Kidney Week

Abstract: FR-PO646

Genome-Wide Association Studies of Pediatric Nephrotic Syndrome Identify Variants Associated with Corticosteroid Response

Session Information

• Genetic Kidney Diseases: Cohort Studies - Genetic Associations and Diagnoses
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1202 Genetic Diseases of the Kidneys: Non-Cystic

Authors

• Tu, Tiffany, Duke University, Durham, North Carolina, United States

Tiffany Tu, MS

• Ochoa, Alejandro, Duke University, Durham, North Carolina, United States

Alejandro Ochoa, PhD

• Sood, Amika, University of Georgia, Athens, Georgia, United States

Amika Sood, PhD

• Chan, Cliburn, Duke University, Durham, North Carolina, United States

Cliburn Chan, MBBS, PhD

• Chambers, Eileen Tsai, Duke University, Durham, North Carolina, United States

Eileen Tsai Chambers, MD

• Jackson, Annette M., Duke University, Durham, North Carolina, United States

Annette M. Jackson, PhD

• Adeyemo, Adebowale A., National Institutes of Health, Bethesda, Maryland, United States

Adebowale A. Adeyemo, MD

• Gbadegesin, Rasheed A., Duke University, Durham, North Carolina, United States

Rasheed A. Gbadegesin, MD, MBBS, FASN

Background

Nephrotic syndrome (NS) is one of the most common glomerular diseases seen in children. It is classified based on response to corticosteroid therapy as either steroid-sensitive nephrotic syndrome (SSNS), or steroid-resistant nephrotic syndrome (SRNS). The genetic architecture and the molecular mechanisms of NS are poorly understood, and there are currently no reliable predictors of therapeutic response. To improve our understanding of the genetic basis of NS and define predictors of therapy response, we carried out genome-wide analyses of previously unstudied multi-ancestry cohorts of children with NS.

Methods

We did genome-wide association studies (GWAS) in 994 children with NS and 3,558 ancestry matched controls using a logistic mixed-effects model as implemented in the SAIGE software package. Replication analysis was done on 1,483 children with NS in two additional independent cohorts. We imputed classical HLA alleles for allelic and haplotype association testing.

Results

Our GWAS showed that common genetic variants in the chromosome 6 major histocompatibility complex (MHC) region (in HLA-DQB1, HLA-DRB1, HLA-DQA1) are robustly associated with SSNS, but not SRNS. The top variant for SSNS is rs17843604 (OR 2.57, 95% CI 2.25-2.94). In addition, we identified a chromosome 16 locus with leading variant rs12925642 (OR 0.67, 95% CI 0.59-0.77) in CLEC16A as a major second genetic hit for SSNS outside of chromosome 6. Two other secondary genome-wide significant loci for NS were found on chromosomes 5 and 10. A haplotype defined by alleles at three HLA classical loci HLA-DQA1*02:01~DQB1*02:02~DRB1*07:01 confers almost 4 times the risk of developing SSNS (OR 3.8, 95% CI 3.3-4.4). A GWAS using SRNS as cases and SSNS patients as controls identified a genome-wide significant HLA-DQB1 locus (lead SNP rs9274639, OR 0.38 [95% CI 0.27-0.52]) that explains the differences in steroid responsiveness.

Conclusion

Our findings of genome-wide HLA class II variants and a robust genome-wide significant HLA haplotype of large effect across multiple ancestries indicate that SSNS, but not SRNS, is a predominantly immune-mediated disorder. The findings of additional secondary loci add to the slowly growing list of non-HLA risk loci and to our knowledge of NS mechanisms.

Funding

• NIDDK Support