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 that were tested (odds ratio, 2.11; 95% confidence interval, 1.56 to 2.86; P=1.68×10(-6) (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=1.42×10(-17)). In the rare variant gene set-based analysis, the best signal was found in PLCG2 (P=7.825×10(-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.
authors.affiliation: Department of Pediatrics, Division of Nephrology and Center for Human Genetics, Duke University Medical Center, Durham, North Carolina;
authors.forename: Rasheed A
authors.initials: RA
authors.lastname: Gbadegesin
authors.affiliation: Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland; rasheed.gbadegesin@duke.edu adeyemoa@mail.nih.gov.
authors.forename: Adebowale
authors.initials: A
authors.lastname: Adeyemo
authors.affiliation: Department of Pediatric Nephrology and NIHR/Wellcome Trust Children's Clinical Research Facility, The University of Manchester, Manchester Academic Health Science Centre, Royal Manchester Children's Hospital, Manchester, United Kingdom;
authors.forename: Nicholas J A
authors.initials: NJ
authors.lastname: Webb
authors.affiliation: Division of Pediatric Nephrology, Emory University School of Medicine and Children's Healthcare of Atlanta, Georgia;
authors.forename: Larry A
authors.initials: LA
authors.lastname: Greenbaum
authors.affiliation: Department of Pediatrics, University of Peradeniya, Peradeniya, Sri Lanka;
authors.forename: Asiri
authors.initials: A
authors.lastname: Abeyagunawardena
authors.affiliation: Department of Pediatrics, University of Peradeniya, Peradeniya, Sri Lanka;
authors.forename: Shenal
authors.initials: S
authors.lastname: Thalgahagoda
authors.affiliation: Division of Nephrology, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas;
authors.forename: Arundhati
authors.initials: A
authors.lastname: Kale
authors.affiliation: Department of Pediatrics, Division of Nephrology, University of Michigan, Ann Arbor, Michigan;
authors.forename: Debbie
authors.initials: D
authors.lastname: Gipson
authors.affiliation: Division of Nephrology, Children's Mercy Hospital, Kansas City, Missouri;
authors.forename: Tarak
authors.initials: T
authors.lastname: Srivastava
authors.affiliation: Department of Pediatrics, Division of Nephrology, Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina;
authors.forename: Jen-Jar
authors.initials: JJ
authors.lastname: Lin
authors.affiliation: Department of Pediatrics, Division of Nephrology, Rush University, Chicago, Illinois;
authors.forename: Deepa
authors.initials: D
authors.lastname: Chand
authors.affiliation: Department of Pediatrics, Division of Nephrology, Vanderbilt University, Nashville, Tennessee;
authors.forename: Tracy E
authors.initials: TE
authors.lastname: Hunley
authors.affiliation: Department of Pediatrics, Division of Nephrology, University of Iowa, Iowa City, Iowa;
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Brophy
authors.affiliation: Department of Pediatrics, Division of Nephrology, All India Institute of Medical Science, Ansari Nagar, New Delhi, India;
authors.forename: Arvind
authors.initials: A
authors.lastname: Bagga
authors.affiliation: Department of Pediatrics, Division of Nephrology, All India Institute of Medical Science, Ansari Nagar, New Delhi, India;
authors.forename: Aditi
authors.initials: A
authors.lastname: Sinha
authors.affiliation: Department of Pediatrics, Division of Nephrology, University of Minnesota Amplatz Children's Hospital, Minneapolis, Minnesota;
authors.forename: Michelle N
authors.initials: MN
authors.lastname: Rheault
authors.affiliation: Department of Nephrology, Royal Melbourne Hospital, Parkville, Australia;
authors.forename: Joanna
authors.initials: J
authors.lastname: Ghali
authors.affiliation: Department of Nephrology, Royal Melbourne Hospital, Parkville, Australia;
authors.forename: Kathy
authors.initials: K
authors.lastname: Nicholls
authors.affiliation: Department of Pediatrics, Division of Nephrology, St. Louis University, St. Louis, Missouri;
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Abraham
authors.affiliation: Pediatric Institute, Center for Pediatric Nephrology, Cleveland Clinic, Cleveland, Ohio;
authors.forename: Halima S
authors.initials: HS
authors.lastname: Janjua
authors.affiliation: Division of Nephrology, Dayton Children's Hospital, Dayton, Ohio;
authors.forename: Abiodun
authors.initials: A
authors.lastname: Omoloja
authors.affiliation: Division of Nephrology, Phoenix Children's Hospital, Phoenix, Arizona;
authors.forename: Gina-Marie
authors.initials: GM
authors.lastname: Barletta
authors.affiliation: Division of Nephrology, Helen Devos Children's Hospital, Grand Rapids, Michigan;
authors.forename: Yi
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Birmingham Children's Hospital, Birmingham, United Kingdom;
authors.forename: David D
authors.initials: DD
authors.lastname: Milford
authors.affiliation: Birmingham Children's Hospital, Birmingham, United Kingdom;
authors.forename: Catherine
authors.initials: C
authors.lastname: O'Brien
authors.affiliation: Division of Nephrology, The Children's University Hospital, Dublin, Ireland;
authors.forename: Atif
authors.initials: A
authors.lastname: Awan
authors.affiliation: Department of Pediatrics, Division of Nephrology, Leeds Teaching Hospital, Leeds, United Kingdom;
authors.forename: Vladimir
authors.initials: V
authors.lastname: Belostotsky
authors.affiliation: Center for Clinical and Translational Research, Research Institute at Nationwide Children's Hospital, Columbus, Ohio; and.
authors.forename: William E
authors.initials: WE
authors.lastname: Smoyer
authors.affiliation: Department of Pediatrics, Division of Nephrology and Center for Human Genetics, Duke University Medical Center, Durham, North Carolina;
authors.forename: Alison
authors.initials: A
authors.lastname: Homstad
authors.affiliation: Department of Medicine, Division of Nephrology and Center for Human Genetics, Duke University Medical Center, Durham, North Carolina.
authors.forename: Gentzon
authors.initials: G
authors.lastname: Hall
authors.affiliation: Department of Medicine, Division of Nephrology and Center for Human Genetics, Duke University Medical Center, Durham, North Carolina.
authors.forename: Guanghong
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Pediatrics, Division of Nephrology and Center for Human Genetics, Duke University Medical Center, Durham, North Carolina;
authors.forename: Shashi
authors.initials: S
authors.lastname: Nagaraj
authors.affiliation: Department of Pediatrics, Division of Nephrology and Center for Human Genetics, Duke University Medical Center, Durham, North Carolina;
authors.forename: Delbert
authors.initials: D
authors.lastname: Wigfall
authors.affiliation: Department of Pediatrics, Division of Nephrology and Center for Human Genetics, Duke University Medical Center, Durham, North Carolina;
authors.forename: John
authors.initials: J
authors.lastname: Foreman
authors.affiliation: Department of Medicine, Division of Nephrology and Center for Human Genetics, Duke University Medical Center, Durham, North Carolina.
authors.forename: Michelle P
authors.initials: MP
authors.lastname: Winn
mesh_terms: D017677:Age Distribution; D017668:Age of Onset; D000483:Alleles; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D005838:Genotype; D059848:HLA-DQ alpha-Chains / Q000235:genetics*; D006801:Humans; D015994:Incidence; D008297:Male; D020125:Mutation, Missense; D009404:Nephrotic Syndrome / Q000188:drug therapy / Q000453:epidemiology* / Q000235:genetics*; D051966:Phospholipase C gamma / Q000235:genetics*; D017678:Sex Distribution; D013188:Sri Lanka / Q000453:epidemiology; D013256:Steroids / Q000627:therapeutic use*
chemical_list: D059848:HLA-DQ alpha-Chains; C069050:HLA-DQA1 antigen; D013256:Steroids; D051966:Phospholipase C gamma
keywords: children; genetic renal disease; glomerular disease; nephrotic syndrome