Basic ResearchLupus Nephritis Susceptibility Loci in Women with Systemic Lupus ErythematosusChung, Sharon A.*; Brown, Elizabeth E.†,‡; Williams, Adrienne H.§; Ramos, Paula S.‖; Berthier, Celine C.¶; Bhangale, Tushar**; Alarcon-Riquelme, Marta E.††,‡‡; Behrens, Timothy W.§§; Criswell, Lindsey A.*; Graham, Deborah Cunninghame‖‖; Demirci, F. Yesim¶¶; Edberg, Jeffrey C.‡; Gaffney, Patrick M.††; Harley, John B.††,***,†††,‡‡‡; Jacob, Chaim O.§§§; Kamboh, M. Ilyas¶¶; Kelly, Jennifer A.††; Manzi, Susan‖‖‖,¶¶¶; Moser-Sivils, Kathy L.††,****; Russell, Laurie P.§; Petri, Michelle††††; Tsao, Betty P.‡‡‡‡; Vyse, Tim J.‖‖; Zidovetzki, Raphael§§§§; Kretzler, Matthias¶; Kimberly, Robert P.‡; Freedman, Barry I.‖‖‖‖; Graham, Robert R.§§; Langefeld, Carl D.§ Author Information *Division of Rheumatology, Rosalind Russell-Ephraim P. Engleman Medical Research Center for Arthritis, University of California, San Francisco, California; †Department of Epidemiology, University of Alabama, Birmingham, Alabama; ‡Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama, Birmingham, Alabama; §Department of Biostatistical Sciences, Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina; ‖Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina; ¶Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; ††Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma; ‡‡Human DNA Variability Area, Pfizer–University of Granada–Andalusian Government Centre for Genomics and Oncological Research, Granada, Spain; **Department of Bioinformatics and Computational Biology, and §§Immunology Tissue Growth and Repair Human Genetics Group, Genentech Inc., South San Francisco, California; ‖‖Divisions of Genetics and Molecular Medicine and Immunology, Infection, and Inflammatory Disease, Kings College, London, United Kingdom; ¶¶Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania; ***Division of Rheumatology, Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; †††University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; ‡‡‡US Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma; §§§Department of Medicine, University of Southern California, Los Angeles, California; ‖‖‖Department of Medicine, West Penn Allegheny Health System, University of Pittsburgh, Pittsburgh, Pennsylvania; ¶¶¶Temple University School of Medicine, Philadelphia, Pennsylvania; ****College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; ††††Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; ‡‡‡‡Division of Rheumatology, Department of Medicine, University of California, Los Angeles, California; §§§§Department of Cell Biology and Neuroscience, University of California, Riverside, California; and ‖‖‖‖Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina Correspondence: Dr. Carl D. Langefeld, Division of Public Health Sciences, Department of Biostatistical Sciences, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157. Email: [email protected] S.A.C. and E.E.B. are co-first authors. Received May 2, 2013 Accepted March 14, 2014 Journal of the American Society of Nephrology 25(12):p 2859-2870, December 2014. | DOI: 10.1681/ASN.2013050446 Buy Metrics Abstract Lupus nephritis is a manifestation of SLE resulting from glomerular immune complex deposition and inflammation. Lupus nephritis demonstrates familial aggregation and accounts for significant morbidity and mortality. We completed a meta-analysis of three genome-wide association studies of SLE to identify lupus nephritis–predisposing loci. Through genotyping and imputation, >1.6 million markers were assessed in 2000 unrelated women of European descent with SLE (588 patients with lupus nephritis and 1412 patients with lupus without nephritis). Tests of association were computed using logistic regression adjusting for population substructure. The strongest evidence for association was observed outside the MHC and included markers localized to 4q11-q13 (PDGFRA, GSX2; P=4.5×10−7), 16p12 (SLC5A11; P=5.1×10−7), 6p22 (ID4; P=7.4×10−7), and 8q24.12 (HAS2, SNTB1; P=1.1×10−6). Both HLA-DR2 and HLA-DR3, two well established lupus susceptibility loci, showed evidence of association with lupus nephritis (P=0.06 and P=3.7×10−5, respectively). Within the class I region, rs9263871 (C6orf15-HCG22) had the strongest evidence of association with lupus nephritis independent of HLA-DR2 and HLA-DR3 (P=8.5×10−6). Consistent with a functional role in lupus nephritis, intra-renal mRNA levels of PDGFRA and associated pathway members showed significant enrichment in patients with lupus nephritis (n=32) compared with controls (n=15). Results from this large-scale genome-wide investigation of lupus nephritis provide evidence of multiple biologically relevant lupus nephritis susceptibility loci. Copyright © 2014 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.