Common risk variants in NPHS1 and TNFSF15 are associated with childhood steroid-sensitive nephrotic syndrome

Jia, Xiaoyuan; McNulty, Michelle T.; Song, Kyuyong; Hitomi, Yuki; Lee, Dongwon; Aiba, Yoshihiro; Khor, Seik‐Soon; Ueno, Kazuko; Kawai, Yosuke; Nagasaki, Masao; Noiri, Eisei; Baek, Jiwon; Abeyagunawardena, Asiri; Lane, Brandon; Chryst-Stangl, Megan; Esezobor, Christopher; Solarin, Adaobi U; Vivarelli, Marina; Dębiec, Hanna; Matsuo, Masafumi; Ronco, Pierre; Sampson, Matthew G.; Tokunaga, Katsushi; Araki, Yoshinori; Nagaoka, Yoshinobu; Okamoto, Takayuki; Sato, Yasuyuki; Hayashi, Asako; Takahashi, Toshiyuki; Aoyagi, Hayato; Ueno, Michihiko; Nakanishi, Masayoshi; Toita, Nariaki; Uetake, Kimiaki; Kobayashi, Norio; Fujita, Shoji; Tsuruga, Kazushi; Kumagai, Naoya; Kudo, Hiroki; Tanaka, Eriko; Omori, Tae; Okada, Mari; Hatai, Yoshiho; Udagawa, Tomohiro; Motoyoshi, Yaeko; Ishikura, Kenji; Kamei, Koichi; Ogura, Masao; Mai, Sabine; Kano, Yuji; Hattori, Masashi; Miura, Kenichiro; Harita, Yutaka; Kanda, Shoichiro; Sawanobori, Emi; Kobayashi, Anna; Kojika, Manabu; Ohwada, Yoko; Kou, Yan; Hataya, Hiroshi; Hamada, Riku; Terano, Chikako; Harada, Ryuichi; Hamasaki, Yuko; Hashimoto, Junya; Ito, Shuichi; Machida, Haruhiko; Inaba, Aya; Matsuyama, Tomohiro; Goto, Miwa; Shimizu, Masaki; Ohta, Kazuhide; Ikezumi, Yohei; Yamada, Takeshi; Suzuki, Toshiaki; Tamamura, Soichi; Mori, Yoshio; Hidaka, Yoshihiko; Matsuoka, Daisuke; Kinoshita, Tatsuya; Noda, Shunsuke; Kitahara, Masashi; Fujita, Naoya; Hibino, Satoshi; Iijima, Kazumoto; Nozu, Kandai; Kono, Hiroshi; Minamikawa, Shogo; Yamamura, Takehira; Nagano, China; Horinouchi, Tomoko; Nakanishi, Keita; Fujimura, Junya; Sakakibara, Noburu; Aoto, Yuya; Ishiko, Shinya; Tanaka, Ryojiro; Kanda, Kyoko; Inaguma, Yosuke; Hashimura, Yuya; Ishimori, Shingo; Kamiyoshi, Naohiro; Shibano, Takayuki; Takeshima, Yasuhiro; Fujimaru, Rika; Ueda, Hiroaki; Ashida, Akira; Matsumura, Hideki; Kubota, Takuo; Kitaoka, Taichi; Okuda, Yusuke; Sawai, Toshihiro; Sakai, Tomoyuki; Shima, Yuko; Hama, Taketsugu; Fujieda, Mikiya; Imamura, Masayuki; Itoh, Shigeru; Iwaki, Takuma; Shimizu, Masaru; Nagatani, Koji; Kubo, Shoji; Urushihara, Maki; Kaku, Yoshitsugu; Nishimura, Manao; Yoshino, Miwa; Hatae, Ken; Hinokiyama, Maiko; Kuroki, Rie; Ohtsuka, Yasufumi; Oka, Masafumi; Nishimura, Satoshi; Satô, Tadashi; Tanaka, Seiji; Zaitsu, Ayuko; Nakazato, Hitoshi; Tamura, Hiroshi; Nakanishi, Koichi; Cho, Min Hyun; Ha, Tae-Sun; Cheong, Hae Il; Kang, Hee Gyung; Ha, Il‐Soo; Kim, Ji Hyun; Park, Peong Gang; Cho, Myung Hyun; Han, Kyoung Hee; Yang, Eun Mi; Quiroga, Alejandro; Moudgil, Asha; Chavers, Blanche M.; Kwon, Charles; Bowers, Corinna; Gipson, Deb; Chand, Deepa H.; Weaver, Donald J.; Abraham, Elizabeth; Janjua, Halima S.; Lin, Jen-Jar; Greenbaum, Larry A.; Kallash, Mahmoud; Rheault, Michelle N.; Gonzalez, Nilka De Jeus; Brophy, Patrick D.; Gbadegesin, Rasheed; Nagaraj, Shashi; Massengill, Susan; Srivastava, Tarak; Hunley, Tray; Cai, Yi; Omoloja, Abiodun Aderogba; Silva, Cynthia; Adeyemo, Adebowale; Thalgahagoda, Shenal; Kari, Jameela A.; Desoky, Sherif El; Abdelhadi, Mohammed; Akil, Rachida; Azib, Sonia; Basmaci, Romain; Benoist, G.; Bensaïd, Philippe; Blanc, Philippe; Boyer, Olivia; Bucher, Julie; Chacé, Anne; Chalvon, Arnaud; Cheminee, Marion; Chendjou, Sandrine; Daoud, Patrick; Deschênes, Georges; Dossier, Claire; Elias, Ossam; Gagliadone, Chantal; Gajdos, Vincent; Galerne, Aurélien; Jacqz-Aigrain, Évelyne; Sanchez, Lydie; Khaled, M. Ben; Khelfaoui, Fatima; Laoudi, Yacine; Larakeb, Anis; Limani, Tarek; Mahdi, Fouad; Mandelcwaijg, Alexis; Muller, Stéphanie; Nacer, Kacem; Nathanson, Sylvie; Pellegrino, B.; Pharaon, I.; Roudault, Véronica; Rouget, Sébastien; Saf, Marc; Simon, Tabassom; Tahiri, C.; Ulinski, Tim; Zenkhri, Férielle

doi:10.1016/j.kint.2020.05.029

Cited by 42 publications

(55 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There are also two GWAS in Japanese SSNS patients (224 vs 419 controls and 987 cases vs 3206 controls, respectively) confirming the association with HLA-DR/DQ is important in a different ethnicity [9,10].…”

Section: The Role Of Hla In Ssnsmentioning

confidence: 77%

“…Remarkably, in both Japanese cohorts studied [9,10], the common risk haplotype of the European and South Asian population (HLA-DQA1*02:01; HLA-DRB1*07:01; HLA-DQB1*02) was not replicated. The haplotype associated with the strongest risk for disease was HLA-DRB1*08:02, DQB1*03:02, and the haplotype with the strongest protective association was HLA-DRB1*13:02, DQB1*06:04 [9].…”

Section: The Role Of Hla In Ssnsmentioning

confidence: 90%

“…One tool to investigate such complex genetic backgrounds is the genome-wide association study (GWAS) [6]. Recently, GWAS of SSNS have started to dissect the polygenic nature of this disease, and indeed have confirmed the long-standing observational findings that the immune system plays a critical role in SSNS development [7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Novel insights in the genetics of steroid-sensitive nephrotic syndrome in childhood

et al. 2020

View full text Add to dashboard Cite

Steroid sensitive nephrotic syndrome (SSNS) is the most common form of nephrotic syndrome in childhood and there is growing evidence that genetics play a role in the susceptibility for the disease. Familial clustering has been observed and led to several studies on familiar SSNS trying to identify a monogenic cause of the disease. Until now, however, none of these have provided convincing evidence for Mendelian inheritance. This and the phenotypic variability within SSNS suggest a complex inheritance pattern, where multiple variants, interactions between those and the environment play a role in disease development. Genome wide association studies (GWAS) have been used to investigate this complex disease. We herein highlight new insights in the genetics of the disease provided by GWAS and how these fit into our understanding of the pathogenesis of SSNS.

show abstract

Section: The Role Of Hla In Ssnsmentioning

confidence: 77%

Section: The Role Of Hla In Ssnsmentioning

confidence: 90%

See 1 more Smart Citation

Novel insights in the genetics of steroid-sensitive nephrotic syndrome in childhood

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Given that NPHS1 encodes the immunoglobulin superfamily protein, nephrin, expressed on glomerular epithelial cells (i.e., podocytes), this landmark study led to a substantial increase in our understanding of podocyte involvement in the development of massive proteinuria observed in NS. Interestingly enough, a recent genome‐wide study with 987 childhood SSNS patients and 3,206 healthy controls with Japanese ancestry demonstrated that common variants in NPHS1‐KIRREL2 (rs56117924) and TNFSF15 (rs6478109) regions achieved genome‐wide significance and that trans‐ethnic meta‐analyses including Japanese, Korean, South Asian, African, European, Hispanic and Maghrebian populations confirmed the significant associations of variants in NPHS1‐KIRREL2 and TNFSF15 loci 26 . Furthermore, analysis of the NPHS1 risk alleles with glomerular NPHS1 mRNA expression from the same person revealed allele‐specific expression with significantly lower expression of the transcript derived from the risk haplotype.…”

Section: Involvement Of Podocytes In the Development Of Proteinuria And Their Association With Regulatory T Lymphocytesmentioning

confidence: 98%

The long and winding road to the etiology of idiopathic nephrotic syndrome in children: Focusing on abnormalities in the gut microbiota

Tsuji

2021

Pediatrics International

View full text Add to dashboard Cite

Childhood nephrotic syndrome is idiopathic in 90% of cases. Despite its relatively high prevalence (30–35 per 100 000 individuals under 15 years old), the etiology of the disease remains elusive. It has become clear that oxidants are elevated, and antioxidants are decreased, at onset of idiopathic nephrotic syndrome (INS). It was suggested that overexpression of podocyte CD80 induced by abnormalities of Tregs was involved in the pathogenesis of INS. Subsequently, it became clear that quantitative or qualitative reduction of Tregs has a profound impact on the development of INS. To address why Tregs are decreased at onset of INS, it was hypothesized that a decrease in Tregs may be associated with dysbiosis. Given the critical role of butyrate‐producing bacteria in the differentiation of Tregs, the gut microbiota was analyzed with a particular focus on the abundance of butyrate‐producing bacteria, and it was found that pediatric patients with INS had low levels of butyrate in their stool and a low percentage of butyrate‐producing bacteria. Interestingly, it was recently reported that gut dysbiosis increases oxidative stress in the intestinal tract. Taken together, we currently hypothesize that gut dysbiosis is associated with a predisposition to INS because of immunological abnormalities characterized by abnormal Tregs with increased oxidative stress.

show abstract

“…There is suggestion that MCD may lead to FSGS in treatment resistant patients and at times it may be difficult to adequately obtain a kidney biopsy sample that reflects the progression of MCD toward FSGS (due to potential biopsy sampling error) (1). Recent evidence from genetic association studies suggests that genetic variation in the adaptive immune response coupled with environmental factors may be very important risk factors for development of MCD (7)(8)(9)(10). The animal model that most closely resembles MCD is the puromycin aminonucleoside nephrosis (PAN) in rats, which leads to the production of reactive oxygen species and direct DNA damage.…”

Section: Introductionmentioning

confidence: 99%

Case Report: Novel Dietary Supplementation Associated With Kidney Recovery and Reduction in Proteinuria in a Dialysis Dependent Patient Secondary to Steroid Resistant Minimal Change Disease

2021

View full text Add to dashboard Cite

Minimal change disease (MCD) is the most common cause of nephrotic syndrome worldwide. For decades, the foundation of the treatment has been corticosteroids. However, relapse rate is high and up to 40% of patients develop frequent relapsing/steroid dependent course and one third become steroid resistant. This requires treatment with repeated courses of corticosteroids, and second and third line immunomodulators increasing the incidence of drug related adverse effects. More recently, there have been reports of a very small subset of Nephrotic Syndrome (NS) patients who are initially steroid sensitive and later become secondarily steroid resistant. The disease course in this small subset is often protracted leading ultimately to end stage kidney disease requiring dialysis or kidney transplantation. Unfortunately, patients with this disease course do not do well post transplantation because 80% of them will develop disease recurrence that will ultimately lead to graft failure. Few approaches have been tried over many years to reduce the frequency of relapses, and steroid dependence and there is absolutely no therapeutic intervention for patients who develop secondary steroid resistance. Nonetheless, their therapeutic index is low, evidencing the need of a safer complementary treatment. Several hypotheses, including an oxidative stress-mediated mechanism, and immune dysregulation have been proposed to date to explain the underlying mechanism of Minimal Change Disease (MCD) but its specific etiology remains elusive. Here, we report a case of a 54-year-old man with steroid and cyclosporine resistant MCD. The patient rapidly progressed to end stage kidney disease requiring initiation of chronic dialysis. Intradialytic parenteral nutrition (IDPN), albumin infusion along with a proprietary dietary supplement, as part of the supportive therapy, led to kidney function recovery and complete remission of MCD without relapses.

show abstract

Common risk variants in NPHS1 and TNFSF15 are associated with childhood steroid-sensitive nephrotic syndrome

Cited by 42 publications

References 57 publications

Novel insights in the genetics of steroid-sensitive nephrotic syndrome in childhood

Novel insights in the genetics of steroid-sensitive nephrotic syndrome in childhood

The long and winding road to the etiology of idiopathic nephrotic syndrome in children: Focusing on abnormalities in the gut microbiota

Case Report: Novel Dietary Supplementation Associated With Kidney Recovery and Reduction in Proteinuria in a Dialysis Dependent Patient Secondary to Steroid Resistant Minimal Change Disease

Contact Info

Product

Resources

About