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

Hanna Debiec, Claire Dossier, Eric Letouzé, Christopher E Gillies, Marina Vivarelli, Rosemary K Putler, Elisabet Ars, Evelyne Jacqz-Aigrain, Valery Elie, Manuela Colucci, Stéphanie Debette, Philippe Amouyel, Siham C Elalaoui, Abdelaziz Sefiani, Valérie Dubois, Tabassome Simon, Matthias Kretzler, Jose Ballarin, Francesco Emma, Matthew G SampsonGeorges Deschênes, Pierre Ronco

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)2000-2013
Number of pages14
JournalJournal of the American Society of Nephrology : JASN
Volume29
Issue number7
DOIs
Publication statusPublished - Jul 2018

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Nephrotic Syndrome
Alleles
Steroids
Genome
Pediatrics
Genome-Wide Association Study
Single Nucleotide Polymorphism
HLA-DRB1 Chains
3' Untranslated Regions
HLA-DRB5 Chains
Meta-Analysis
Nephrosis
Quantitative Trait Loci
Age of Onset
Introns
Haplotypes
Epidemiologic Studies
Histology
Cohort Studies
Viruses

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Transethnic, Genome-Wide Analysis Reveals Immune-Related Risk Alleles and Phenotypic Correlates in Pediatric Steroid-Sensitive Nephrotic Syndrome. / Debiec, Hanna; Dossier, Claire; Letouzé, Eric; Gillies, Christopher E; Vivarelli, Marina; Putler, Rosemary K; Ars, Elisabet; Jacqz-Aigrain, Evelyne; Elie, Valery; Colucci, Manuela; Debette, Stéphanie; Amouyel, Philippe; Elalaoui, Siham C; Sefiani, Abdelaziz; Dubois, Valérie; Simon, Tabassome; Kretzler, Matthias; Ballarin, Jose; Emma, Francesco; Sampson, Matthew G; Deschênes, Georges; Ronco, Pierre.

In: Journal of the American Society of Nephrology : JASN, Vol. 29, No. 7, 07.2018, p. 2000-2013.

Research output: Contribution to journalArticle

Debiec, H, Dossier, C, Letouzé, E, Gillies, CE, Vivarelli, M, Putler, RK, Ars, E, Jacqz-Aigrain, E, Elie, V, Colucci, M, Debette, S, Amouyel, P, Elalaoui, SC, Sefiani, A, Dubois, V, Simon, T, Kretzler, M, Ballarin, J, Emma, F, Sampson, MG, Deschênes, G & Ronco, P 2018, 'Transethnic, Genome-Wide Analysis Reveals Immune-Related Risk Alleles and Phenotypic Correlates in Pediatric Steroid-Sensitive Nephrotic Syndrome', Journal of the American Society of Nephrology : JASN, vol. 29, no. 7, pp. 2000-2013. https://doi.org/10.1681/ASN.2017111185
Debiec, Hanna ; Dossier, Claire ; Letouzé, Eric ; Gillies, Christopher E ; Vivarelli, Marina ; Putler, Rosemary K ; Ars, Elisabet ; Jacqz-Aigrain, Evelyne ; Elie, Valery ; Colucci, Manuela ; Debette, Stéphanie ; Amouyel, Philippe ; Elalaoui, Siham C ; Sefiani, Abdelaziz ; Dubois, Valérie ; Simon, Tabassome ; Kretzler, Matthias ; Ballarin, Jose ; Emma, Francesco ; Sampson, Matthew G ; Deschênes, Georges ; Ronco, Pierre. / Transethnic, Genome-Wide Analysis Reveals Immune-Related Risk Alleles and Phenotypic Correlates in Pediatric Steroid-Sensitive Nephrotic Syndrome. In: Journal of the American Society of Nephrology : JASN. 2018 ; Vol. 29, No. 7. pp. 2000-2013.
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title = "Transethnic, Genome-Wide Analysis Reveals Immune-Related Risk Alleles and Phenotypic Correlates in Pediatric Steroid-Sensitive Nephrotic Syndrome",
abstract = "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.",
author = "Hanna Debiec and Claire Dossier and Eric Letouz{\'e} and Gillies, {Christopher E} and Marina Vivarelli and Putler, {Rosemary K} and Elisabet Ars and Evelyne Jacqz-Aigrain and Valery Elie and Manuela Colucci and St{\'e}phanie Debette and Philippe Amouyel and Elalaoui, {Siham C} and Abdelaziz Sefiani and Val{\'e}rie Dubois and Tabassome Simon and Matthias Kretzler and Jose Ballarin and Francesco Emma and Sampson, {Matthew G} and Georges Desch{\^e}nes and Pierre Ronco",
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doi = "10.1681/ASN.2017111185",
language = "English",
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T1 - Transethnic, Genome-Wide Analysis Reveals Immune-Related Risk Alleles and Phenotypic Correlates in Pediatric Steroid-Sensitive Nephrotic Syndrome

AU - Debiec, Hanna

AU - Dossier, Claire

AU - Letouzé, Eric

AU - Gillies, Christopher E

AU - Vivarelli, Marina

AU - Putler, Rosemary K

AU - Ars, Elisabet

AU - Jacqz-Aigrain, Evelyne

AU - Elie, Valery

AU - Colucci, Manuela

AU - Debette, Stéphanie

AU - Amouyel, Philippe

AU - Elalaoui, Siham C

AU - Sefiani, Abdelaziz

AU - Dubois, Valérie

AU - Simon, Tabassome

AU - Kretzler, Matthias

AU - Ballarin, Jose

AU - Emma, Francesco

AU - Sampson, Matthew G

AU - Deschênes, Georges

AU - Ronco, Pierre

N1 - Copyright © 2018 by the American Society of Nephrology.

PY - 2018/7

Y1 - 2018/7

N2 - 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.

AB - 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.

U2 - 10.1681/ASN.2017111185

DO - 10.1681/ASN.2017111185

M3 - Article

C2 - 29903748

VL - 29

SP - 2000

EP - 2013

JO - Journal of the American Society of Nephrology : JASN

JF - Journal of the American Society of Nephrology : JASN

SN - 1046-6673

IS - 7

ER -