Search

Chronic kidney disease (CKD) is a syndrome characterized by a gradual loss of kidney function with decreased estimated glomerular filtration rate (eGFR), which may be accompanied by an increase in the urine albumin-to-creatinine ratio (UACR). Although trans-ethnic genome-wide association studies (GWASs) have been conducted for kidney-related traits, there have been few analyses in the Japanese population, especially for the UACR trait. In this study, we conducted a GWAS to identify loci related to multiple kidney-related traits in Japanese individuals. First, to detect loci associated with CKD, eGFR, and UACR, we performed separate GWASs with the following two datasets: 475 cases of CKD diagnosed at seven university hospitals and 3471 healthy subjects (dataset 1) and 3664 cases of CKD-suspected individuals with eGFR <60 ml/min/1.73 m 2 or urinary protein ≥ 1+ and 5952 healthy subjects (dataset 2). Second, we performed a meta-analysis between these two datasets and detected the following associated loci: 10 loci for CKD, 9 loci for eGFR, and 22 loci for UACR. Among the loci detected, 22 have never been reported previously. Half of the significant loci for CKD were shared with those for eGFR, whereas most of the loci associated with UACR were different from those associated with CKD or eGFR. The GWAS of the Japanese population identified novel genetic components that were not previously detected. The results also suggest that the group primarily characterized by increased UACR possessed genetically different features from the group characterized by decreased eGFR., (© 2022. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis in many parts of the world. Although previous genome-wide association studies (GWAS) identified the major susceptibility loci for IgAN, the causal genes currently remain unknown. We performed a GWAS using 23 465 microsatellite (MS) markers to identify genes related to IgAN in a Japanese population. A pooled sample analysis was conducted in three-stage screenings of three independent case-control populations, and after the final step of individual typing, 11 markers survived. Of these, we focused on two regions on 6p21 and 12q21 because they (i) showed the strongest relationship with IgAN, and (ii) appeared to be highly relevant to IgAN in view of several previous studies. These regions contained the HLA, TSPAN8 and PTPRR genes. This study on GWAS, using >20 000 MS markers, provides a new approach regarding susceptible genes for IgAN for investigators seeking new tools for the prevention and treatment of IgAN.

Immunoglobulin A (IgA) nephropathy is the most common form of primary glomerulonephritis worldwide. The pathogenesis of IgA nephropathy is unknown, but it is certain that some genetic factors are involved in susceptibility to the disease. Employing a large-scale, case-control association study using gene-based single-nucleotide polymorphism (SNP) markers, we previously reported four candidate genes. We report here an additional significant association between IgA nephropathy and an SNP located in the gene encoding immunoglobulin micro-binding protein 2 (IGHMBP2) at chromosome 11q13.2-q13.4. The association (chi2 =17.1, p = 0.00003; odds ratio of 1.85 with 95% confidence interval of 1.39-2.50 in a dominant association model) was found using DNA from 465 affected individuals and 634 controls. The SNP (G34448A) caused an amino acid substitution from glutamine to lysine (E928K). As the gene product is involved in immunoglobulin-class switching and patients with the A allele revealed higher serum levels of IgA (p = 0.048), the amino acid change might influence a class switch to increase serum IgA levels, resulting in a higher risk of IgA nephropathy.

Immunoglobulin A nephropathy (IgAN) is a primary glomerulonephritis of common incidence world-wide whose etiology and pathogenesis remain unresolved, although genetic factors are assumed to be involved in the development and progression of this disease. To identify genetic variations that might confer susceptibility to IgAN, we performed a case-control association study involving 389 Japanese IgAN patients and 465 controls. Genome-wide analysis of approximately 80,000 single-nucleotide polymorphisms (SNPs) identified a significant association between IgAN and six SNPs located in the PIGR (polymeric immuoglobulin receptor) gene at chromosome 1q31-q41. One of them, PIGR-17, caused an amino-acid substitution from alanine to valine at codon 580 (chi(2)=13.05, P=0.0003, odds ratio [OR] =1.59, 95% confidence interval [95% CI] =1.24-2.05); the OR of minor homozygotes to others was 2.71 (95% CI=1.31-5.61). Another SNP, PIGR-2, could affect promoter activity (chi(2)=11.95, P=0.00055, OR=1.60, 95% CI=1.22-2.08); the OR of minor homozygotes to others was 2.08 (95% CI=0.94-4.60). Pairwise analyses demonstrated that all six SNPs were in almost complete linkage disequilibrium. Biopsy specimens from IgAN patients were positively stained by antibody against the secretory component of PIGR, but corresponding tissues from non-IgAN patients were not. Our results suggest that a gene associated with susceptibility to IgAN lies within or close to the PIGR gene locus on chromosome 1q in the Japanese population.

The molecular mechanisms of immunoglobulin A glomerulonephritis (IgAN), the most prevalent form of primary glomerulonephritis, remain poorly understood. Recently, the essential role of soluble Fc alpha receptor (FcalphaR) in the formation of the pathogenic immune complex has been revealed. We screened genomic DNA samples from patients with IgAN and those with other glomerular diseases for polymorphisms in the promoter and the 5'-untranslated region region of the FcalphaR gene by direct nucleotide sequencing. We found three common polymorphisms in this region, T-114C, T-27C, and T+56C from the putative transcription initiation site. Each genotype was determined in 151 patients with IgAN and 163 patients with other glomerular diseases shown to have no mesangial IgA deposition by renal biopsy. The haplotype analysis revealed tight linkage disequilibrium among them. An association study for the genotype, allele, and haplotype frequencies of the polymorphisms between the patients with histologically proven IgAN and those with other glomerular diseases showed no significant difference in the genotype, allele, and haplotype distributions between the two groups. The present study indicates that the analyzed polymorphisms of the FcalphaR gene do not appear to be primarily involved in the susceptibility to IgAN.