scholarly journals An updated view of the pathogenesis of steroid-sensitive nephrotic syndrome

2022 ◽  
Author(s):  
Tomoko Horinouchi ◽  
Kandai Nozu ◽  
Kazumoto Iijima
Keyword(s):  
Nephrotic Syndrome ◽  
Genome Wide Association Study ◽  
Human Leukocyte ◽  
Leukocyte Antigen ◽  
Genome Wide ◽  
A Genome ◽  
Immunological Mechanisms ◽  
Steroid Sensitive Nephrotic Syndrome ◽  
Steroid Sensitive ◽  
Genetic Techniques

Abstract Idiopathic nephrotic syndrome is the most common childhood glomerular disease. Most forms of this syndrome respond to corticosteroids at standard doses and are, therefore, defined as steroid-sensitive nephrotic syndrome (SSNS). Immunological mechanisms and subsequent podocyte disorders play a pivotal role in SSNS and have been studied for years; however, the precise pathogenesis remains unclear. With recent advances in genetic techniques, an exhaustive hypothesis-free approach called a genome-wide association study (GWAS) has been conducted in various populations. GWASs in pediatric SSNS peaked in the human leukocyte antigen class II region in various populations. Additionally, an association of immune-related CALHM6/FAM26F, PARM1, BTNL2, and TNFSF15 genes, as well as NPHS1, which encodes nephrin expressed in podocytes, has been identified as a locus that achieves genome-wide significance in pediatric SSNS. However, the specific mechanism of SSNS development requires elucidation. This review describes an updated view of SSNS pathogenesis from immunological and genetic aspects, including interactions with infections or allergies, production of circulating factors, and an autoantibody hypothesis.

scholarly journals Strong Association of the HLA-DR/DQ Locus with Childhood Steroid-Sensitive Nephrotic Syndrome in the Japanese Population

2018 ◽  
Vol 29 (8) ◽  
pp. 2189-2199 ◽  
Author(s):  
Xiaoyuan Jia ◽  
Tomoko Horinouchi ◽  
Yuki Hitomi ◽  
Akemi Shono ◽  
Seik-Soon Khor ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Japanese Population ◽  
Molecular Mechanisms ◽  
Genome Wide Association Study ◽  
Minor Allele ◽  
Healthy Controls ◽  
Hla Dr ◽  
A Genome ◽  
Steroid Sensitive Nephrotic Syndrome ◽  
Steroid Sensitive

Background Nephrotic syndrome is the most common cause of chronic glomerular disease in children. Most of these patients develop steroid-sensitive nephrotic syndrome (SSNS), but the loci conferring susceptibility to childhood SSNS are mainly unknown.Methods We conducted a genome-wide association study (GWAS) in the Japanese population; 224 patients with childhood SSNS and 419 adult healthy controls were genotyped using the Affymetrix Japonica Array in the discovery stage. Imputation for six HLA genes (HLA-A, -C, -B, -DRB1, -DQB1, and -DPB1) was conducted on the basis of Japanese-specific references. We performed genotyping for HLA-DRB1/-DQB1 using a sequence-specific oligonucleotide-probing method on a Luminex platform. Whole-genome imputation was conducted using a phased reference panel of 2049 healthy Japanese individuals. Replication was performed in an independent Japanese sample set including 216 patients and 719 healthy controls. We genotyped candidate single-nucleotide polymorphisms using the DigiTag2 assay.Results The most significant association was detected in the HLA-DR/DQ region and replicated (rs4642516 [minor allele G], combined Pallelic=7.84×10−23; odds ratio [OR], 0.33; 95% confidence interval [95% CI], 0.26 to 0.41; rs3134996 [minor allele A], combined Pallelic=1.72×10−25; OR, 0.29; 95% CI, 0.23 to 0.37). HLA-DRB1*08:02 (Pc=1.82×10−9; OR, 2.62; 95% CI, 1.94 to 3.54) and HLA-DQB1*06:04 (Pc=2.09×10−12; OR, 0.10; 95% CI, 0.05 to 0.21) were considered primary HLA alleles associated with childhood SSNS. HLA-DRB1*08:02-DQB1*03:02 (Pc=7.01×10−11; OR, 3.60; 95% CI, 2.46 to 5.29) was identified as the most significant genetic susceptibility factor.Conclusions The most significant association with childhood SSNS was detected in the HLA-DR/DQ region. Further HLA allele/haplotype analyses should enhance our understanding of molecular mechanisms underlying SSNS.

Human leukocyte antigen association with familial steroid-sensitive nephrotic syndrome

2020 ◽  
Vol 179 (9) ◽  
pp. 1481-1486 ◽  
Author(s):  
Trine Korsgaard ◽  
Shivani Joshi ◽  
Rene F. Andersen ◽  
Kristina Moeller ◽  
Tomás Seeman ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Human Leukocyte Antigen ◽  
Human Leukocyte ◽  
Leukocyte Antigen ◽  
Steroid Sensitive Nephrotic Syndrome ◽  
Steroid Sensitive

scholarly journals Neolithic genomes reveal a distinct ancient HLA allele pool and population transformation in Europe

2019 ◽  
Author(s):  
Alexander Immel ◽  
Christoph Rinne ◽  
John Meadows ◽  
Rodrigo Barquera ◽  
András Szolek ◽  
...  
Keyword(s):  
Western Europe ◽  
Viral Infections ◽  
Human Leukocyte ◽  
Neolithic Period ◽  
Late Neolithic ◽  
Leukocyte Antigen ◽  
Cultural Transformations ◽  
Farming Community ◽  
Genome Wide ◽  
A Genome

AbstractThe Wartberg culture (WBC, 3,500-2,800 BCE) dates to the Late Neolithic period, a time of important demographic and cultural transformations in western Europe. We perform a genome-wide analysis of 42 individuals who were interred in a WBC collective burial in Niedertiefenbach, Germany (3,300-3,200 cal. BCE). Our results highlight that the Niedertiefenbach population indeed emerged at the beginning of the WBC. This farming community was genetically heterogeneous and carried a surprisingly large hunter-gatherer ancestry component (40%). We detect considerable differences in the human leukocyte antigen gene pool between contemporary Europeans and the Niedertiefenbach individuals whose immune response was primarily geared towards defending viral infections.

scholarly journals Genetic Identification of Two Novel Loci Associated with Steroid-Sensitive Nephrotic Syndrome

2019 ◽  
Vol 30 (8) ◽  
pp. 1375-1384 ◽  
Author(s):  
Stephanie Dufek ◽  
Chris Cheshire ◽  
Adam P. Levine ◽  
Richard S. Trompeter ◽  
Naomi Issler ◽  
...  
Keyword(s):  
Immune Response ◽  
Nephrotic Syndrome ◽  
Genetic Identification ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Hla Association ◽  
Genome Wide ◽  
Steroid Sensitive Nephrotic Syndrome ◽  
Steroid Sensitive ◽  
Genome Wide Significance

BackgroundSteroid-sensitive nephrotic syndrome (SSNS), the most common form of nephrotic syndrome in childhood, is considered an autoimmune disease with an established classic HLA association. However, the precise etiology of the disease is unclear. In other autoimmune diseases, the identification of loci outside the classic HLA region by genome-wide association studies (GWAS) has provided critical insights into disease pathogenesis. Previously conducted GWAS of SSNS have not identified non-HLA loci achieving genome-wide significance.MethodsIn an attempt to identify additional loci associated with SSNS, we conducted a GWAS of a large cohort of European ancestry comprising 422 ethnically homogeneous pediatric patients and 5642 ethnically matched controls.ResultsThe GWAS found three loci that achieved genome-wide significance, which explain approximately 14% of the genetic risk for SSNS. It confirmed the previously reported association with the HLA-DR/DQ region (lead single-nucleotide polymorphism [SNP] rs9273542, P=1.59×10−43; odds ratio [OR], 3.39; 95% confidence interval [95% CI], 2.86 to 4.03) and identified two additional loci outside the HLA region on chromosomes 4q13.3 and 6q22.1. The latter contains the calcium homeostasis modulator family member 6 gene CALHM6 (previously called FAM26F). CALHM6 is implicated in immune response modulation; the lead SNP (rs2637678, P=1.27×10−17; OR, 0.51; 95% CI, 0.44 to 0.60) exhibits strong expression quantitative trait loci effects, the risk allele being associated with lower lymphocytic expression of CALHM6.ConclusionsBecause CALHM6 is implicated in regulating the immune response to infection, this may provide an explanation for the typical triggering of SSNS onset by infections. Our results suggest that a genetically conferred risk of immune dysregulation may be a key component in the pathogenesis of SSNS.

scholarly journals Association Between Human Leukocyte Antigen Class I and II Diversity and Non-virus-associated Solid Tumors

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhiwei Liu ◽  
Allan Hildesheim
Keyword(s):  
Human Leukocyte Antigen ◽  
Solid Tumors ◽  
Genome Wide Association Study ◽  
Disease Risk ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Class I ◽  
European Ancestry ◽  
Leukocyte Antigen ◽  
Genome Wide

Homozygosity at human leukocyte antigen (HLA) loci might lead to reduced immunosurveillance and increased disease risk, including cancers caused by infection or of hematopoietic origin. To investigate the association between HLA zygosity and risk of non-virus-associated solid tumors, we leveraged genome-wide association study (GWAS) data from over 28,000 individuals of European ancestry who participated in studies of 12 cancer sites (bladder, brain, breast, colon, endometrial, kidney, lung, ovary, pancreas, prostate, skin, and testis). Information on HLA zygosity was obtained by imputation; individuals were classified as homozygotes at a given locus when imputed to carry the same four-digit allele at that locus. We observed no evidence for an association between zygosity at six HLA loci and all cancers combined. Increase in number of homozygous at HLA class I loci, class II loci, or class I and II loci was also not associated with cancer overall (Ptrend = 0.28), with adjusted odds ratios (ORs) for risk-per-locus of 1.00 [95% confidence intervals (CIs) = 0.97, 1.03], 1.02 (0.99, 1.04), and 1.01 (0.99, 1.02), respectively. This study does not support a strong role for HLA zygosity on risk of non-virus-associated solid tumors.

scholarly journals Transethnic, Genome-Wide Analysis Reveals Immune-Related Risk Alleles and Phenotypic Correlates in Pediatric Steroid-Sensitive Nephrotic Syndrome

2018 ◽  
Vol 29 (7) ◽  
pp. 2000-2013 ◽  
Author(s):  
Hanna Debiec ◽  
Claire Dossier ◽  
Eric Letouzé ◽  
Christopher E. Gillies ◽  
Marina Vivarelli ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Untranslated Region ◽  
Meta Analysis ◽  
Conditional Analysis ◽  
Risk Haplotype ◽  
Genome Wide Association Studies ◽  
Risk Alleles ◽  
Genome Wide ◽  
Steroid Sensitive Nephrotic Syndrome ◽  
Steroid Sensitive

Background Steroid-sensitive nephrotic syndrome (SSNS) is a childhood disease with unclear pathophysiology and genetic architecture. We investigated the genomic basis of SSNS in children recruited in Europe and the biopsy-based North American NEPTUNE cohort.Methods We performed three ancestry-matched, genome-wide association studies (GWAS) in 273 children with NS (Children Cohort Nephrosis and Virus [NEPHROVIR] cohort: 132 European, 56 African, and 85 Maghrebian) followed by independent replication in 112 European children, transethnic meta-analysis, and conditional analysis. GWAS alleles were used to perform glomerular cis-expression quantitative trait loci studies in 39 children in the NEPTUNE cohort and epidemiologic studies in GWAS and NEPTUNE (97 children) cohorts.Results Transethnic meta-analysis identified one SSNS-associated single-nucleotide polymorphism (SNP) rs1063348 in the 3′ untranslated region of HLA-DQB1 (P=9.3×10−23). Conditional analysis identified two additional independent risk alleles upstream of HLA-DRB1 (rs28366266, P=3.7×10−11) and in the 3′ untranslated region of BTNL2 (rs9348883, P=9.4×10−7) within introns of HCG23 and LOC101929163. These three risk alleles were independent of the risk haplotype DRB1*07:01-DQA1*02:01-DQB1*02:02 identified in European patients. Increased burden of risk alleles across independent loci was associated with higher odds of SSNS. Increased burden of risk alleles across independent loci was associated with higher odds of SSNS, with younger age of onset across all cohorts, and with increased odds of complete remission across histologies in NEPTUNE children. rs1063348 associated with decreased glomerular expression of HLA-DRB1, HLA-DRB5, and HLA-DQB1.Conclusions Transethnic GWAS empowered discovery of three independent risk SNPs for pediatric SSNS. Characterization of these SNPs provide an entry for understanding immune dysregulation in NS and introducing a genomically defined classification.

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