Research paperNovel genes and variants associated with IgA nephropathy by co-segregating with the disease phenotypes in 10 IgAN families
Introduction
IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis worldwide. Approximately 20% to 30% of individuals with IgAN develop end-stage renal disease (ESRD) within 10 to 20 years following initial diagnosis (Bisceglia et al., 2006, Le et al., 2012, Wyatt and Julian, 2013). Despite varying clinical presentations, IgAN is diagnosed by immunohistochemical analysis on renal biopsies and is characterized by predominant mesangial IgA deposition. The etiology of IgAN remains unclear. Genetic contribution to the etiology is implicated by the presence of large extended IgAN families and familial aggregation of IgAN. Evidence for a genetic component is further revealed by genome-wide association studies and candidate association studies (Klein et al., 2005, Feehally et al., 2010, Kiryluk et al., 2010, Kiryluk et al., 2014, Gharavi et al., 2011, Yu et al., 2012, Xie et al., 2013). Intriguingly, the prevalence of IgAN varies greatly among different ethnicities, being higher in Asians (especially among Chinese and Japanese) but lower in Africans (Hall et al., 2004, Kiryluk et al., 2010, Kiryluk et al., 2012).
IgAN families are enriched in genetic components predisposing individuals to IgAN. Next-generation sequencing has been proven to be an effective way to interrogate the whole exome or the whole genome to identify genes and gene variants that underlie both monogenic and complex diseases. We performed exome sequencing on individuals from 10 families with IgAN (9 families were unrelated) and identified 6 variations in 4 genes that co-segregated with the IgAN disease phenotype. These variants are good candidates for the genes causing IgAN.
Section snippets
Study subjects
Ten families with at least two members that had IgAN as demonstrated by a biopsy, were recruited from the Queen Mary Hospital, University of Hong Kong (Fig. 1). A total of 20 IgAN subjects were included in this cohort. Detailed clinical and laboratory investigations were performed on each of the family members available for the study. IgAN was diagnosed following the WHO criteria on renal biopsy, with the exclusion of systemic lupus erythematosis, Henoch–Schonlein purpura and hepatic diseases
Ten IgAN families were recruited
Ten families comprising 20 patients with IgAN and a total of 34 unaffected family members were included in this study. Each family had two patients with IgAN confirmed by biopsy following the WHO standards (Maisonneuve et al., 2000, Li et al., 2004, Wyatt and Julian, 2013). Eighteen IgAN patients and 11 unaffected family members were available for the study (Fig. 1). Clinical data for the IgAN patients are shown in Supplementary Table 2. We followed up with the unaffected family members for a
Discussion
We examined 7 genetic variants of 5 genes in ten IgAN families using exome sequencing, bioinformatics tools, genotype–phenotype co-segregation analysis and haplotype construction. We reported 6 deleterious variants in 4 genes, which co-segregated with the IgAN disease phenotype in the study families. The MYCT1, CARD8 and ZNF543 genes were novel. We also confirmed an association between one of the DEFA cluster genes, DEFA4, with IgAN (Yu et al., 2012, Kiryluk et al., 2014, Xu et al., 2014) and
Conflict of interest statement
None to declare.
Acknowledgments
The project is supported by the National Natural Science Foundation of China (31271342, 31471193), China Medical Board in New York (050827), the Doctoral Program of the Ministry of Education (20110171110047), Basic Research Funds of the Key Universities (10ykjc07), and Doctoral grant of the Ministry of Education (50000-3191016).
References (30)
- et al.
Genetic heterogeneity in Italian families with IgA nephropathy: suggestive linkage for two novel IgA nephropathy loci
Am. J. Hum. Genet.
(2006) - et al.
CARDINAL, a novel caspase recruitment domain protein, is an inhibitor of multiple NF-kappa B activation pathways
J. Biol. Chem.
(2001) - et al.
Proto-oncogene expression in peripheral blood mononuclear cells in IgA nephropathy
Kidney Int.
(1991) - et al.
Regulation of progenitor cell fusion by ABCB5 P-glycoprotein, a novel human ATP-binding cassette transporter
J. Biol. Chem.
(2003) - et al.
Distribution of primary renal diseases leading to end-stage renal failure in the United States, Europe, and Australia/New Zealand: results from an international comparative study
Am. J. Kidney Dis.
(2000) - et al.
Severity of tubulointerstitial inflammation and prognosis in immunoglobulin A nephropathy
Kidney Int.
(2007) - et al.
Role of differential and cell type-specific expression of cell cycle regulatory proteins in mediating progressive glomerular injury in human IgA nephropathy
Lab. Investig.
(2004) - et al.
CARD-8 protein, a new CARD family member that regulates caspase-1 activation and apoptosis
J. Biol. Chem.
(2002) - et al.
HLA has strongest association with IgA nephropathy in genome-wide analysis
J. Am. Soc. Nephrol.
(2010) - et al.
Genome-wide association study identifies susceptibility loci for IgA nephropathy
Nat. Genet.
(2011)
Interleukin-1 cluster gene polymorphisms in childhood IgA nephropathy
Pediatr. Nephrol.
Race/ethnicity and disease severity in IgA nephropathy
BMC Nephrol.
Genetic studies of IgA nephropathy: past, present, and future
Pediatr. Nephrol.
Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis
PLoS Genet.
Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens
Nat. Genet.
Cited by (14)
MYCT1 in cancer development: Gene structure, regulation, and biological implications for diagnosis and treatment
2023, Biomedicine and PharmacotherapyBiomarkers and Precision Medicine in IgA Nephropathy
2018, Seminars in NephrologyCitation Excerpt :Nevertheless, this approach has the difficult task of pinpointing a causal variant from an enormous number of identified rare variants. A few studies have described a low number of rare variants.70,71 The failure to identify a single rare variant suggests that IgAN is caused by a panel of variants involved in one or more pathways with a cumulative effect.
Genetic Determinants of IgA Nephropathy: Western Perspective
2018, Seminars in NephrologyCitation Excerpt :When combined with linkage analysis, WES represents a powerful tool for the detection of novel causal variants that segregate in families. To date, WES has been performed in several Chinese and Italian pedigrees with familial IgAN,61,62 but these results have not been conclusive because the findings do not meet the accepted criteria for genetic causality.63 Nevertheless, WES and WGS are ideally suited to study families with pre-existing linkage data, holding promise to ultimately elucidate causal genes for familial IgAN.
Gain-of-function variants in NLRP1 protect against the development of diabetic kidney disease: NLRP1 inflammasome role in metabolic stress sensing?
2018, Clinical ImmunologyCitation Excerpt :In humans, gain-of-function mutations in NLRP3 and pyrin/MEFV are cause of rare autoinflammatory syndromes often with kidney complications [5]. Moreover polymorphisms in NLRP3 and CARD8 have been recently associated with pediatric renal infections [6] and IgA nephropathy, respectively [7]. In previous studies, our group reported the genetic association of NLRP3 with T1D [8], and of NLRP1 [9] and IL1B [10] with systemic lupus erythematosus (SLE).
An Update on the Genetics of IgA Nephropathy
2024, Journal of Clinical MedicineA Novel Mutation of UMOD in a Chinese Family with IgA Nephropathy: A Case Report
2023, Case Reports in Nephrology and Dialysis
- 1
These authors contributed equally to this work.