HLA-DQA1 and PLCG2 Are Candidate Risk Loci for... : Journal of the American Society of Nephrology (original) (raw)

Clinical Research

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

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

*Department of Pediatrics, Division of Nephrology and Center for Human Genetics, Duke University Medical Center, Durham, North Carolina;

†Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland;

‡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;

§Division of Pediatric Nephrology, Emory University School of Medicine and Children’s Healthcare of Atlanta, Georgia;

‖Department of Pediatrics, University of Peradeniya, Peradeniya, Sri Lanka;

¶Division of Nephrology, Baylor College of Medicine and Texas Children’s Hospital, Houston, Texas;

**Department of Pediatrics, Division of Nephrology, University of Michigan, Ann Arbor, Michigan;

††Division of Nephrology, Children’s Mercy Hospital, Kansas City, Missouri;

‡‡Department of Pediatrics, Division of Nephrology, Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina;

§§Department of Pediatrics, Division of Nephrology, Rush University, Chicago, Illinois;

‖‖Department of Pediatrics, Division of Nephrology, Vanderbilt University, Nashville, Tennessee;

¶¶Department of Pediatrics, Division of Nephrology, University of Iowa, Iowa City, Iowa;

***Department of Pediatrics, Division of Nephrology, All India Institute of Medical Science, Ansari Nagar, New Delhi, India;

†††Department of Pediatrics, Division of Nephrology, University of Minnesota Amplatz Children's Hospital, Minneapolis, Minnesota;

‡‡‡Department of Nephrology, Royal Melbourne Hospital, Parkville, Australia;

§§§Department of Pediatrics, Division of Nephrology, St. Louis University, St. Louis, Missouri;

‖‖‖Pediatric Institute, Center for Pediatric Nephrology, Cleveland Clinic, Cleveland, Ohio;

¶¶¶Division of Nephrology, Dayton Children’s Hospital, Dayton, Ohio;

****Division of Nephrology, Phoenix Children’s Hospital, Phoenix, Arizona;

††††Division of Nephrology, Helen Devos Children’s Hospital, Grand Rapids, Michigan;

‡‡‡‡Birmingham Children’s Hospital, Birmingham, United Kingdom;

§§§§Division of Nephrology, The Children's University Hospital, Dublin, Ireland;

‖‖‖‖Department of Pediatrics, Division of Nephrology, Leeds Teaching Hospital, Leeds, United Kingdom;

¶¶¶¶Center for Clinical and Translational Research, Research Institute at Nationwide Children’s Hospital, Columbus, Ohio; and

*****Department of Medicine, Division of Nephrology and Center for Human Genetics, Duke University Medical Center, Durham, North Carolina

R.A.G and A.A. contributed equally to this work.

Correspondence: Dr. Rasheed Gbadegesin, Department of Pediatrics, Division of Nephrology and Center for Human Genetics, Duke University Medical Center, T-Level RM0909 CHC, Box 3959, Durham, NC 27710, or Dr. Adeyemo Adebowale, Center for Research on Genomics and Global Health, National Human Genome Research Institute, 12 South Drive, MSC 5635, Building 12A, Room 4047, Bethesda, MD 20892-5635. Email: [email protected] or [email protected].

Received March 7, 2014

Accepted September 9, 2014

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.