Common risk variants in NPHS1 and TNFSF15 are associated with childhood steroid-sensitive nephrotic syndrome

The Research Consortium on Genetics of Childhood Idiopathic Nephrotic Syndrome in Japan, Korean Consortium of Hereditary Renal Diseases in Children, Midwest Pediatric Nephrology Consortium (Genetics of Nephrotic Syndrome Study Group), NEPHROVIR

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2 Scopus citations

Abstract

To understand the genetics of steroid-sensitive nephrotic syndrome (SSNS), we conducted a genome-wide association study in 987 childhood SSNS patients and 3,206 healthy controls with Japanese ancestry. Beyond known associations in the HLA-DR/DQ region, common variants in NPHS1-KIRREL2 (rs56117924, P=4.94E-20, odds ratio (OR) =1.90) and TNFSF15 (rs6478109, P=2.54E-8, OR=0.72) regions achieved genome-wide significance and were replicated in Korean, South Asian and African populations. Trans-ethnic meta-analyses including Japanese, Korean, South Asian, African, European, Hispanic and Maghrebian populations confirmed the significant associations of variants in NPHS1-KIRREL2 (Pmeta=6.71E-28, OR=1.88) and TNFSF15 (Pmeta=5.40E-11, OR=1.33) loci. Analysis of the NPHS1 risk alleles with glomerular NPHS1 mRNA expression from the same person revealed allele specific expression with significantly lower expression of the transcript derived from the risk haplotype (Wilcox test p=9.3E-4). Because rare pathogenic variants in NPHS1 cause congenital nephrotic syndrome of the Finnish type (CNSF), the present study provides further evidence that variation along the allele frequency spectrum in the same gene can cause or contribute to both a rare monogenic disease (CNSF) and a more complex, polygenic disease (SSNS).

Original languageEnglish (US)
Pages (from-to)1308-1322
Number of pages15
JournalKidney international
Volume98
Issue number5
DOIs
StatePublished - Nov 2020

Bibliographical note

Funding Information:
We thank all patients who participated in this study and their families, and Ms. Yoshimi Nozu and Ms. Ming Juan Ye for their technical assistance. We thank Minoru Nakamura, Hitoshi Okazaki, and Mika Matsuhashi for their support in functional studies. We thank J. Ludovic Croxford, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript. Summarized data of variants in the discovery GWAS are available through the Japan National Bioscience Database Center database (Research ID: hum0126.v2.imp-gwas.v1, https://humandbs.biosciencedbc.jp/en/hum0126-v2). This work was supported by: the Japan Agency for Medical Research and Development (AMED) under grant number JP17km0405108h0005 to KIi, KIs, KN, and KT, and JP17km0405205h0002 and 18km0405205h0003 to KT and MN; and by the Japan Society for the Promotion of Science (JSPS) under Grant-in-Aid for Scientific Research fostering Joint International Research (B) 18KK0244 to KIi, YH, TH, CN, and KN. Part of this study was funded by European Research Council grant ERC-2012-ADG_20120314 (grant agreement 322947) and Agence Nationale pour la Recherche ?Genetransnephrose? grant ANR-16-CE17-004-01 to PR. RG is supported by National Institutes of Health/National Institutes of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK) grants 5R01DK098135 and 5R01DK094987, the Doris Duke Charitable Foundation Clinical Scientist Development Award 2009033, and a Duke Health Scholars award. MGS is supported by a National Institutes of Health grant (R01-DK108805). The Nephrotic Syndrome Study Network Consortium (NEPTUNE; U54-DK-083912) is a part of the National Center for Advancing Translational Sciences (NCATS). The Rare Disease Clinical Research Network (RDCRN) was supported through a collaboration between the Office of Rare Diseases Research (ORDR), NCATS, and the National Institute of Diabetes, Digestive, and Kidney Diseases. The RDCRN is an initiative of the ORDR of NCATS. Additional funding and/or programmatic support for this project was provided by the University of Michigan, NephCure Kidney International, and the Halpin Foundation. The NEPHROVIR cohort was supported by 2 grants to Georges Desch?nes from the Programme Hospitalier de Recherche Clinique: grants PHRC 2007-AOM07018 and PHRC 2011-AOM11002. The NEPHROVIR network is coordinated by the Pediatric Nephrology Unit of Robert Debr? Hospital, the ?Unit? de Recherche Clinique de l'Est Parisien,? and the ?D?l?gation de la Recherche Clinique de la R?gion Ile-de-France.? Marina Vivarelli was supported by the Associazione per la Cura del bambino Nefropatico ONLUS (Organizzazione Non Lucrativa di Utilit? Sociale).

Funding Information:
This work was supported by: the Japan Agency for Medical Research and Development (AMED) under grant number JP17km0405108h0005 to KIi, KIs, KN, and KT, and JP17km0405205h0002 and 18km0405205h0003 to KT and MN; and by the Japan Society for the Promotion of Science (JSPS) under Grant-in-Aid for Scientific Research fostering Joint International Research (B) 18KK0244 to KIi, YH, TH, CN, and KN. Part of this study was funded by European Research Council grant ERC-2012-ADG_20120314 (grant agreement 322947) and Agence Nationale pour la Recherche “Genetransnephrose” grant ANR-16-CE17-004-01 to PR. RG is supported by National Institutes of Health / National Institutes of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK) grants 5R01DK098135 and 5R01DK094987 , the Doris Duke Charitable Foundation Clinical Scientist Development Award 2009033, and a Duke Health Scholars award. MGS is supported by a National Institutes of Health grant ( R01-DK108805 ). The Nephrotic Syndrome Study Network Consortium (NEPTUNE; U54-DK-083912) is a part of the National Center for Advancing Translational Sciences (NCATS). The Rare Disease Clinical Research Network (RDCRN) was supported through a collaboration between the Office of Rare Diseases Research (ORDR), NCATS, and the National Institute of Diabetes, Digestive, and Kidney Diseases. The RDCRN is an initiative of the ORDR of NCATS. Additional funding and/or programmatic support for this project was provided by the University of Michigan, NephCure Kidney International, and the Halpin Foundation. The NEPHROVIR cohort was supported by 2 grants to Georges Deschênes from the Programme Hospitalier de Recherche Clinique: grants PHRC 2007-AOM07018 and PHRC 2011-AOM11002. The NEPHROVIR network is coordinated by the Pediatric Nephrology Unit of Robert Debré Hospital, the “Unité de Recherche Clinique de l’Est Parisien,” and the “Délégation de la Recherche Clinique de la Région Ile-de-France.” Marina Vivarelli was supported by the Associazione per la Cura del bambino Nefropatico ONLUS (Organizzazione Non Lucrativa di Utilità Sociale).

Publisher Copyright:
© 2020 International Society of Nephrology

Keywords

  • glomerulus
  • nephrotic syndrome
  • pediatric nephrology
  • podocyte

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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