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

被引：50

作者：

Debiec, Hanna ^{[1
]}

Dossier, Claire ^{[2
]}

Letouze, Eric ^{[4
,5
,6
,7
]}

Gillies, Christopher E. ^{[8
]}

Vivarelli, Marina ^{[9
]}

Putler, Rosemary K. ^{[8
]}

Ars, Elisabet ^{[10
]}

Jacqz-Aigrain, Evelyne ^{[3
]}

Elie, Valery ^{[3
]}

Colucci, Manuela ^{[9
]}

Debette, Stephanie ^{[11
]}

Amouyel, Philippe ^{[12
]}

Elalaoui, Siham C. ^{[13
]}

Sefiani, Abdelaziz ^{[14
]}

Dubois, Valerie ^{[15
]}

Simon, Tabassome ^{[16
,17
]}

Kretzler, Matthias ^{[18
]}

Ballarin, Jose ^{[19
]}

Emma, Francesco ^{[9
]}

Sampson, Matthew G. ^{[8
]}

Deschenes, Georges ^{[2
,20
]}

Ronco, Pierre ^{[1
,21
]}

机构：

[1] Sorbonne Univ, UPMC Paris 06, INSERM, Unite Mixte Rech S1155, Paris, France

[2] Hop Robert Debre, Dept Paediat Nephrol, Paris, France

[3] Hop Robert Debre, CIC1426, Pediat Pharmacol & Pharmacogenet, Paris, France

[4] INSERM, Unite Mixte Rech 1162, Genom Fonct Tumeurs Solides, Equipe Labellisee Ligue Canc, Paris, France

[5] Univ Paris 05, Labex Immunooncol, Sorbonne Paris Cite, Paris, France

[6] Univ Paris 13, Sorbonne Paris Cite, Unite Format & Rech Sante, Med,Biol,Humaine,Bobigny, Bobigny, France

[7] Univ Paris Diderot, Inst Univ Hematol, Paris, France

[8] Univ Michigan, Sch Med, Pediat Nephrol, Ann Arbor, MI USA

[9] Osped Pediat Bambino Gesu, Nephrol & Dialysis Dept, Ist Ricovero & Cura Carattere Sci, Rome, Italy

[10] Univ Autonoma Barcelona, Inst Invest Biomed St Pau, Fundacio Puigvert, Mol Biol Lab, Barcelona, Spain

[11] Univ Bordeaux, INSERM, Bordeaux Populat Hlth Res Ctr, CHU Bordeaux,Unite Mixte Rech 1219, Bordeaux, France

[12] Univ Lille, INSERM, CHU Lille, Inst Pasteur Lille,RID AGE,U1167, Lille, France

[13] Inst Natl Hyg, Dept Med Genet, Rabat, Morocco

[14] Univ Mohamed V Rabat, Human Genom Ctr, Fac Med & Pharm Rabat, Rabat, Morocco

[15] Etab Francais Sang Rhone Alpes, Lyon, France

[16] Hop St Antoine, AP HP, Dept Clin Pharmacol, Unite Rech Clin, Paris, France

[17] INSERM, Unite Mixte Rech S1148, Paris, France

[18] Univ Michigan, Dept Internal Med & Computat Med & Bioinformat, Ann Arbor, MI 48109 USA

[19] Fdn Puigvert, Dept Nephrol, Barcelona, Spain

[20] Univ Sorbonne Paris Cite, INSERM, U1149, Unite Format & Rech Med Xavier Bichat, Paris, France

[21] Tenon Hosp, AP HP, Nephrol & Dialysis Dept, Paris, France

来源：

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY | 2018年 / 29卷 / 07期

基金：

欧洲研究理事会; 美国国家卫生研究院;

关键词：

SUSCEPTIBILITY LOCI; ASSOCIATION; ONSET; HLA-DQA1; METAANALYSIS; NEPHROPATHY; PODOCYTES; VARIANTS; CHILDREN; DISEASE;

D O I：

10.1681/ASN.2017111185

中图分类号：

R5 [内科学]; R69 [泌尿科学（泌尿生殖系疾病）];

学科分类号：

1002 ; 100201 ;

摘要：

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-9.3x10(-23)). Conditional analysis identified two additional independent risk alleles upstream of HLA-DRB1 (rs28366266, P=3.7x10(-11)) and in the 3' untranslated region of BTNL2 (rs9348883, P=9.4x10(-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.

引用

页码：2000 / 2013

页数：14

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