Abstract: SA-PO397
Genetic Identification of Two Novel Loci Associated with Steroid-Sensitive Nephrotic Syndrome
Session Information
- Genetic Diseases of the Kidney - III
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1002 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Cheshire, Chris, University College London, London, United Kingdom
- Dufek, Stephanie, University College London, London, United Kingdom
- Levine, Adam P., University College London, London, United Kingdom
- Stubbs, Matthew James, University College London, London, United Kingdom
- Mozere, Monika, University College London, London, United Kingdom
- Gupta, Sanjana, University College London, London, United Kingdom
- Levtchenko, Elena N., University Hospitals Leuven, Herent, Belgium
- Wetzels, Jack F., Radboud University Medical Center, Nijmegen, Netherlands
- Kari, Jameela Abdulaziz, King abdulaziz University, Jeddah, Saudi Arabia
- Thalgahagoda, Shenal, University of Peradeniya, Peradeniya, Sri Lanka
- Ranawaka, Randula, University of Colombo, Kiribathgoda, Sri Lanka
- Abeyagunawardena, Asiri S., University of Peradeniya, Sri Lanka, Peradeniya, Sri Lanka
- Adeyemo, Adebowale A., National Institutes of Health, Bethesda, Maryland, United States
- Gbadegesin, Rasheed A., Duke University Medical Center, Durham, North Carolina, United States
- Gale, Daniel P., University College London, London, United Kingdom
- Bockenhauer, Detlef, University College London, London, United Kingdom
Background
Steroid-sensitive nephrotic syndrome (SSNS), the most common form of nephrotic syndrome in childhood, is considered an autoimmune disease with an established classical HLA association. However, the precise etiology of the disease is unclear. In other autoimmune diseases, the identification of loci outside the classical HLA region by genome-wide association studies (GWAS) has provided critical insights into disease pathogenesis. Previously conducted GWAS of SSNS have not identified non-HLA loci achieving genome-wide significance.
Methods
In an attempt to identify additional loci associated with SSNS, we conducted a GWAS of a large cohort of European ancestry comprising 422 ethnically homogeneous pediatric cases and 5642 ethnically matched controls.
Results
The GWAS found three loci that achieved genome-wide significance, which explain approximately 14% of the genetic risk for SSNS. It confirmed the previously reported association with the HLA-DR/DQ region (lead single nucleotide polymorphism [SNP] rs9273542, P=1.59×10-43; odds ratio [OR], 3.39), and identified two additional loci outside the HLA region, on chromosomes 4q13.3 and 6q22.1. The latter contains the calcium homeostasis modulator family member six gene CALHM6 (previously called FAM26F). CALHM6 is implicated in immune response modulation; the lead SNP (rs2637678, P=1.27×10-17; OR, 0.51) exhibits strong expression quantitative trait loci effects, the risk allele being associated with lower lymphocytic expression of CALHM6.
Conclusion
As CALHM6 is implicated in regulating the immune response to infection, this may explain the typical triggering of SSNS onset by infections. Our results suggest a genetically conferred risk of immune dysregulation may be a key component in the pathogenesis of SSNS.
Funding
- Private Foundation Support