HLA-DQA1 and PLCG2 Are Candidate Risk Loci for Childhood-Onset Steroid-Sensitive Nephrotic Syndrome

被引：96

作者：

Gbadegesin, Rasheed A. ^{[1
,2
]}

Adeyemo, Adebowale ^{[3
]}

Webb, Nicholas J. A. ^{[12
]}

Greenbaum, Larry A. ^{[6
,7
]}

Abeyagunawardena, Asiri ^{[8
]}

Thalgahagoda, Shenal ^{[8
]}

Kale, Arundhati ^{[9
,10
]}

Gipson, Debbie ^{[11
]}

Srivastava, Tarak ^{[4
,5
]}

Lin, Jen-Jar ^{[13
]}

Chand, Deepa ^{[14
]}

Hunley, Tracy E. ^{[15
]}

Brophy, Patrick D. ^{[16
]}

Bagga, Arvind ^{[17
]}

Sinha, Aditi ^{[17
]}

Rheault, Michelle N. ^{[18
]}

Ghali, Joanna ^{[19
]}

Nicholls, Kathy ^{[19
]}

Abraham, Elizabeth ^{[20
]}

Janjua, Halima S. ^{[15
,21
]}

Omoloja, Abiodun ^{[22
]}

Barletta, Gina-Marie ^{[23
]}

Cai, Yi ^{[24
]}

Milford, David D. ^{[25
]}

O'Brien, Catherine ^{[25
]}

Awan, Atif ^{[26
]}

Belostotsky, Vladimir ^{[27
]}

Smoyer, William E. ^{[28
]}

Homstad, Alison ^{[1
,2
]}

Hall, Gentzon ^{[29
,30
]}

Wu, Guanghong ^{[29
,30
]}

Nagaraj, Shashi ^{[1
,2
]}

Wigfall, Delbert ^{[1
,2
]}

Foreman, John ^{[1
,2
]}

Winn, Michelle P. ^{[29
,30
]}

机构：

[1] Duke Univ Med Ctr, Div Nephrol & Ctr Human Genet, Dept Pediat, Durham, NC USA

[2] Duke Univ, Med Ctr, Ctr Human Genet, Durham, NC 27710 USA

[3] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA

[4] Univ Manchester, Manchester Acad Hlth Sci Ctr, Royal Manchester Childrens Hosp, Dept Pediat Nephrol, Manchester, Lancs, England

[5] Univ Manchester, Manchester Acad Hlth Sci Ctr, Royal Manchester Childrens Hosp, NIHR Wellcome Trust Childrens Clin Res Facil, Manchester, Lancs, England

[6] Emory Univ, Sch Med, Div Pediat Nephrol, Atlanta, GA 30322 USA

[7] Childrens Healthcare Atlanta, Atlanta, GA USA

[8] Univ Peradeniya, Dept Pediat, Peradeniya, Sri Lanka

[9] Baylor Coll Med, Div Nephrol, Houston, TX 77030 USA

[10] Texas Childrens Hosp, Houston, TX 77030 USA

[11] Univ Michigan, Dept Pediat, Div Nephrol, Ann Arbor, MI 48109 USA

[12] Childrens Mercy Hosp, Div Nephrol, Kansas City, MO 64108 USA

[13] Wake Forest Univ, Baptist Med Ctr, Div Nephrol, Dept Pediat, Winston Salem, NC 27109 USA

[14] Rush Univ, Dept Pediat, Div Nephrol, Chicago, IL 60612 USA

[15] Vanderbilt Univ, Dept Pediat, Div Nephrol, Nashville, TN USA

[16] Univ Iowa, Dept Pediat, Div Nephrol, Iowa City, IA 52242 USA

[17] All India Inst Med Sci, Dept Pediat, Div Nephrol, New Delhi, India

[18] Univ Minnesota, Dept Pediat, Div Nephrol, Amplatz Childrens Hosp, Minneapolis, MN 55455 USA

[19] Royal Melbourne Hosp, Dept Nephrol, Parkville, Vic 3050, Australia

[20] St Louis Univ, Div Nephrol, Dept Pediat, St Louis, MO 63103 USA

[21] Cleveland Clin, Ctr Pediat Nephrol, Inst Pediat, Cleveland, OH 44106 USA

[22] Dayton Childrens Hosp, Div Nephrol, Dayton, OH USA

[23] Phoenix Childrens Hosp, Div Nephrol, Phoenix, AZ USA

[24] Helen Devos Childrens Hosp, Div Nephrol, Grand Rapids, MI USA

[25] Birmingham Childrens Hosp, Birmingham, W Midlands, England

[26] Childrens Univ Hosp, Div Nephrol, Dublin, Ireland

[27] Leeds Teaching Hosp, Div Nephrol, Dept Pediat, Leeds, W Yorkshire, England

[28] Nationwide Childrens Hosp, Ctr Clin & Translat Res, Res Inst, Columbus, OH USA

[29] Duke Univ, Med Ctr, Dept Med, Div Nephrol, Durham, NC 27710 USA

[30] Duke Univ, Med Ctr, Ctr Human Genet, Durham, NC USA

来源：

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY | 2015年 / 26卷 / 07期

基金：

美国国家卫生研究院;

关键词：

children; nephrotic syndrome; genetic renal disease; glomerular disease; ASSOCIATION; DISEASE; RARE; VARIANT; COMMON; AUTOIMMUNITY; METAANALYSIS; ANTIGENS; MUTATION; TESTS;

D O I：

10.1681/ASN.2014030247

中图分类号：

R5 [内科学]; R69 [泌尿科学（泌尿生殖系疾病）];

学科分类号：

1002 ; 100201 ;

摘要：

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 that were tested (odds ratio, 2.11; 95% confidence interval, 1.56 to 2.86; P=1.68x10(-6) (Fisher exact test). Two of these SNPsthe missense variants C34Y (rs1129740) and F41S (rs1071630) in HLA-DQA1were replicated in an independent cohort of children of white European ancestry with SSNS (100 cases and 589 controls; P=1.42x10(-17)). In the rare variant gene set-based analysis, the best signal was found in PLCG2 (P=7.825x10(-5)). 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.

引用

页码：1701 / 1710

页数：10

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