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

作者全名：Chan, Han; Ni, Fenfen; Zhao, Bo; Jiang, Huimin; Ding, Juanjuan; Wang, Li; Wang, Xiaowen; Cui, Jingjing; Feng, Shipin; Gao, Xiaojie; Yang, Xueying; Chi, Huan; Lee, Hao; Chen, Xuelan; Li, Xiaoqin; Jiao, Jia; Wu, Daoqi; Zhang, Gaofu; Wang, Mo; Cun, Yupeng; Ruan, Xiongzhong; Yang, Haiping; Li, Qiu

作者地址：[Chan, Han; Jiang, Huimin; Yang, Xueying; Chi, Huan; Lee, Hao; Chen, Xuelan; Li, Xiaoqin; Jiao, Jia; Wu, Daoqi; Zhang, Gaofu; Wang, Mo; Yang, Haiping; Li, Qiu] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Minist Educ Key Lab Child Dev & Disorders, Dept Nephrol,Childrens Hosp,Chongqing Key Lab Pedi, Chongqing 400014, Peoples R China; [Ni, Fenfen; Gao, Xiaojie] Shenzhen Childrens Hosp, Dept Nephrol, Shenzhen 518034, Guangdong, Peoples R China; [Zhao, Bo; Cui, Jingjing] Kunming Med Univ, Kunming Childrens Hosp, Dept Nephrol, Kunming 650228, Yunnan, Peoples R China; [Ding, Juanjuan; Wang, Xiaowen] Huazhong Univ Sci & Technol, Wuhan Childrens Hosp, Dept Nephrol, Tongji Med Coll, Wuhan 430015, Hubei, Peoples R China; [Wang, Li; Feng, Shipin] Chengdu Women & Children Cent Hosp, Dept Nephrol, Chengdu 610073, Sichuan, Peoples R China; [Cun, Yupeng] Chongqing Med Univ, Pediat Res Inst, Natl Clin Res Ctr Child Hlth & Disorders, Minist Educ Key Lab Child Dev & Disorde,Chongqing, Chongqing 400014, Peoples R China; [Ruan, Xiongzhong] UCL, Univ Coll London Med Sch, Dept Nephrol, John Moorhead Res Lab, Royal Free Campus, London NW3 2PF, England

通信作者：Yang, HP; Li, Q (通讯作者)，Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Minist Educ Key Lab Child Dev & Disorders, Dept Nephrol,Childrens Hosp,Chongqing Key Lab Pedi, Chongqing 400014, Peoples R China.

来源：GENES & DISEASES

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001222305400001

JCR分区：Q1

影响因子：6.9

年份：2024

卷号：11

期号：4

开始页：　

结束页：　

文献类型：Article

关键词：Frequent relapse; Genome-wide association study; Human leukocyte antigen region; Steroid-sensitive nephrotic syndrome

摘要：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 regiondependent 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.

基金机构：China National Natural Science Foundation [81970618, 82170720, 82200788]; China National Clinical Research Centre Foundation [NCRC-2019-GP-02]; Science and Technology Research Project of Chongqing Education Commission of China [KJZD-M201900401]; Chongqing Science and Health Joint Medical Research Project (China) [2023GGXM001]; National Key R & D Program of China [2022YFC2705101]

基金资助正文：This study was funded by the China National Natural Science Foundation (No. 81970618, 82170720, 82200788) , China National Clinical Research Centre Foundation (No. NCRC-2019-GP-02) , Science and Technology Research Project of Chongqing Education Commission of China (No. KJZD-M201900401) , Chongqing Science and Health Joint Medical Research Project (China) (No. 2023GGXM001) , and National Key R & D Program of China (No. 2022YFC2705101) . The authors declare that they have no relevant financial interests.