HLA-DQA1 and PLCG2 are candidate risk loci for childhood-onset steroid-sensitive nephrotic syndrome

Rasheed A. Gbadegesin; Adebowale Adeyemo; Nicholas J.A. Webb; Larry A. Greenbaum; Asiri Abeyagunawardena; Shenal Thalgahagoda; Arundhati Kale; Debbie Gipson; Tarak Srivastava; Jen Jar Lin; Deepa Chand; Tracy E. Hunley; Patrick D. Brophy; Arvind Bagga; Aditi Sinha; Michelle N. Rheault; Joanna Ghali; Kathy Nicholls; Elizabeth Abraham; Halima S. Janjua; Abiodun Omoloja; Gina Marie Barletta; Yi Cai; David D. Milford; Catherine O'Brien; Atif Awan; Vladimir Belostotsky; William E. Smoyer; Alison Homstad; Gentzon Hall; Guanghong Wu; Shashi Nagaraj; Delbert Wigfall; John Foreman; Michelle P. Winn

doi:10.1681/ASN.2014030247

HLA-DQA1 and PLCG2 are candidate risk loci for childhood-onset steroid-sensitive nephrotic syndrome

Rasheed A. Gbadegesin, Adebowale Adeyemo, Nicholas J.A. Webb, Larry A. Greenbaum, Asiri Abeyagunawardena, Shenal Thalgahagoda, Arundhati Kale, Debbie Gipson, Tarak Srivastava, Jen Jar Lin, Deepa Chand, Tracy E. Hunley, Patrick D. Brophy, Arvind Bagga, Aditi Sinha, Michelle N. Rheault, Joanna Ghali, Kathy Nicholls, Elizabeth Abraham, Halima S. JanjuaAbiodun Omoloja, Gina Marie Barletta, Yi Cai, David D. Milford, Catherine O'Brien, Atif Awan, Vladimir Belostotsky, William E. Smoyer, Alison Homstad, Gentzon Hall, Guanghong Wu, Shashi Nagaraj, Delbert Wigfall, John Foreman, Michelle P. Winn

Division of Nephrology, Hypertension & Apheresis

Research output: Contribution to journal › Article › peer-review

108 Scopus citations

Abstract

Steroid-sensitive nephrotic syndrome(SSNS) accounts for.80%of cases of nephrotic syndrome in childhood. However, the etiology and pathogenesis of SSNS remain obscure. Hypothesizing that coding variation may underlie SSNS risk, we conducted an exome array association study of SSNS.We enrolled a discovery set of 363 persons (214 South Asian children with SSNS and 149 controls) and genotyped them using the Illumina HumanExome Beadchip. Four common single nucleotide polymorphisms (SNPs) in HLA-DQA1 and HLA-DQB1 (rs1129740, rs9273349, rs1071630, and rs1140343) were significantly associated with SSNS at or near the Bonferroni-adjusted P value for the number of single variants thatwere tested (odds ratio, 2.11; 95%confidence interval, 1.56 to 2.86; P=1.6831026 (Fisher exact test). Two of these SNPs-the missense variants C34Y (rs1129740) and F41S (rs1071630) in HLA-DQA1-were replicated in an independent cohort of children of white European ancestry with SSNS (100 cases and 589 controls; P=1.42310217). In the rare variant gene set-based analysis, the best signal was found in PLCG2 (P=7.82531025). In conclusion, this exome array study identified HLA-DQA1 and PLCG2 missense coding variants as candidate loci for SSNS. The finding of a MHC class II locus underlying SSNS risk suggests a major role for immune response in the pathogenesis of SSNS.

Original language	English
Pages (from-to)	1701-1710
Number of pages	10
Journal	Journal of the American Society of Nephrology
Volume	26
Issue number	7
DOIs	https://doi.org/10.1681/ASN.2014030247
State	Published - Jul 1 2015

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Gbadegesin, R. A., Adeyemo, A., Webb, N. J. A., Greenbaum, L. A., Abeyagunawardena, A., Thalgahagoda, S., Kale, A., Gipson, D., Srivastava, T., Lin, J. J., Chand, D., Hunley, T. E., Brophy, P. D., Bagga, A., Sinha, A., Rheault, M. N., Ghali, J., Nicholls, K., Abraham, E., ... Winn, M. P. (2015). HLA-DQA1 and PLCG2 are candidate risk loci for childhood-onset steroid-sensitive nephrotic syndrome. Journal of the American Society of Nephrology, 26(7), 1701-1710. https://doi.org/10.1681/ASN.2014030247

@article{f098063cb5eb471ebea44dac24931a45,

title = "HLA-DQA1 and PLCG2 are candidate risk loci for childhood-onset steroid-sensitive nephrotic syndrome",

abstract = "Steroid-sensitive nephrotic syndrome(SSNS) accounts for.80%of cases of nephrotic syndrome in childhood. However, the etiology and pathogenesis of SSNS remain obscure. Hypothesizing that coding variation may underlie SSNS risk, we conducted an exome array association study of SSNS.We enrolled a discovery set of 363 persons (214 South Asian children with SSNS and 149 controls) and genotyped them using the Illumina HumanExome Beadchip. Four common single nucleotide polymorphisms (SNPs) in HLA-DQA1 and HLA-DQB1 (rs1129740, rs9273349, rs1071630, and rs1140343) were significantly associated with SSNS at or near the Bonferroni-adjusted P value for the number of single variants thatwere tested (odds ratio, 2.11; 95%confidence interval, 1.56 to 2.86; P=1.6831026 (Fisher exact test). Two of these SNPs-the missense variants C34Y (rs1129740) and F41S (rs1071630) in HLA-DQA1-were replicated in an independent cohort of children of white European ancestry with SSNS (100 cases and 589 controls; P=1.42310217). In the rare variant gene set-based analysis, the best signal was found in PLCG2 (P=7.82531025). In conclusion, this exome array study identified HLA-DQA1 and PLCG2 missense coding variants as candidate loci for SSNS. The finding of a MHC class II locus underlying SSNS risk suggests a major role for immune response in the pathogenesis of SSNS.",

author = "Gbadegesin, {Rasheed A.} and Adebowale Adeyemo and Webb, {Nicholas J.A.} and Greenbaum, {Larry A.} and Asiri Abeyagunawardena and Shenal Thalgahagoda and Arundhati Kale and Debbie Gipson and Tarak Srivastava and Lin, {Jen Jar} and Deepa Chand and Hunley, {Tracy E.} and Brophy, {Patrick D.} and Arvind Bagga and Aditi Sinha and Rheault, {Michelle N.} and Joanna Ghali and Kathy Nicholls and Elizabeth Abraham and Janjua, {Halima S.} and Abiodun Omoloja and Barletta, {Gina Marie} and Yi Cai and Milford, {David D.} and Catherine O'Brien and Atif Awan and Vladimir Belostotsky and Smoyer, {William E.} and Alison Homstad and Gentzon Hall and Guanghong Wu and Shashi Nagaraj and Delbert Wigfall and John Foreman and Winn, {Michelle P.}",

note = "Publisher Copyright: Copyright {\textcopyright} 2015 by the American Society of Nephrology.",

year = "2015",

month = jul,

day = "1",

doi = "10.1681/ASN.2014030247",

language = "English",

volume = "26",

pages = "1701--1710",

journal = "Journal of the American Society of Nephrology",

issn = "1046-6673",

number = "7",

}

Gbadegesin, RA, Adeyemo, A, Webb, NJA, Greenbaum, LA, Abeyagunawardena, A, Thalgahagoda, S, Kale, A, Gipson, D, Srivastava, T, Lin, JJ, Chand, D, Hunley, TE, Brophy, PD, Bagga, A, Sinha, A, Rheault, MN, Ghali, J, Nicholls, K, Abraham, E, Janjua, HS, Omoloja, A, Barletta, GM, Cai, Y, Milford, DD, O'Brien, C, Awan, A, Belostotsky, V, Smoyer, WE, Homstad, A, Hall, G, Wu, G, Nagaraj, S, Wigfall, D, Foreman, J & Winn, MP 2015, 'HLA-DQA1 and PLCG2 are candidate risk loci for childhood-onset steroid-sensitive nephrotic syndrome', Journal of the American Society of Nephrology, vol. 26, no. 7, pp. 1701-1710. https://doi.org/10.1681/ASN.2014030247

TY - JOUR

T1 - HLA-DQA1 and PLCG2 are candidate risk loci for childhood-onset steroid-sensitive nephrotic syndrome

AU - Gbadegesin, Rasheed A.

AU - Adeyemo, Adebowale

AU - Webb, Nicholas J.A.

AU - Greenbaum, Larry A.

AU - Abeyagunawardena, Asiri

AU - Thalgahagoda, Shenal

AU - Kale, Arundhati

AU - Gipson, Debbie

AU - Srivastava, Tarak

AU - Lin, Jen Jar

AU - Chand, Deepa

AU - Hunley, Tracy E.

AU - Brophy, Patrick D.

AU - Bagga, Arvind

AU - Sinha, Aditi

AU - Rheault, Michelle N.

AU - Ghali, Joanna

AU - Nicholls, Kathy

AU - Abraham, Elizabeth

AU - Janjua, Halima S.

AU - Omoloja, Abiodun

AU - Barletta, Gina Marie

AU - Cai, Yi

AU - Milford, David D.

AU - O'Brien, Catherine

AU - Awan, Atif

AU - Belostotsky, Vladimir

AU - Smoyer, William E.

AU - Homstad, Alison

AU - Hall, Gentzon

AU - Wu, Guanghong

AU - Nagaraj, Shashi

AU - Wigfall, Delbert

AU - Foreman, John

AU - Winn, Michelle P.

PY - 2015/7/1

Y1 - 2015/7/1

N2 - Steroid-sensitive nephrotic syndrome(SSNS) accounts for.80%of cases of nephrotic syndrome in childhood. However, the etiology and pathogenesis of SSNS remain obscure. Hypothesizing that coding variation may underlie SSNS risk, we conducted an exome array association study of SSNS.We enrolled a discovery set of 363 persons (214 South Asian children with SSNS and 149 controls) and genotyped them using the Illumina HumanExome Beadchip. Four common single nucleotide polymorphisms (SNPs) in HLA-DQA1 and HLA-DQB1 (rs1129740, rs9273349, rs1071630, and rs1140343) were significantly associated with SSNS at or near the Bonferroni-adjusted P value for the number of single variants thatwere tested (odds ratio, 2.11; 95%confidence interval, 1.56 to 2.86; P=1.6831026 (Fisher exact test). Two of these SNPs-the missense variants C34Y (rs1129740) and F41S (rs1071630) in HLA-DQA1-were replicated in an independent cohort of children of white European ancestry with SSNS (100 cases and 589 controls; P=1.42310217). In the rare variant gene set-based analysis, the best signal was found in PLCG2 (P=7.82531025). In conclusion, this exome array study identified HLA-DQA1 and PLCG2 missense coding variants as candidate loci for SSNS. The finding of a MHC class II locus underlying SSNS risk suggests a major role for immune response in the pathogenesis of SSNS.

AB - Steroid-sensitive nephrotic syndrome(SSNS) accounts for.80%of cases of nephrotic syndrome in childhood. However, the etiology and pathogenesis of SSNS remain obscure. Hypothesizing that coding variation may underlie SSNS risk, we conducted an exome array association study of SSNS.We enrolled a discovery set of 363 persons (214 South Asian children with SSNS and 149 controls) and genotyped them using the Illumina HumanExome Beadchip. Four common single nucleotide polymorphisms (SNPs) in HLA-DQA1 and HLA-DQB1 (rs1129740, rs9273349, rs1071630, and rs1140343) were significantly associated with SSNS at or near the Bonferroni-adjusted P value for the number of single variants thatwere tested (odds ratio, 2.11; 95%confidence interval, 1.56 to 2.86; P=1.6831026 (Fisher exact test). Two of these SNPs-the missense variants C34Y (rs1129740) and F41S (rs1071630) in HLA-DQA1-were replicated in an independent cohort of children of white European ancestry with SSNS (100 cases and 589 controls; P=1.42310217). In the rare variant gene set-based analysis, the best signal was found in PLCG2 (P=7.82531025). In conclusion, this exome array study identified HLA-DQA1 and PLCG2 missense coding variants as candidate loci for SSNS. The finding of a MHC class II locus underlying SSNS risk suggests a major role for immune response in the pathogenesis of SSNS.

UR - http://www.scopus.com/inward/record.url?scp=84934784384&partnerID=8YFLogxK

U2 - 10.1681/ASN.2014030247

DO - 10.1681/ASN.2014030247

M3 - Article

C2 - 25349203

AN - SCOPUS:84934784384

SN - 1046-6673

VL - 26

SP - 1701

EP - 1710

JO - Journal of the American Society of Nephrology

JF - Journal of the American Society of Nephrology

IS - 7

ER -

HLA-DQA1 and PLCG2 are candidate risk loci for childhood-onset steroid-sensitive nephrotic syndrome

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