Shared genetic risk across different presentations of gene test-negative idiopathic nephrotic syndrome

Mallory L Downie; Sanjana Gupta; Melanie M Y Chan; Omid Sadeghi-Alavijeh; Jingjing Cao; Rulan S Parekh; Carmen Bugarin Diz; Agnieszka Bierzynska; Adam P Levine; Ruth J Pepper; Horia Stanescu; Moin A Saleem; Robert Kleta; Detlef Bockenhauer; Ania B Koziell; Daniel P Gale

doi:10.1007/s00467-022-05789-7

Shared genetic risk across different presentations of gene test-negative idiopathic nephrotic syndrome

Mallory L Downie, Sanjana Gupta, Melanie M Y Chan, Omid Sadeghi-Alavijeh, Jingjing Cao, Rulan S Parekh, Carmen Bugarin Diz, Agnieszka Bierzynska, Adam P Levine, Ruth J Pepper, Horia Stanescu, Moin A Saleem, Robert Kleta, Detlef Bockenhauer, Ania B Koziell, Daniel P Gale

Bristol Medical School (THS)

Research output: Contribution to journal › Article (Academic Journal) › peer-review

4 Citations (Scopus)

Abstract

BACKGROUND: Idiop athic nephrotic syndrome (INS) is classified in children according to response to initial corticosteroid therapy into steroid-sensitive (SSNS) and steroid-resistant nephrotic syndrome (SRNS), and in adults according to histology into minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). However, there is well-recognised phenotypic overlap between these entities. Genome-wide association studies (GWAS) have shown a strong association between SSNS and variation at HLA, suggesting an underlying immunological basis. We sought to determine whether a risk score generated from genetic variants associated with SSNS could be used to gain insight into the pathophysiology of INS presenting in other ways.

METHODS: We developed an SSNS genetic risk score (SSNS-GRS) from the five variants independently associated with childhood SSNS in a previous European GWAS. We quantified SSNS-GRS in independent cohorts of European individuals with childhood SSNS, non-monogenic SRNS, MCD, and FSGS, and contrasted them with SSNS-GRS quantified in individuals with monogenic SRNS, membranous nephropathy (a different immune-mediated disease-causing nephrotic syndrome), and healthy controls.

RESULTS: The SSNS-GRS was significantly elevated in cohorts with SSNS, non-monogenic SRNS, MCD, and FSGS compared to healthy participants and those with membranous nephropathy. The SSNS-GRS in all cohorts with non-monogenic INS were also significantly elevated compared to those with monogenic SRNS.

CONCLUSIONS: The shared genetic risk factors among patients with different presentations of INS strongly suggests a shared autoimmune pathogenesis when monogenic causes are excluded. Use of the SSNS-GRS, in addition to testing for monogenic causes, may help to classify patients presenting with INS. A higher resolution version of the Graphical abstract is available as Supplementary information.

Original language	English
Journal	Pediatric Nephrology
Early online date	10 Nov 2022
DOIs	https://doi.org/10.1007/s00467-022-05789-7
Publication status	E-pub ahead of print - 10 Nov 2022

Bibliographical note

Funding Information:
MLD and DPG are supported by St. Peter’s Trust for Kidney, Bladder, & Prostate Research. MLD is supported by the KRESCENT Post-Doctoral Fellowship from the Kidney Foundation of Canada. MMYC is supported by a Kidney Research UK Training Fellowship. CBD and ABK are supported by the Guys and St Thomas’ Charity and the Medical Research Council. AB is supported by Kidney Research UK.

Funding Information:
This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK, and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. We thank NIHR BioResource volunteers for their participation, and gratefully acknowledge NIHR BioResource centres, NHS Trusts, and staff for their contribution. We thank the National Institute for Health Research, NHS Blood and Transplant, and Health Data Research UK as part of the Digital Innovation Hub Programme.

Publisher Copyright:
© 2022, The Author(s).

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Downie, M. L., Gupta, S., Chan, M. M. Y., Sadeghi-Alavijeh, O., Cao, J., Parekh, R. S., Diz, C. B., Bierzynska, A., Levine, A. P., Pepper, R. J., Stanescu, H., Saleem, M. A., Kleta, R., Bockenhauer, D., Koziell, A. B., & Gale, D. P. (2022). Shared genetic risk across different presentations of gene test-negative idiopathic nephrotic syndrome. Pediatric Nephrology. Advance online publication. https://doi.org/10.1007/s00467-022-05789-7

@article{08a9963c5a454bd799b8dcd745997233,

title = "Shared genetic risk across different presentations of gene test-negative idiopathic nephrotic syndrome",

abstract = "BACKGROUND: Idiop athic nephrotic syndrome (INS) is classified in children according to response to initial corticosteroid therapy into steroid-sensitive (SSNS) and steroid-resistant nephrotic syndrome (SRNS), and in adults according to histology into minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). However, there is well-recognised phenotypic overlap between these entities. Genome-wide association studies (GWAS) have shown a strong association between SSNS and variation at HLA, suggesting an underlying immunological basis. We sought to determine whether a risk score generated from genetic variants associated with SSNS could be used to gain insight into the pathophysiology of INS presenting in other ways.METHODS: We developed an SSNS genetic risk score (SSNS-GRS) from the five variants independently associated with childhood SSNS in a previous European GWAS. We quantified SSNS-GRS in independent cohorts of European individuals with childhood SSNS, non-monogenic SRNS, MCD, and FSGS, and contrasted them with SSNS-GRS quantified in individuals with monogenic SRNS, membranous nephropathy (a different immune-mediated disease-causing nephrotic syndrome), and healthy controls.RESULTS: The SSNS-GRS was significantly elevated in cohorts with SSNS, non-monogenic SRNS, MCD, and FSGS compared to healthy participants and those with membranous nephropathy. The SSNS-GRS in all cohorts with non-monogenic INS were also significantly elevated compared to those with monogenic SRNS.CONCLUSIONS: The shared genetic risk factors among patients with different presentations of INS strongly suggests a shared autoimmune pathogenesis when monogenic causes are excluded. Use of the SSNS-GRS, in addition to testing for monogenic causes, may help to classify patients presenting with INS. A higher resolution version of the Graphical abstract is available as Supplementary information.",

author = "Downie, {Mallory L} and Sanjana Gupta and Chan, {Melanie M Y} and Omid Sadeghi-Alavijeh and Jingjing Cao and Parekh, {Rulan S} and Diz, {Carmen Bugarin} and Agnieszka Bierzynska and Levine, {Adam P} and Pepper, {Ruth J} and Horia Stanescu and Saleem, {Moin A} and Robert Kleta and Detlef Bockenhauer and Koziell, {Ania B} and Gale, {Daniel P}",

note = "Funding Information: MLD and DPG are supported by St. Peter{\textquoteright}s Trust for Kidney, Bladder, & Prostate Research. MLD is supported by the KRESCENT Post-Doctoral Fellowship from the Kidney Foundation of Canada. MMYC is supported by a Kidney Research UK Training Fellowship. CBD and ABK are supported by the Guys and St Thomas{\textquoteright} Charity and the Medical Research Council. AB is supported by Kidney Research UK. Funding Information: This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK, and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. We thank NIHR BioResource volunteers for their participation, and gratefully acknowledge NIHR BioResource centres, NHS Trusts, and staff for their contribution. We thank the National Institute for Health Research, NHS Blood and Transplant, and Health Data Research UK as part of the Digital Innovation Hub Programme. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = nov,

day = "10",

doi = "10.1007/s00467-022-05789-7",

language = "English",

journal = "Pediatric Nephrology",

issn = "0931-041X",

publisher = "Springer Verlag",

}

Downie, ML, Gupta, S, Chan, MMY, Sadeghi-Alavijeh, O, Cao, J, Parekh, RS, Diz, CB, Bierzynska, A, Levine, AP, Pepper, RJ, Stanescu, H, Saleem, MA, Kleta, R, Bockenhauer, D, Koziell, AB & Gale, DP 2022, 'Shared genetic risk across different presentations of gene test-negative idiopathic nephrotic syndrome', Pediatric Nephrology. https://doi.org/10.1007/s00467-022-05789-7

TY - JOUR

T1 - Shared genetic risk across different presentations of gene test-negative idiopathic nephrotic syndrome

AU - Downie, Mallory L

AU - Gupta, Sanjana

AU - Chan, Melanie M Y

AU - Sadeghi-Alavijeh, Omid

AU - Cao, Jingjing

AU - Parekh, Rulan S

AU - Diz, Carmen Bugarin

AU - Bierzynska, Agnieszka

AU - Levine, Adam P

AU - Pepper, Ruth J

AU - Stanescu, Horia

AU - Saleem, Moin A

AU - Kleta, Robert

AU - Bockenhauer, Detlef

AU - Koziell, Ania B

AU - Gale, Daniel P

N1 - Funding Information: MLD and DPG are supported by St. Peter’s Trust for Kidney, Bladder, & Prostate Research. MLD is supported by the KRESCENT Post-Doctoral Fellowship from the Kidney Foundation of Canada. MMYC is supported by a Kidney Research UK Training Fellowship. CBD and ABK are supported by the Guys and St Thomas’ Charity and the Medical Research Council. AB is supported by Kidney Research UK. Funding Information: This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK, and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. We thank NIHR BioResource volunteers for their participation, and gratefully acknowledge NIHR BioResource centres, NHS Trusts, and staff for their contribution. We thank the National Institute for Health Research, NHS Blood and Transplant, and Health Data Research UK as part of the Digital Innovation Hub Programme. Publisher Copyright: © 2022, The Author(s).

PY - 2022/11/10

Y1 - 2022/11/10

N2 - BACKGROUND: Idiop athic nephrotic syndrome (INS) is classified in children according to response to initial corticosteroid therapy into steroid-sensitive (SSNS) and steroid-resistant nephrotic syndrome (SRNS), and in adults according to histology into minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). However, there is well-recognised phenotypic overlap between these entities. Genome-wide association studies (GWAS) have shown a strong association between SSNS and variation at HLA, suggesting an underlying immunological basis. We sought to determine whether a risk score generated from genetic variants associated with SSNS could be used to gain insight into the pathophysiology of INS presenting in other ways.METHODS: We developed an SSNS genetic risk score (SSNS-GRS) from the five variants independently associated with childhood SSNS in a previous European GWAS. We quantified SSNS-GRS in independent cohorts of European individuals with childhood SSNS, non-monogenic SRNS, MCD, and FSGS, and contrasted them with SSNS-GRS quantified in individuals with monogenic SRNS, membranous nephropathy (a different immune-mediated disease-causing nephrotic syndrome), and healthy controls.RESULTS: The SSNS-GRS was significantly elevated in cohorts with SSNS, non-monogenic SRNS, MCD, and FSGS compared to healthy participants and those with membranous nephropathy. The SSNS-GRS in all cohorts with non-monogenic INS were also significantly elevated compared to those with monogenic SRNS.CONCLUSIONS: The shared genetic risk factors among patients with different presentations of INS strongly suggests a shared autoimmune pathogenesis when monogenic causes are excluded. Use of the SSNS-GRS, in addition to testing for monogenic causes, may help to classify patients presenting with INS. A higher resolution version of the Graphical abstract is available as Supplementary information.

AB - BACKGROUND: Idiop athic nephrotic syndrome (INS) is classified in children according to response to initial corticosteroid therapy into steroid-sensitive (SSNS) and steroid-resistant nephrotic syndrome (SRNS), and in adults according to histology into minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). However, there is well-recognised phenotypic overlap between these entities. Genome-wide association studies (GWAS) have shown a strong association between SSNS and variation at HLA, suggesting an underlying immunological basis. We sought to determine whether a risk score generated from genetic variants associated with SSNS could be used to gain insight into the pathophysiology of INS presenting in other ways.METHODS: We developed an SSNS genetic risk score (SSNS-GRS) from the five variants independently associated with childhood SSNS in a previous European GWAS. We quantified SSNS-GRS in independent cohorts of European individuals with childhood SSNS, non-monogenic SRNS, MCD, and FSGS, and contrasted them with SSNS-GRS quantified in individuals with monogenic SRNS, membranous nephropathy (a different immune-mediated disease-causing nephrotic syndrome), and healthy controls.RESULTS: The SSNS-GRS was significantly elevated in cohorts with SSNS, non-monogenic SRNS, MCD, and FSGS compared to healthy participants and those with membranous nephropathy. The SSNS-GRS in all cohorts with non-monogenic INS were also significantly elevated compared to those with monogenic SRNS.CONCLUSIONS: The shared genetic risk factors among patients with different presentations of INS strongly suggests a shared autoimmune pathogenesis when monogenic causes are excluded. Use of the SSNS-GRS, in addition to testing for monogenic causes, may help to classify patients presenting with INS. A higher resolution version of the Graphical abstract is available as Supplementary information.

U2 - 10.1007/s00467-022-05789-7

DO - 10.1007/s00467-022-05789-7

M3 - Article (Academic Journal)

C2 - 36357634

SN - 0931-041X

JO - Pediatric Nephrology

JF - Pediatric Nephrology

ER -

Shared genetic risk across different presentations of gene test-negative idiopathic nephrotic syndrome

Abstract

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