Kidney Week

Abstract: TH-OR118

Common Risk Variants in NPHS1 and TNFSF15 Are Associated with Childhood Steroid-Sensitive Nephrotic Syndrome

Session Information

• Pediatric Nephrology Research
  November 07, 2019 | Location: 152, Walter E. Washington Convention Center
  Abstract Time: 04:30 PM - 04:42 PM

Category: Pediatric Nephrology

• 1700 Pediatric Nephrology

Authors

• Horinouchi, Tomoko, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan, Kobe, Japan

Tomoko Horinouchi, MD, PhD



Tomoko Horinouchi is an assistant professor of Department of Pediatrics at Kobe University Graduate School of Medicine. Her specialties are pediatric nephrology and genetics.

• Yamamura, Tomohiko, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan, Kobe, Japan

Tomohiko Yamamura,

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

Rasheed A. Gbadegesin,

• Sampson, Matt G., University of Michigan, Ann Arbor, Michigan, United States

Matt G. Sampson,

• Nagano, China, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan, Kobe, Japan

China Nagano,

• Nozu, Kandai, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan, Kobe, Japan

Kandai Nozu,

• Ishikura, Kenji, National Center for Child Health and Development, Tokyo, ToKyo, Japan

Kenji Ishikura,

• Ronco, Pierre M., Hospital Tenon, Paris, France

Pierre M. Ronco,

• Cheong, Hae Il, Seoul National University Children's Hospital, Seoul, Korea (the Republic of)

Hae Il Cheong,

• Iijima, Kazumoto, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan, Kobe, Japan

Kazumoto Iijima,

Background

Although steroid-sensitive nephrotic syndrome (SSNS) is the most common cause of glomerular disease in children, the pathogenesis remains unclear. Recent genome-wide association studies (GWASs) have shown that variants in the HLA-DR/DQ region are significantly associated with the disease in different populations. However risk loci outside of the HLA region are largely unknown.

Methods

We conducted a GWAS in 1,017 Japanese children with SSNS and 3,332 ancestry matched controls. We performed replication studies and trans-ethnic meta-analysis in Korean, South Asian, sub-Saharan African, European, and Hispanic populations.

Results

The most significant association was detected in HLA-DR/DQ region (p=2.8 x10^-33, odds ratio [OR]=2.49, 95%CI: 2.15-2.89). In addition, common variants in NPHS1-KIRREL2 (p=4.94 x 10^-20, OR=1.70, 95%CI: 1.66-2.18), TNFSF15 (p=2.54 x 10^-8OR=0.72, 95%CI: 0.64-0.81) and TNFRSF11A (p=7.68 x 10^-8, OR=1.38, 95%CI: 1.23-1.56) regions achieved genome-wide or marginal genome-wide significance. Trans-ethnic meta-analysis confirmed the significant associations in NPHS1 (p_meta=7.06 x 10^-2, OR=1.91) and TNFSF15 (p_meta=4.05 x 10^-13, OR=0.72) loci.

Discussion:
NPHS1 encodes nephrin and mutations in NPHS1 cause congenital nephrotic syndrome of the Finnish type (CNSF). The two synonymous variants in NPHS1 may induce aberrant splicing which could decrease the wild-type nephrin production and may affect the glomerular filtration barrier function. In addition, one of the two variants in NPHS1 has been previously reported to induce TRPC6 activation. TNFSF15 encodes the TNF super-family member 15 (TNFSF15), ligand of death receptor 3. Activation of TNFS15 enhances the proliferation of human regulatory T cells (Tregs). The risk allele in TNFS15 is associated with reduced expression of TNFSF15, which attenuate the proliferation of Tregs, consistent with findings reported in SSNS patients.

Conclusion

The present study markedly improves the understanding of genetic background of childhood SSNS, and provides another evidence that the gene responsible for a monogenic rare disease (CNSF) could be the susceptibility gene for a relatively common multifactorial disease (SSNS).
[Collaborators: Xiaoyuan Jia, Yuki Hitomi, Katsushi Tokunaga]

Funding

• Government Support - Non-U.S.