A genomic association study revealing subphenotypes of childhood steroid-sensitive nephrotic syndrome in a larger genomic sequencing cohort

Dissecting the genetic components that contribute to the two main subphenotypes of steroid-sensitive nephrotic syndrome(SSNS)using genome-wide association studies(GWAS)strategy is important for understanding the disease.We conducted a multicenter cohort study(360 patients and 1835 controls)combined with a GWAS strategy to identify susceptibility var-iants associated with the following two subphenotypes of ssNS:steroid-sensitive nephrotic syn-drome without relapse(SSNswR,181 patients)and steroid-dependent/frequent relapse nephrotic syndrome(SDNS/FRNS,179 patients).The distribution of two single-nucleotide poly-morphisms(SNPs)in ANKRD36 and ALPG was significant between SSNSWR and healthy controls,and that of two SNPs in GAD1 and HLA-DQA1 was significant between SDNS/FRNS and healthy controls.Interestingly,rs1047989 in HLA-DQA1 was a candidate locus for SDNS/FRNS but not for SSNSWR.No significant SNPs were observed between SSNSWR and SDNS/FRNS.Meanwhile,chromosome 2:171713702 in GAD1 was associated with a greater steroid dose(>0.75 mg/kg/d)upon relapse to first remission in patients with SDNS/FRNS(odds ratio=3.14;95%confidence interval,0.97-9.87;P=0.034).rs117014418 in APOL4 was significantly associated with a decrease in eGFR of greater than 20%compared with the baseline in SDNS/FRNS patients(P=0.0001).Protein-protein intersection network construction suggested that HLA-DQA1 and HLA-DQB1 function together through GSDMA.Thus,SSNSWR belongs to non-HLA region-dependent nephropathy,and the HLA-DQA/DQB region is likely strongly associated with dis-ease relapse,especially in SDNS/FRNS.The study provides a novel approach for the GWAS strategy of SsNS and contributes to our understanding of the pathological mechanisms of SSNSWRandSDNS/FRNS.

Association between HLA alleles and sub-phenotype of childhood steroid-sensitive nephrotic syndrome

BACKGROUND Few studies have addressed the effects of human leukocyte antigen(HLA)alleles on different clinical sub-phenotypes in childhood steroid-sensitive nephrotic syndrome(SSNS),including SSNS without recurrence(SSNSWR)and steroid-dependent nephrotic syndrome/frequently relapse nephrotic syndrome(SDNS/FRNS).In this study,we investigated the relationship between HLA system and children with SSNSWR and SDNS/FRNS and clarified the value of HLA allele detection for precise typing of childhood SSNS.METHODS A total of 241 Chinese Han individuals with SSNS were genotyped using GenCap-WES Capture Kit,and four-digit resolution HLA alleles were imputed from available Genome Wide Association data.The distribution and carrying frequency of HLA alleles in SSNSWR and SDNS/FRNS were investigated.Additionally,logistic regression and mediating effects were used to examine the relationship between risk factors for disease process and HLA system.RESULTS Compared with SSNSWR,significantly decreased serum levels of complement 3(C3)and complement 4(C4)at onset were detected in SDNS/FRNS(C3,P<0.001;C4,P=0.018).The average time to remission after sufficient initial steroid treatment in SDNS/FRNS was significantly longer than that in SSNSWR(P=0.0001).Low level of C4 was further identified as an independent risk factor for SDNS/FRNS(P=0.008,odds ratio=0.174,95% confidence interval 0.048-0.630).The HLA-A*11:01 allele was independently associated with SSNSWR and SDNS/FRNS(P=0.0012 and P=0.0006,respectively).No significant HLA alleles were detected between SSNSWR and SDNS/FRNS.In addition,a mediating effect among HLA-I alleles(HLA-B*15:11,HLA-B*44:03 and HLA-C*07:06),C4 level and SDNS/FRNS was identified.CONCLUSIONS HLA-I alleles provide novel genetic markers for SSNSWR and SDNS/FRNS.HLA-I antigens may be involved in steroid dependent or frequent relapse in children with SSNS as mediators of immunoregulation.

Evaluation of thyroid profile among children aged 1-15 years with nephrotic syndrome:An observation study

BACKGROUND The interaction between the kidney and the thyroid is important for normal function of both organs.In nephrotic syndrome,proteinuria leads to loss of several proteins,which in turn causes hypothyroidism.AIM To assess the thyroid function in children with nephrotic syndrome.METHODS This cross-sectional study was conducted in a tertiary center,Bhopal,from February 2020 to January 2021.Consecutive children aged 1-15 years admitted with nephrotic syndrome(first-time diagnosed and all relapse cases)were included in the study.A thyroid profile was sent along with routine investigations,and thyroid hormone status was assessed in nephrotic syndrome children.RESULTS Of the 70 patients,39(55.7%)showed abnormal thyroid profiles;19(27.1%)had overt hypothyroidism,and 20(28.6%)had subclinical hypothyroidism.Overt hypothyroidism was seen in 16.1%of newly diagnosed cases,40%of second relapses,and 2.7%of frequently relapsed cases(P<0.001).The mean serum free T3 and free T4 levels in frequent relapses were 2.50±0.39 ng/dL and 0.78±0.12 ng/dL,respectively,which were significantly lower than in newly diagnosed cases(2.77±0.37 ng/dL and 0.91±0.19 ng/dL,respectively).The mean thyroidstimulating hormone(TSH)level was significantly higher in frequent relapses (5.86±1.56μIU/mL)and second relapse(5.81±1.78μIU/mL)than in newly diagnosed cases(4.83±0.76μIU/mL)and first relapse cases(4.74±1.17μIU/mL),(P<0.01).CONCLUSION An abnormal thyroid profile was commonly observed in children with nephrotic syndrome,and overt hypothyroidism was more common in frequent relapse cases.Therefore,thyroid screening should be a part of the management of nephrotic syndrome so that hypothyroidism can be detected and managed at an early stage.