Genetic Identification of Two Novel Loci Associated with Steroid-Sensitive Nephrotic Syndrome
Authors: Dufek Stephanie , Cheshire Chris , Levine Adam P. , Trompeter Richard S. , Issler Naomi , Stubbs Matthew , Mozere Monika , Gupta Sanjana , Klootwijk Enriko , Patel Vaksha , Hothi Daljit , Waters Aoife , Webb Hazel , Tullus Kjell , Jenkins Lucy , Godinho Lighta , Levtchenko Elena , Wetzels Jack , Knoers Nine , Teeninga Nynke , Nauta Jeroen , Shalaby Mohamed , Eldesoky Sherif , Kari Jameela A. , Thalgahagoda Shenal , Ranawaka Randula , Abeyagunawardena Asiri , Adeyemo Adebowale , Kristiansen Mark , Gbadegesin Rasheed , Webb Nicholas J. , Gale Daniel P. , Stanescu Horia C. , Kleta Robert , Bockenhauer Detlef 
Published: July 2019

Significance Statement
Although steroid-sensitive nephrotic syndrome (SSNS) is considered an autoimmune disease, its etiology is poorly understood. Genome-wide association studies (GWAS) have provided important insights into other autoimmune diseases, but so far, such studies have reported associations only in the classical HLA region for SSNS. In a GWAS of a large cohort of European ancestry comprising 422 ethnically homogeneous pediatric patients and 5642 ethnically matched controls, the authors found two loci outside the HLA region associated with SSNS at genome-wide significance. The locus with strongest association contains the calcium homeostasis modulator family member 6 gene CALHM6, which has been implicated in the regulation of the immune system. These findings suggest that impaired downregulation of the immune system may be a key mechanism in the pathogenesis of SSNS.

Background
Steroid-sensitive nephrotic syndrome (SSNS), the most common form of nephrotic syndrome in childhood, is considered an autoimmune disease with an established classic HLA association. However, the precise etiology of the disease is unclear. In other autoimmune diseases, the identification of loci outside the classic 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 patients 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; 95% confidence interval [95% CI], 2.86 to 4.03) 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 6 gene CALHM6 (previously called FAM26F). CALHM6 is implicated in immune response modulation; the lead SNP (rs2637678, P=1.27×10−17; OR, 0.51; 95% CI, 0.44 to 0.60) exhibits strong expression quantitative trait loci effects, the risk allele being associated with lower lymphocytic expression of CALHM6.

Conclusions
Because CALHM6 is implicated in regulating the immune response to infection, this may provide an explanation for the typical triggering of SSNS onset by infections. Our results suggest that a genetically conferred risk of immune dysregulation may be a key component in the pathogenesis of SSNS.