4>Background</h4>IgA nephropathy (IgAN) is a common complex disease with a strong genetic involvement. We aimed to identify novel, rare, highly penetrant risk variants combining family-based linkage analysis with whole-exome sequencing (WES).<h4>Methods</h4>Linkage analysis of 16 kindreds of South Italian ancestry was performed using an 'affected-only' strategy. Eight most informative trios composed of two familial cases and an intrafamilial control were selected for WES. High-priority variant ...[more]

PMID: 27730700

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Project description:IntroductionChildhood IgA nephropathy (cIgAN) is a primary glomerulonephritis clinically characterized by microscopic hematuria and proteinuria, the presence of which may potentially overlap with Alport syndrome. Interestingly, earlier studies suggested that familial IgAN could be linked to the chromosome 2q36 region, also the coding region for collagen type 4 alpha 3/4 (COL4A3/A4).MethodsTo investigate a possible relationship or phenocopy between Alport syndrome and cIgAN, COL4A3, COL4A4, and COL4A5 exons were sequenced in 36 cIgAN patients. Clinical data and treatment were collected retrospectively. COL4A3/A4/A5 variants were classified according to American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) guidelines.ResultsFour of 36 cIgAN patients were affected by ACMG class 4/5 COL4A3 heterozygous variants (COL4A3-cIgAN). We found no COL4A4 or COL4A5 variant. Despite having rare and deleterious COL4A3 variants, 3 of 4 COL4A3-cIgAN children developed clinical and biologic features of active IgAN rather than Alport syndrome. Response to intensive immunosuppressive treatment was favorable, leading to a reduction of endocapillary and extracapillary proliferation lesions. High levels of immune immunoglobulin G and A (IgG/IgA) complexes, reduction of proteinuria, and gradual stabilization of estimated glomerular filtration rate (eGFR) argued against Alport syndrome. Nevertheless, COL4A3-cIgAN patients seemed predisposed to a more serious IgAN presentation compared with the non‒COL4A3-cIgAN group, with more glomerulosclerosis and a lower eGFR over time. One of the 4 patients underwent kidney transplant with subsequent IgAN recurrence.ConclusionsPredisposition factors for developing serious cIgAN flare-up should be considered for cIgAN with COL4A3 pathologic heterozygous variants. COL4A3 variants, usually responsible for Alport syndrome in adults, should not automatically exclude an immunosuppressive regimen in cIgAN. Moreover, evidence of an ACMG class 4/5 COL4A3 variant in early-stage cIgAN could be a helpful tool for stratifying severity of cIgAN beyond the Oxford classification.

Project description:ObjectiveTo compare the genetic architecture of susceptibility variants of IgA nephropathy (IgAN) in Chinese and Europeans.MethodsWe selected the independent genome-wide significant variants of IgAN in European population as candidate variants. Their associations, risk alleles, risk allele frequencies, odds ratios and population attributable risk scores were derived and calculated, then compared with those in the current Chinese population, including 1 194 IgAN patients and 902 controls. Using the significant variants, genetic risk scores were calculated and compared between the East Asians and the Europeans. The correlation between the genetic risk scores and clinical manifestations was also evaluated.ResultsThere were 16 independent single nucleotide polymorphisms (SNPs) located in 11 loci showing significantly association with susceptibility to IgAN in the Europeans. 93.75% (15/16) of them also showed significant associations in the Chinese (P<0.05). The effects of all the associated SNPs were in the same direction, either risk or being protective for IgAN, between the Chinese and the Europeans. On the contrary, remarkable higher risk allelic odds ratio (P=1.94×10-2), higher risk allele frequency (P=3.09×10-2), and higher population attributable risk (P=3.03×10-4) were observed for most of the associated SNPs in the Chinese than in the Europeans. Furthermore, genetic risk scores were significantly larger in the Asian populations compared with the Europeans (P=1.78×10-163). While there was no significance among the subpopulations in both the East Asians and the Europeans. Compared with the healthy controls, the genetic risk score in the IgAN patients was significantly larger (P=3.60×10-27). Clinical analysis showed the genetic risk score was positively associated with serum levels of IgA and IgA1, phases of chronic kidney disease and Haas grades.ConclusionOur study provides further evidence in the shared genetic architecture between Chinese and Europeans, while differences with respect to the effect sizes and risk allele frequencies across ethnicities, contributing partially to the differences of disease prevalence.

Project description:Both IgA nephropathy (IgAN) and lupus nephritis (LN) are immunity-related diseases with a complex, polygenic, and pleiotropic genetic architecture. However, the mechanism by which the genetic variants impart immunity or renal dysfunction remains to be clarified. In this study, using gene expression datasets as a quantitative readout of peripheral blood mononuclear cell (PBMC)- and kidney-based molecular phenotypes, we analyzed the similarities and differences in the patterns of gene expression perturbations associated with the systematic and kidney immunity in IgAN and LN. Original gene expression datasets for PBMC, glomerulus, and tubule from IgAN and systemic lupus erythematosus (SLE) patients as well as corresponding controls were obtained from the Gene Expression Omnibus (GEO) database. The similarities and differences in the expression patterns were detected according to gene differential expression. Weighted gene co-expression network analysis (WGCNA) was used to cluster and screen the co-expressed gene modules. The disease correlations were then identified by cell-specific and functional enrichment analyses. By combining these results with the genotype data, we identified the differentially expressed genes causatively associated with the disease. There was a significant positive correlation with the kidney expression profile, but no significant correlation with PBMC. Three co-expression gene modules were screened by WGCNA and enrichment analysis. Among them, blue module was enriched for glomerulus and podocyte (P < 0.05) and positively correlated with both diseases (P < 0.05), mainly via immune regulatory pathways. Pink module and purple module were enriched for tubular epithelium and correlated with both diseases (P < 0.05) through predominant cell death and extracellular vesicle pathways, respectively. In genome-wide association study (GWAS) enrichment analysis, blue module was identified as the high-risk gene module that distinguishes LN from SLE and contains PSMB8 and PSMB9, the susceptibility genes for IgAN. In conclusion, IgAN and LN showed different systematic immunity but similarly abnormal immunity in kidney. Immunological pathways may be involved in the glomerulopathy and cell death together with the extracellular vesicle pathway, which may be involved in the tubular injury in both diseases. Blue module may cover the causal susceptibility gene for IgAN and LN.

Dataset Information

Multiple rare genetic variants co-segregating with familial IgA nephropathy all act within a single immune-related network.

Publications

Multiple rare genetic variants co-segregating with familial IgA nephropathy all act within a single immune-related network.

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