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Abstract: FR-PO303

Multi-Population Meta-Analysis Highlights the Role of Immune Dysregulation in Pediatric Steroid-Sensitive Nephrotic Syndrome

Session Information

Category: Genetic Diseases of the Kidneys

  • 1102 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Barry, Alexandra, Boston Children's Hospital, Boston, Massachusetts, United States
  • Mcnulty, Michelle, Boston Children's Hospital, Boston, Massachusetts, United States
  • Jia, Xiaoyuan, Kokuritsu Kenkyu Kaihatsu Hojin Kokuritsu Kokusai Iryo Kenkyu Center, Shinjuku-ku, Tokyo, Japan
  • Debiec, Hanna, Sorbonne Universite, Paris, Île-de-France, France
  • Gupta, Yask, Columbia University College of Physicians and Surgeons, New York, New York, United States
  • Dossier, Claire, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Pediatrico Bambino Gesu, Rome, Italy
  • Luo, Yang, Harvard Medical School, Boston, Massachusetts, United States
  • Nagano, China, Boston Children's Hospital, Boston, Massachusetts, United States
  • Horinouchi, Tomoko, Kobe Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Kobe, Hyogo, Japan
  • Nozu, Kandai, Kobe Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Kobe, Hyogo, Japan
  • Bagga, Arvind, All India Institute of Medical Sciences, New Delhi, Delhi, India
  • Vivarelli, Marina, Hopital Robert Debre, Reims, Champagne-Ardenne, France
  • Sanna-Cherchi, Simone, Columbia University College of Physicians and Surgeons, New York, New York, United States
  • Ronco, Pierre M., Sorbonne Universite, Paris, Île-de-France, France
  • Iijima, Kazumoto, Kobe Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Kobe, Hyogo, Japan
  • Sampson, Matt G., Boston Children's Hospital, Boston, Massachusetts, United States
Background

Steroid-sensitive nephrotic syndrome (SSNS) is the most common form of NS observed in children. Previous genome-wide association studies (GWAS) have identified associations at four loci, including HLA. Additional heritability of SSNS has remained unknown.

Methods

We conducted a multi-population meta-analysis of 2,486 pediatric SSNS patients of Admixed-American, African, East Asian, European and South Asian ancestries vs. 35,739 ancestry-matched controls. Significant and suggestive loci were followed-up with gene-based annotation, and colocalization with immune- and kidney-cell eQTL data. The HLA locus was fine-mapped via HLA-specific imputation using a multi-ethnic HLA reference for association at classical HLA alleles, haplotypes, and amino acid positions.

Results

Multi-population meta-analysis discovered 5 new significant associations near CAPDS, CD28, AHI1, BTC, and CLEC16A. There were 12 additional suggestive risk loci. The known GWAS loci were replicated. We found three non-HLA GWAS loci with high colocalization probability across various immune cell eQTLs, including CALHM6, AHI1, TNFSF15. Colocalization with monocytes was observed for all three loci. HLA-focused analyses discovered two independent associations within the HLA-DR/DQ region and fine-mapping identified an association at amino acid position 47 and position 52 in HLA-DQA1. Conditional analysis identified a secondary association at amino acid position 26 in HLA-DQB1. Of note, no new GWAS loci colocalized with kidney eQTLs.

Conclusion

Increased cohort diversity and size empowered the discovery of novel pediatric SSNS risk loci, further implicating the key role of immune dysregulation in this disease.

Manhattan plot of multi-population GWAS of pediatric SSNS

Funding

  • NIDDK Support