Common Risk Variants in AHI1 Are Associated With Childhood Steroid Sensitive Nephrotic Syndrome

Mallory L. Downie; Sanjana Gupta; Catalin Voinescu; Adam P. Levine; Omid Sadeghi-Alavijeh; Stephanie Dufek-Kamperis; Jingjing Cao; Martin Christian; Jameela A. Kari; Shenal Thalgahagoda; Randula Ranawaka; Asiri Abeyagunawardena; Rasheed Gbadegesin; Rulan Parekh; Robert Kleta; Detlef Bockenhauer; Horia C. Stanescu; Daniel P. Gale

doi:10.1016/j.ekir.2023.05.018

Common Risk Variants in AHI1 Are Associated With Childhood Steroid Sensitive Nephrotic Syndrome

Mallory L. Downie, Sanjana Gupta, Catalin Voinescu, Adam P. Levine, Omid Sadeghi-Alavijeh, Stephanie Dufek-Kamperis, Jingjing Cao, Martin Christian, Jameela A. Kari, Shenal Thalgahagoda, Randula Ranawaka, Asiri Abeyagunawardena, Rasheed Gbadegesin, Rulan Parekh, Robert Kleta, Detlef Bockenhauer, Horia C. Stanescu, Daniel P. Gale^*

^*Corresponding author for this work

Department of Clinical Medicine - Department of Paediatrics

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

5 Citations (Scopus)

Abstract

Introduction: Steroid-sensitive nephrotic syndrome (SSNS) is the most common form of kidney disease in children worldwide. Genome-wide association studies (GWAS) have demonstrated the association of SSNS with genetic variation at HLA-DQ/DR and have identified several non-HLA loci that aid in further understanding of disease pathophysiology. We sought to identify additional genetic loci associated with SSNS in children of Sri Lankan and European ancestry. Methods: We conducted a GWAS in a cohort of Sri Lankan individuals comprising 420 pediatric patients with SSNS and 2339 genetic ancestry matched controls obtained from the UK Biobank. We then performed a transethnic meta-analysis with a previously reported European cohort of 422 pediatric patients and 5642 controls. Results: Our GWAS confirmed the previously reported association of SSNS with HLA-DR/DQ (rs9271602, P = 1.12 × 10⁻²⁷, odds ratio [OR] = 2.75). Transethnic meta-analysis replicated these findings and identified a novel association at AHI1 (rs2746432, P = 2.79 × 10⁻⁸, OR = 1.37), which was also replicated in an independent South Asian cohort. AHI1 is implicated in ciliary protein transport and immune dysregulation, with rare variation in this gene contributing to Joubert syndrome type 3. Conclusions: Common variation in AHI1 confers risk of the development of SSNS in both Sri Lankan and European populations. The association with common variation in AHI1 further supports the role of immune dysregulation in the pathogenesis of SSNS and demonstrates that variation across the allele frequency spectrum in a gene can contribute to disparate monogenic and polygenic diseases.

Original language	English
Journal	Kidney International Reports
Volume	8
Issue	8
Pages (from-to)	1562-1574
Number of pages	13
ISSN	2468-0249
DOIs	https://doi.org/10.1016/j.ekir.2023.05.018
Publication status	Published - Aug 2023

Keywords

AHI1
GWAS
HLA
pediatric nephrology
SSNS

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Downie, M. L., Gupta, S., Voinescu, C., Levine, A. P., Sadeghi-Alavijeh, O., Dufek-Kamperis, S., Cao, J., Christian, M., Kari, J. A., Thalgahagoda, S., Ranawaka, R., Abeyagunawardena, A., Gbadegesin, R., Parekh, R., Kleta, R., Bockenhauer, D., Stanescu, H. C., & Gale, D. P. (2023). Common Risk Variants in AHI1 Are Associated With Childhood Steroid Sensitive Nephrotic Syndrome. Kidney International Reports, 8(8), 1562-1574. https://doi.org/10.1016/j.ekir.2023.05.018

@article{6e0fe6e3b5fc4f4ea50283aba25448b9,

title = "Common Risk Variants in AHI1 Are Associated With Childhood Steroid Sensitive Nephrotic Syndrome",

abstract = "Introduction: Steroid-sensitive nephrotic syndrome (SSNS) is the most common form of kidney disease in children worldwide. Genome-wide association studies (GWAS) have demonstrated the association of SSNS with genetic variation at HLA-DQ/DR and have identified several non-HLA loci that aid in further understanding of disease pathophysiology. We sought to identify additional genetic loci associated with SSNS in children of Sri Lankan and European ancestry. Methods: We conducted a GWAS in a cohort of Sri Lankan individuals comprising 420 pediatric patients with SSNS and 2339 genetic ancestry matched controls obtained from the UK Biobank. We then performed a transethnic meta-analysis with a previously reported European cohort of 422 pediatric patients and 5642 controls. Results: Our GWAS confirmed the previously reported association of SSNS with HLA-DR/DQ (rs9271602, P = 1.12 × 10−27, odds ratio [OR] = 2.75). Transethnic meta-analysis replicated these findings and identified a novel association at AHI1 (rs2746432, P = 2.79 × 10−8, OR = 1.37), which was also replicated in an independent South Asian cohort. AHI1 is implicated in ciliary protein transport and immune dysregulation, with rare variation in this gene contributing to Joubert syndrome type 3. Conclusions: Common variation in AHI1 confers risk of the development of SSNS in both Sri Lankan and European populations. The association with common variation in AHI1 further supports the role of immune dysregulation in the pathogenesis of SSNS and demonstrates that variation across the allele frequency spectrum in a gene can contribute to disparate monogenic and polygenic diseases.",

keywords = "AHI1, GWAS, HLA, pediatric nephrology, SSNS",

author = "Downie, {Mallory L.} and Sanjana Gupta and Catalin Voinescu and Levine, {Adam P.} and Omid Sadeghi-Alavijeh and Stephanie Dufek-Kamperis and Jingjing Cao and Martin Christian and Kari, {Jameela A.} and Shenal Thalgahagoda and Randula Ranawaka and Asiri Abeyagunawardena and Rasheed Gbadegesin and Rulan Parekh and Robert Kleta and Detlef Bockenhauer and Stanescu, {Horia C.} and Gale, {Daniel P.}",

note = "Publisher Copyright: {\textcopyright} 2023 International Society of Nephrology",

year = "2023",

month = aug,

doi = "10.1016/j.ekir.2023.05.018",

language = "English",

volume = "8",

pages = "1562--1574",

journal = "Kidney International Reports",

issn = "2468-0249",

publisher = "Elsevier Inc.",

number = "8",

}

Downie, ML, Gupta, S, Voinescu, C, Levine, AP, Sadeghi-Alavijeh, O, Dufek-Kamperis, S, Cao, J, Christian, M, Kari, JA, Thalgahagoda, S, Ranawaka, R, Abeyagunawardena, A, Gbadegesin, R, Parekh, R, Kleta, R, Bockenhauer, D, Stanescu, HC & Gale, DP 2023, 'Common Risk Variants in AHI1 Are Associated With Childhood Steroid Sensitive Nephrotic Syndrome', Kidney International Reports, vol. 8, no. 8, pp. 1562-1574. https://doi.org/10.1016/j.ekir.2023.05.018

Common Risk Variants in AHI1 Are Associated With Childhood Steroid Sensitive Nephrotic Syndrome. / Downie, Mallory L.; Gupta, Sanjana; Voinescu, Catalin et al.
In: Kidney International Reports, Vol. 8, No. 8, 08.2023, p. 1562-1574.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Common Risk Variants in AHI1 Are Associated With Childhood Steroid Sensitive Nephrotic Syndrome

AU - Downie, Mallory L.

AU - Gupta, Sanjana

AU - Voinescu, Catalin

AU - Levine, Adam P.

AU - Sadeghi-Alavijeh, Omid

AU - Dufek-Kamperis, Stephanie

AU - Cao, Jingjing

AU - Christian, Martin

AU - Kari, Jameela A.

AU - Thalgahagoda, Shenal

AU - Ranawaka, Randula

AU - Abeyagunawardena, Asiri

AU - Gbadegesin, Rasheed

AU - Parekh, Rulan

AU - Kleta, Robert

AU - Bockenhauer, Detlef

AU - Stanescu, Horia C.

AU - Gale, Daniel P.

PY - 2023/8

Y1 - 2023/8

N2 - Introduction: Steroid-sensitive nephrotic syndrome (SSNS) is the most common form of kidney disease in children worldwide. Genome-wide association studies (GWAS) have demonstrated the association of SSNS with genetic variation at HLA-DQ/DR and have identified several non-HLA loci that aid in further understanding of disease pathophysiology. We sought to identify additional genetic loci associated with SSNS in children of Sri Lankan and European ancestry. Methods: We conducted a GWAS in a cohort of Sri Lankan individuals comprising 420 pediatric patients with SSNS and 2339 genetic ancestry matched controls obtained from the UK Biobank. We then performed a transethnic meta-analysis with a previously reported European cohort of 422 pediatric patients and 5642 controls. Results: Our GWAS confirmed the previously reported association of SSNS with HLA-DR/DQ (rs9271602, P = 1.12 × 10−27, odds ratio [OR] = 2.75). Transethnic meta-analysis replicated these findings and identified a novel association at AHI1 (rs2746432, P = 2.79 × 10−8, OR = 1.37), which was also replicated in an independent South Asian cohort. AHI1 is implicated in ciliary protein transport and immune dysregulation, with rare variation in this gene contributing to Joubert syndrome type 3. Conclusions: Common variation in AHI1 confers risk of the development of SSNS in both Sri Lankan and European populations. The association with common variation in AHI1 further supports the role of immune dysregulation in the pathogenesis of SSNS and demonstrates that variation across the allele frequency spectrum in a gene can contribute to disparate monogenic and polygenic diseases.

AB - Introduction: Steroid-sensitive nephrotic syndrome (SSNS) is the most common form of kidney disease in children worldwide. Genome-wide association studies (GWAS) have demonstrated the association of SSNS with genetic variation at HLA-DQ/DR and have identified several non-HLA loci that aid in further understanding of disease pathophysiology. We sought to identify additional genetic loci associated with SSNS in children of Sri Lankan and European ancestry. Methods: We conducted a GWAS in a cohort of Sri Lankan individuals comprising 420 pediatric patients with SSNS and 2339 genetic ancestry matched controls obtained from the UK Biobank. We then performed a transethnic meta-analysis with a previously reported European cohort of 422 pediatric patients and 5642 controls. Results: Our GWAS confirmed the previously reported association of SSNS with HLA-DR/DQ (rs9271602, P = 1.12 × 10−27, odds ratio [OR] = 2.75). Transethnic meta-analysis replicated these findings and identified a novel association at AHI1 (rs2746432, P = 2.79 × 10−8, OR = 1.37), which was also replicated in an independent South Asian cohort. AHI1 is implicated in ciliary protein transport and immune dysregulation, with rare variation in this gene contributing to Joubert syndrome type 3. Conclusions: Common variation in AHI1 confers risk of the development of SSNS in both Sri Lankan and European populations. The association with common variation in AHI1 further supports the role of immune dysregulation in the pathogenesis of SSNS and demonstrates that variation across the allele frequency spectrum in a gene can contribute to disparate monogenic and polygenic diseases.

KW - AHI1

KW - GWAS

KW - HLA

KW - pediatric nephrology

KW - SSNS

UR - http://www.scopus.com/inward/record.url?scp=85163302357&partnerID=8YFLogxK

U2 - 10.1016/j.ekir.2023.05.018

DO - 10.1016/j.ekir.2023.05.018

M3 - Journal article

C2 - 37547536

AN - SCOPUS:85163302357

SN - 2468-0249

VL - 8

SP - 1562

EP - 1574

JO - Kidney International Reports

JF - Kidney International Reports

IS - 8

ER -

Common Risk Variants in AHI1 Are Associated With Childhood Steroid Sensitive Nephrotic Syndrome

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