Academic Journal
Novel immune-related susceptibility loci associated with pediatric steroid-sensitive nephrotic syndrome identified by a transethnic genome-wide association study.
| Τίτλος: | Novel immune-related susceptibility loci associated with pediatric steroid-sensitive nephrotic syndrome identified by a transethnic genome-wide association study. |
|---|---|
| Συγγραφείς: | Yang X; Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents' Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key laboratory of Pediatric Metabolism and inflammatory Diseases, Chongqing, China., Tian Z; College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China., Chen X; Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents' Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key laboratory of Pediatric Metabolism and inflammatory Diseases, Chongqing, China., Shao J; Guangzhou National Laboratory, Guangzhou, Guangdong, China., Wang L; Department of Nephrology, Chengdu Women and Children Central Hospital, Chengdu, Sichuan, China., Ni F; Department of Nephrology, Shenzhen Children's Hospital, Shenzhen, Guangdong, China., Liang R; Department of Pediatrics, The University of Hong Kong - Shenzhen Hospital, Shenzhen, Guangdong, China., Zhao B; Department of Nephrology, Kunming Children's Hospital, Kunming Medical University, Kunming, Yunnan, China., Feng S; Department of Nephrology, Chengdu Women and Children Central Hospital, Chengdu, Sichuan, China., Gao X; Department of Nephrology, Shenzhen Children's Hospital, Shenzhen, Guangdong, China., Cui J; Department of Nephrology, Kunming Children's Hospital, Kunming Medical University, Kunming, Yunnan, China., Yang X; Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents' Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key laboratory of Pediatric Metabolism and inflammatory Diseases, Chongqing, China., Chen X; Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents' Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key laboratory of Pediatric Metabolism and inflammatory Diseases, Chongqing, China., Li X; Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents' Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key laboratory of Pediatric Metabolism and inflammatory Diseases, Chongqing, China., Yang B; Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents' Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key laboratory of Pediatric Metabolism and inflammatory Diseases, Chongqing, China., Wan J; Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents' Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key laboratory of Pediatric Metabolism and inflammatory Diseases, Chongqing, China., Jiao J; Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents' Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key laboratory of Pediatric Metabolism and inflammatory Diseases, Chongqing, China., Wang A; Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents' Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key laboratory of Pediatric Metabolism and inflammatory Diseases, Chongqing, China., Yang Q; Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents' Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key laboratory of Pediatric Metabolism and inflammatory Diseases, Chongqing, China., Yang X; Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents' Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key laboratory of Pediatric Metabolism and inflammatory Diseases, Chongqing, China., Wu D; Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents' Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key laboratory of Pediatric Metabolism and inflammatory Diseases, Chongqing, China., Zhang G; Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents' Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key laboratory of Pediatric Metabolism and inflammatory Diseases, Chongqing, China., Wang M; Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents' Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key laboratory of Pediatric Metabolism and inflammatory Diseases, Chongqing, China., Zhou K; Guangzhou National Laboratory, Guangzhou, Guangdong, China.; School of Public Health, Guangzhou Medical University, Guangzhou, Guangdong, China., Chan H; Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents' Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key laboratory of Pediatric Metabolism and inflammatory Diseases, Chongqing, China., Yang H; Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents' Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key laboratory of Pediatric Metabolism and inflammatory Diseases, Chongqing, China., Li Q; Department of Nephrology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents' Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key laboratory of Pediatric Metabolism and inflammatory Diseases, Chongqing, China. |
| Πηγή: | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association [Nephrol Dial Transplant] 2026 Aug 27; Vol. 41 (9), pp. 1629-1641. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Oxford University Press Country of Publication: England NLM ID: 8706402 Publication Model: Print Cited Medium: Internet ISSN: 1460-2385 (Electronic) Linking ISSN: 09310509 NLM ISO Abbreviation: Nephrol Dial Transplant Subsets: MEDLINE |
| Imprint Name(s): | Publication: Oxford : Oxford University Press Original Publication: [Berlin ; New York, NY] : Springer International, [c1986- |
| Ιατρικοί όροι (MeSH): | Nephrotic Syndrome*/genetics , Nephrotic Syndrome*/drug therapy , Nephrotic Syndrome*/immunology , Steroids*/therapeutic use , Genome-Wide Association Study* , Genetic Predisposition to Disease* , Polymorphism, Single Nucleotide* , Quantitative Trait Loci*, Humans ; Child ; Male ; Female ; Case-Control Studies ; Prognosis ; Child, Preschool ; Follow-Up Studies ; Genetic Risk Score ; Mendelian Randomization Analysis ; Adolescent |
| Περίληψη: | Background: Steroid-sensitive nephrotic syndrome (SSNS) is a relatively rare glomerular disease with considerable clinical and genetic heterogeneity. Although efforts have been made to explore the genetic determinants of SSNS, the underlying genetic architecture has still been hampered by limited sample size and remains to be elucidated. Methods: We conducted a genome-wide association study involving 510 sporadic pediatrics of SSNS and 1062 controls with Chinese ancestry, followed by a transethnic meta-analysis involving 2942 cases and 37 041 controls. We evaluated the colocalization probability between single-cell expression quantitative trait loci, plasma protein quantitative trait loci, and the novel loci using the colocalization method. We explored the potential causal effects using Mendelian randomization (MR) and assessed the clinical associations of polygenic risk scores (PRS) for SSNS. Results: Two novel genome-wide significant signals, rs4309200 from M6PR-KLRG1 (P = 4.70 × 10-9, OR = 1.23, 95%CI = 1.16-1.30) and rs9303279 from GSDMB-ORMDL3 (P = 7.25 × 10-9, OR = 0.82, 95%CI = 0.75-0.89), both highly related to immunological function, were identified for SSNS. Colocalization and MR analyses revealed that a genetic tendency toward higher M6PR expression in NK and CD4+ T cells with an effector memory or central memory phenotype (CD4 ET) was associated with an increased risk of SSNS (NK: PPH4 = 0.93; P = 2.04 × 10-4, OR = 1.60; CD4 ET: PPH4 = 0.91; P = 8.14 × 10-3, OR = 2.28), whereas higher ORMDL3 expression in B memory and CD4 ET cells was associated with a lower risk of SSNS (B memory: PPH4 = 0.93; P = 3.83 × 10-8, OR = 0.61; CD4 ET: PPH4 = 0/92; P = 1.82 × 10-9, OR = 0.49). The clinical correlation analysis confirmed that a higher PRS is associated with an earlier age of onset, and the rs56117924 from the NPHS1 gene may predominantly drive this association. Conclusion: We identified two novel immune-related loci associated with susceptibility to SSNS, nominating M6PR and ORMDL3 as potential contributors to SSNS risk in a cell-type-specific manner, and confirmed the association of PRS with earlier disease onset. These findings expand our knowledge of the genetic architecture of SSNS and highlight the importance of large-scale collaborations in uncovering genetic associations related to SSNS. (© The Author(s) 2026. Published by Oxford University Press on behalf of the ERA.) |
| References: | Nat Genet. 2016 Jul;48(7):740-6. (PMID: 27213287) Am J Hum Genet. 2024 Nov 7;111(11):2444-2457. (PMID: 39362218) BMJ Open. 2019 Aug 28;9(8):e028717. (PMID: 31467050) Bioinformatics. 2010 Sep 1;26(17):2190-1. (PMID: 20616382) Bioinformatics. 2018 Aug 15;34(16):2781-2787. (PMID: 29617937) Am J Hum Genet. 2007 Sep;81(3):559-75. (PMID: 17701901) Lancet Respir Med. 2019 Jun;7(6):509-522. (PMID: 31036433) Am J Respir Crit Care Med. 2019 Feb 15;199(4):478-488. (PMID: 30339462) Brief Bioinform. 2021 Jul 20;22(4):. (PMID: 33126247) J Epidemiol. 2015;25(5):370-7. (PMID: 25843432) J Allergy Clin Immunol. 2022 Sep;150(3):622-630. (PMID: 35381269) Pediatr Nephrol. 2018 Apr;33(4):573-584. (PMID: 28451893) Cell. 2022 Sep 1;185(18):3426-3440.e19. (PMID: 36055201) Mol Cell Pediatr. 2021 Nov 18;8(1):18. (PMID: 34792685) Kidney Int. 2020 Nov;98(5):1308-1322. (PMID: 32554042) Pediatr Nephrol. 2020 Aug;35(8):1529-1561. (PMID: 32382828) N Engl J Med. 2024 Aug 1;391(5):422-433. (PMID: 38804512) Precis Clin Med. 2023 Feb 23;6(1):pbad002. (PMID: 36968613) J Am Soc Nephrol. 2017 May;28(5):1651-1664. (PMID: 27852637) Am J Hum Genet. 2025 Jul 3;112(7):1597-1609. (PMID: 40555237) Nature. 2023 Oct;622(7982):329-338. (PMID: 37794186) Am J Hum Genet. 2018 Sep 6;103(3):338-348. (PMID: 30100085) Nephrol Dial Transplant. 2026 Feb 27;41(3):428-436. (PMID: 40815258) Elife. 2018 May 30;7:. (PMID: 29846171) Cell. 2021 May 27;184(11):3006-3021.e17. (PMID: 33930287) Lancet. 2018 Jul 7;392(10141):61-74. (PMID: 29910038) J Immunol. 2017 Sep 1;199(5):1647-1659. (PMID: 28747345) Nucleic Acids Res. 2024 Jan 5;52(D1):D1010-D1017. (PMID: 37791879) Genomics. 2000 Apr 15;65(2):129-36. (PMID: 10783260) Clin J Am Soc Nephrol. 2016 Oct 7;11(10):1760-1768. (PMID: 27445165) Nat Commun. 2023 Apr 29;14(1):2481. (PMID: 37120605) Am J Hum Genet. 2011 Jan 7;88(1):76-82. (PMID: 21167468) Biol Open. 2022 Sep 15;11(9):. (PMID: 35929543) Front Immunol. 2024 Apr 23;15:1376629. (PMID: 38715613) Science. 2024 May 24;384(6698):eadh0829. (PMID: 38781368) Science. 2022 Apr 8;376(6589):eabf3041. (PMID: 35389779) Annu Rev Pathol. 2020 Jan 24;15:287-313. (PMID: 31622560) Nature. 1999 Feb 18;397(6720):621-5. (PMID: 10050856) J Am Soc Nephrol. 2018 Jul;29(7):2000-2013. (PMID: 29903748) J Am Soc Nephrol. 2022 Jan;33(1):238-252. (PMID: 34732507) Nat Commun. 2021 Feb 24;12(1):1264. (PMID: 33627654) Nat Rev Mol Cell Biol. 2003 Mar;4(3):202-12. (PMID: 12612639) Nat Commun. 2023 Feb 16;14(1):896. (PMID: 36797296) J Virol. 2020 Jul 30;94(16):. (PMID: 32493818) Sci China Life Sci. 2024 Mar;67(3):579-595. (PMID: 38038885) Bioinformatics. 2010 Sep 15;26(18):2336-7. (PMID: 20634204) Pharmacol Ther. 2023 May;245:108401. (PMID: 37003301) Nat Rev Nephrol. 2019 Dec;15(12):750-765. (PMID: 31654044) Semin Cancer Biol. 2019 Apr;55:53-60. (PMID: 29727703) J Am Soc Nephrol. 2019 Aug;30(8):1375-1384. (PMID: 31263063) Bioinformatics. 2021 Apr 20;37(3):416-418. (PMID: 32735319) Lancet. 2023 Sep 2;402(10404):809-824. (PMID: 37659779) Nat Rev Methods Primers. 2022 Feb 10;2:. (PMID: 37325194) Nat Rev Mol Cell Biol. 2006 Aug;7(8):568-79. (PMID: 16936697) Bioinform Adv. 2025 Jan 16;5(1):vbaf006. (PMID: 40099154) Kidney Int Rep. 2023 May 27;8(8):1562-1574. (PMID: 37547536) Nat Genet. 2021 Nov;53(11):1616-1621. (PMID: 34737426) J Am Soc Nephrol. 2018 Aug;29(8):2189-2199. (PMID: 30012571) Nat Genet. 2021 Dec;53(12):1712-1721. (PMID: 34857953) |
| Grant Information: | Chongqing Science and Technology Bureau; 2023GGXM001 Health Commission Foundation; NCRCCHD-2023-MP-01 Chongqing Medical University; 2022YFC2705101 National Key Research and Development Program of China; W0098 Program for Youth Innovation in Future Medicine; KJZD-M202200401 Project of Science and Technology Research of Chongqing Education Commission; CSTB2022NSCQ-BHX0653 Postdoctoral Fund of Chongqing Natural Science Foundation |
| Contributed Indexing: | Keywords: Mendelian randomization; genome-wide association study; polygenic risk scores; quantitative trait loci; steroid-sensitive nephrotic syndrome |
| Substance Nomenclature: | 0 (Steroids) |
| Entry Date(s): | Date Created: 20260223 Date Completed: 20260827 Latest Revision: 20260829 |
| Update Code: | 20260829 |
| PubMed Central ID: | PMC13518090 |
| DOI: | 10.1093/ndt/gfag041 |
| PMID: | 41728924 |
| Βάση Δεδομένων: | MEDLINE |
καταχωρήστε σχόλιο πρώτοι!