Transethnic, Genome-Wide Analysis Reveals Immune-Related Risk Alleles and Phenotypic Correlates in Pediatric Steroid-Sensitive Nephrotic Syndrome

Abstract

Steroid-sensitive nephrotic syndrome (SSNS) is a childhood disease with unclear pathophysiology and genetic architecture. We investigated the genomic basis of SSNS in children recruited in Europe and the biopsy-based North American NEPTUNE cohort. We performed three ancestry-matched, genome-wide association studies (GWAS) in 273 children with NS (Children Cohort Nephrosis and Virus [NEPHROVIR] cohort: 132 European, 56 African, and 85 Maghrebian) followed by independent replication in 112 European children, transethnic meta-analysis, and conditional analysis. GWAS alleles were used to perform glomerular -expression quantitative trait loci studies in 39 children in the NEPTUNE cohort and epidemiologic studies in GWAS and NEPTUNE (97 children) cohorts. Transethnic meta-analysis identified one SSNS-associated single-nucleotide polymorphism (SNP) rs1063348 in the 3' untranslated region of (=9.3×10). Conditional analysis identified two additional independent risk alleles upstream of (rs28366266,=3.7×10) and in the 3' untranslated region of (rs9348883,=9.4×10) within introns of and These three risk alleles were independent of the risk haplotype identified in European patients. Increased burden of risk alleles across independent loci was associated with higher odds of SSNS. Increased burden of risk alleles across independent loci was associated with higher odds of SSNS, with younger age of onset across all cohorts, and with increased odds of complete remission across histologies in NEPTUNE children. rs1063348 associated with decreased glomerular expression of HLA-DRB1, HLA-DRB5, and HLA-DQB1. Transethnic GWAS empowered discovery of three independent risk SNPs for pediatric SSNS. Characterization of these SNPs provide an entry for understanding immune dysregulation in NS and introducing a genomically defined classification.

Detection of Allosteric Effects of lncRNA Secondary Structures Altered by SNPs in Human Diseases

“…These results revealed that HCG23 on chromosome 6 plays a major role in adenocarcinoma of the lung. And according to previous study, HCG23 was also supported participating immune-related diseases (Debiec et al, 2018).…”

Leveraging Ancestral Heterogeneity to Map Shared Genetic Risk Loci in Pediatric Steroid-Sensitive Nephrotic Syndrome

“…1,10 Two of the loci described in the work by Debiec et al 8 were also within the HLA-DR/DQ region, and all three loci remained significant when controlled for HLA haplotype and these previously discovered risk alleles at the HLA-DQA1 locus. Debiec et al 8 also showed that having more disease-associated variants was associated with decreased age at disease onset and increased likelihood of complete remission. Both characteristics are strongly associated with SSNS, consistent with the notion that the associations reported are indeed with an SSNS and not an SRNS phenotype.…”

“…Although it requires more sophisticated statistical genetics, the approach can uncover significant associations with loci of interest that would otherwise elude identification for rare diseases with complex inheritance patterns. 6,7 In this issue of the Journal of the American Society of Nephrology, Debiec et al 8 performed just such a transethnic genome-wide association study of SSNS, resulting in the discovery of three genetic loci in the HLA region with a lead risk allele upstream of HLA-DQB1.…”

The Genetic Architecture of Kidney Disease

“…Conversely, systemic diseases, such as hypertension, may be driven by genes that primarily affect kidney function (20). Common variation in immune regulatory genes seems to affect the risk of various glomerular phenotypes (21). Diabetes, the most common cause of CKD, is the result in large part of combinations of variation in nonkidney genes; the verdict is still out on whether susceptibility to nephropathy in the setting of diabetes is driven primarily by genes directly affecting the kidney (22,23).…”