HLA-DQA1 and APOL1 as Risk Loci for Childhood-Onset Steroid-Sensitive and Steroid-Resistant Nephrotic Syndrome

Adeyemo, Adebowale; Esezobor, Christopher Imokhuede; Solarin, Adaobi; Abeyagunawardena, Asiri; Kari, Jameela A.; Desoky, Sherif El; Greenbaum, Larry A.; Kamel, Margret; Kallash, Mahmoud; Silva, Cynthia; Young, Alex P.; Hunley, Tracy E.; Jesus-Gonzalez, Nilka de; Srivastava, Tarak; Gbadegesin, Rasheed

doi:10.1053/j.ajkd.2017.10.013

Cited by 47 publications

(40 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…35,49,50 We identified the risk haplotype DRB1*07:01-DQA1*02:01-DQB1*02:02 in European patients. Similar findings were recently reported in the study by Adeyemo et al, 51 which showed that DRB1*07:01, DQA1*02:01, and DQB1*02:01 were the classic HLA alleles the most significantly associated with earlyonset NS in black children. The HLA-DRB1*07:01-HLA-DQA1*02:01-HLA-DQB1*02:02 haplotype is associated with a high risk of Escherichia coli-derived asparaginase hypersensitivity in childhood acute lymphoblastic leukemia, 52 which is reminiscent of allergic trigger in some patients with SSNS.…”

Section: Discussionsupporting

confidence: 91%

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

Dębiec

Dossier²,

Letouzé

et al. 2018

JASN

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 91%

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

Dębiec

Dossier²,

Letouzé

et al. 2018

JASN

View full text Add to dashboard Cite

show abstract

“…Notably, refinement of the HLA-DQA1 association was recently done by HLA imputation using exome array data in the same South Asian samples. 51 were significantly associated with childhood SSNS. However, HLA-DRB1*07:01 and HLA-DQB1*02:01 were not replicated in our study, because they are at a low allele frequency in the Japanese population (HLA-DRB1*07:01 [0.375%], HLA-DQB1*02:01 [0.134%], http://hla.or.jp).…”

Section: Discussionmentioning

confidence: 90%

Strong Association of the HLA-DR/DQ Locus with Childhood Steroid-Sensitive Nephrotic Syndrome in the Japanese Population

Jia

Horinouchi

Hitomi

et al. 2018

JASN

View full text Add to dashboard Cite

Nephrotic syndrome is the most common cause of chronic glomerular disease in children. Most of these patients develop steroid-sensitive nephrotic syndrome (SSNS), but the loci conferring susceptibility to childhood SSNS are mainly unknown. We conducted a genome-wide association study (GWAS) in the Japanese population; 224 patients with childhood SSNS and 419 adult healthy controls were genotyped using the Affymetrix Japonica Array in the discovery stage. Imputation for six genes (, ,, , and) was conducted on the basis of Japanese-specific references. We performed genotyping for /- using a sequence-specific oligonucleotide-probing method on a Luminex platform. Whole-genome imputation was conducted using a phased reference panel of 2049 healthy Japanese individuals. Replication was performed in an independent Japanese sample set including 216 patients and 719 healthy controls. We genotyped candidate single-nucleotide polymorphisms using the DigiTag2 assay. The most significant association was detected in the region and replicated (rs4642516 [minor allele G], combined=7.84×10; odds ratio [OR], 0.33; 95% confidence interval [95% CI], 0.26 to 0.41; rs3134996 [minor allele A], combined =1.72×10; OR, 0.29; 95% CI, 0.23 to 0.37). (=1.82×10; OR, 2.62; 95% CI, 1.94 to 3.54) and (=2.09×10; OR, 0.10; 95% CI, 0.05 to 0.21) were considered primary alleles associated with childhood SSNS. (=7.01×10; OR, 3.60; 95% CI, 2.46 to 5.29) was identified as the most significant genetic susceptibility factor. The most significant association with childhood SSNS was detected in the region. Further allele/haplotype analyses should enhance our understanding of molecular mechanisms underlying SSNS.

show abstract

“…30 Dyslipidemia is also a prominent feature of NS, and our study identified APOL1 and other apolipoproteins that could distinguish children with SSNS versus SRNS, both before and after steroid treatment. 7,8,[31][32][33][34][35] Adiponectin (ADIPOQ) levels have also been shown to be increased in patients with NS. 36 Our studies found that although adiponectin levels started lower and decreased with steroid treatment in children with SSNS, adiponectin levels started higher and increased further with steroid treatment in those with SRNS.…”

Section: Resultsmentioning

confidence: 99%

Predicting and Defining Steroid Resistance in Pediatric Nephrotic Syndrome Using Plasma Proteomics

Agrawal

Merchant

Kino

et al. 2020

Kidney International Reports

Self Cite

View full text Add to dashboard Cite

Introduction: Nephrotic syndrome (NS) is a characterized by massive proteinuria, edema, hypoalbuminemia, and dyslipidemia. Glucocorticoids (GCs), the primary therapy for >60 years, are ineffective in approximately 50% of adults and approximately 20% of children. Unfortunately, there are no validated biomarkers able to predict steroid-resistant NS (SRNS) or to define the pathways regulating SRNS. Methods: We performed proteomic analyses on paired pediatric NS patient plasma samples obtained both at disease presentation before glucocorticoid initiation and after approximately 7 weeks of GC therapy to identify candidate biomarkers able to either predict steroid resistance before treatment or define critical molecular pathways/targets regulating steroid resistance. Results: Proteomic analyses of 15 paired NS patient samples identified 215 prevalent proteins, including 13 candidate biomarkers that predicted SRNS before GC treatment, and 66 candidate biomarkers that mechanistically differentiated steroid-sensitive NS (SSNS) from SRNS. Ingenuity Pathway Analyses and protein networking pathways approaches further identified proteins and pathways associated with SRNS. Validation using 37 NS patient samples (24 SSNS/13 SRNS) confirmed vitamin D binding protein (VDB) and APOL1 as strong predictive candidate biomarkers for SRNS, and VDB, hemopexin (HPX), adiponectin (ADIPOQ), sex hormone-binding globulin (SHBG), and APOL1 as strong candidate biomarkers to mechanistically distinguish SRNS from SSNS. Logistic regression analysis identified a candidate biomarker panel (VDB, ADIPOQ, and matrix metalloproteinase 2 [MMP-2]) with significant ability to predict SRNS at disease presentation (P ¼ 0.003; area under the receiver operating characteristic curve ¼ 0.78). Conclusion: Plasma proteomic analyses and immunoblotting of serial samples in childhood NS identified a candidate biomarker panel able to predict SRNS at disease presentation, as well as candidate molecular targets/pathways associated with clinical steroid resistance.

show abstract

HLA-DQA1 and APOL1 as Risk Loci for Childhood-Onset Steroid-Sensitive and Steroid-Resistant Nephrotic Syndrome

Cited by 47 publications

References 38 publications

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

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

Strong Association of the HLA-DR/DQ Locus with Childhood Steroid-Sensitive Nephrotic Syndrome in the Japanese Population

Predicting and Defining Steroid Resistance in Pediatric Nephrotic Syndrome Using Plasma Proteomics

Contact Info

Product

Resources

About