A genomic association study revealing subphenotypes of childhood steroid-sensitive nephrotic syndrome in a larger genomic sequencing cohort
© 2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd..
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 variants associated with the following two subphenotypes of SSNS: steroid-sensitive nephrotic syndrome without relapse (SSNSWR, 181 patients) and steroid-dependent/frequent relapse nephrotic syndrome (SDNS/FRNS, 179 patients). The distribution of two single-nucleotide polymorphisms (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 disease 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 SSNSWR and SDNS/FRNS.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
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| Enthalten in: |
Genes & diseases - 11(2024), 4 vom: 27. Apr., Seite 101126 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Chan, Han [VerfasserIn] |
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| Links: |
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| Themen: |
Frequent relapse |
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| Anmerkungen: |
Date Revised 03.04.2024 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1016/j.gendis.2023.101126 |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 2 | |a A genomic association study revealing subphenotypes of childhood steroid-sensitive nephrotic syndrome in a larger genomic sequencing cohort |
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| 520 | |a 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 variants associated with the following two subphenotypes of SSNS: steroid-sensitive nephrotic syndrome without relapse (SSNSWR, 181 patients) and steroid-dependent/frequent relapse nephrotic syndrome (SDNS/FRNS, 179 patients). The distribution of two single-nucleotide polymorphisms (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 disease 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 SSNSWR and SDNS/FRNS | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Frequent relapse | |
| 650 | 4 | |a Genome-wide association study | |
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| 700 | 1 | |a Ni, Fenfen |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Bo |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Huimin |e verfasserin |4 aut | |
| 700 | 1 | |a Ding, Juanjuan |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Li |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xiaowen |e verfasserin |4 aut | |
| 700 | 1 | |a Cui, Jingjing |e verfasserin |4 aut | |
| 700 | 1 | |a Feng, Shipin |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Xiaojie |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Xueying |e verfasserin |4 aut | |
| 700 | 1 | |a Chi, Huan |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Hao |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Xuelan |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Xiaoqin |e verfasserin |4 aut | |
| 700 | 1 | |a Jiao, Jia |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Daoqi |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Gaofu |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Mo |e verfasserin |4 aut | |
| 700 | 1 | |a Cun, Yupeng |e verfasserin |4 aut | |
| 700 | 1 | |a Ruan, Xiongzhong |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Haiping |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Qiu |e verfasserin |4 aut | |
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