Genetic Identification of Two Novel Loci Associated with Steroid-Sensitive Nephrotic Syndrome

Abstract

BackgroundSteroid-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.MethodsIn 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.ResultsThe 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.ConclusionsBecause 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.

Comprehensive Review of Steroid-Sensitive Nephrotic Syndrome Genetic Risk Loci and Transcriptional Regulation as a Possible Mechanistic Link to Disease Risk

“…Progress has already been made in understanding the resultant changes in gene expression associated with identified risk loci. Two groups have previously described the presence of expression quantitative trait loci (eQTLs) associated with SSNS risk variants, which further supports a model of allelic transcriptional regulation (19,22). Specifically, three of the SNPs identified in a GWAS by Dufek et al alter…”

“…Most recently, Dufek et al assembled a large cohort of patients with SSNS and J o u r n a l P r e -p r o o f a matched set of healthy controls. They identified three genome-wide significant loci, including two loci outside of the HLA region -4q13.3 and 6q22.1 (22). Altogether, these groups have independently replicated and confirmed the importance of the HLA locus as well as several other disease risk loci in patients with SSNS.…”

“…In addition, the fact that (47,48) and the association of nephrotic syndrome with T cell lymphomas (49). Finally, as described above, several genetic variants in the human leukocyte antigen (HLA) region have been shown to associate with SSNS in multiple studies (18,19,21,22), although the mechanisms underlying these associations have not yet been elucidated.…”

“…To identify all possible candidates, we used Pubmed and the GWAS catalog (23) to identify SSNS risk variants from genome wide association and candidate gene studies that reported significant genetic association for SSNS. A total of eight studies met our search criteria (18)(19)(20)(21)(22)(36)(37)(38). Five of the candidate genetic variant (18,20,21) and genome wide association studies (19,21,22) which sought to identify the origins of complex genetic risk for SSNS successfully identified loci with p-values less than 0.0001 ( Table 1).…”

“…While there are likely only one or two causal variants per SSNS risk locus, all of the variants on the LD-expanded list are candidates based on genetic association. Using the National Center for Biotechnology Information's (NCBI) dbSNP database (22,39), annotations of the position of the LDexpanded SSNS risk variants relative to gene coding regions were assessed ( Supplementary Table S4). Only ten variants from this LD-expanded list are located in coding regions.…”