title: Lupus nephritis susceptibility loci in women with systemic lupus erythematosus.
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.
authors.affiliation: Division of Rheumatology, Rosalind Russell-Ephraim P. Engleman Medical Research Center for Arthritis, University of California, San Francisco, California;
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Chung
authors.affiliation: Department of Epidemiology, University of Alabama, Birmingham, Alabama; Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama, Birmingham, Alabama;
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Brown
authors.affiliation: Department of Biostatistical Sciences, Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina;
authors.forename: Adrienne H
authors.initials: AH
authors.lastname: Williams
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina;
authors.forename: Paula S
authors.initials: PS
authors.lastname: Ramos
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan;
authors.forename: Celine C
authors.initials: CC
authors.lastname: Berthier
authors.affiliation: Department of Bioinformatics and Computational Biology, and.
authors.forename: Tushar
authors.initials: T
authors.lastname: Bhangale
authors.affiliation: 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;
authors.forename: Marta E
authors.initials: ME
authors.lastname: Alarcon-Riquelme
authors.affiliation: Immunology Tissue Growth and Repair Human Genetics Group, Genentech Inc., South San Francisco, California;
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Behrens
authors.affiliation: Division of Rheumatology, Rosalind Russell-Ephraim P. Engleman Medical Research Center for Arthritis, University of California, San Francisco, California;
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Criswell
authors.affiliation: Divisions of Genetics and Molecular Medicine and Immunology, Infection, and Inflammatory Disease, Kings College, London, United Kingdom;
authors.forename: Deborah Cunninghame
authors.initials: DC
authors.lastname: Graham
authors.affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania;
authors.forename: F Yesim
authors.initials: FY
authors.lastname: Demirci
authors.affiliation: Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama, Birmingham, Alabama;
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Edberg
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma;
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Gaffney
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma; 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;
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
authors.affiliation: Department of Medicine, University of Southern California, Los Angeles, California;
authors.forename: Chaim O
authors.initials: CO
authors.lastname: Jacob
authors.affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania;
authors.forename: M Ilyas
authors.initials: MI
authors.lastname: Kamboh
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma;
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Kelly
authors.affiliation: Department of Medicine, West Penn Allegheny Health System, University of Pittsburgh, Pittsburgh, Pennsylvania; Temple University School of Medicine, Philadelphia, Pennsylvania;
authors.forename: Susan
authors.initials: S
authors.lastname: Manzi
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma; College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Moser-Sivils
authors.affiliation: Department of Biostatistical Sciences, Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina;
authors.forename: Laurie P
authors.initials: LP
authors.lastname: Russell
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Michelle
authors.initials: M
authors.lastname: Petri
authors.affiliation: Division of Rheumatology, Department of Medicine, University of California, Los Angeles, California;
authors.forename: Betty P
authors.initials: BP
authors.lastname: Tsao
authors.affiliation: Divisions of Genetics and Molecular Medicine and Immunology, Infection, and Inflammatory Disease, Kings College, London, United Kingdom;
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Vyse
authors.affiliation: Department of Cell Biology and Neuroscience, University of California, Riverside, California; and.
authors.forename: Raphael
authors.initials: R
authors.lastname: Zidovetzki
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan;
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
authors.affiliation: Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama, Birmingham, Alabama;
authors.forename: Robert P
authors.initials: RP
authors.lastname: Kimberly
authors.affiliation: Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Barry I
authors.initials: BI
authors.lastname: Freedman
authors.affiliation: Immunology Tissue Growth and Repair Human Genetics Group, Genentech Inc., South San Francisco, California;
authors.forename: Robert R
authors.initials: RR
authors.lastname: Graham
authors.affiliation: Department of Biostatistical Sciences, Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina; clangefe@wakehealth.edu.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D015802:HLA-DR2 Antigen / Q000235:genetics; D015803:HLA-DR3 Antigen / Q000235:genetics; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D008181:Lupus Nephritis / Q000235:genetics*; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D015802:HLA-DR2 Antigen; D015803:HLA-DR3 Antigen; D012333:RNA, Messenger
keywords: SLE; epidemiology; genetic renal disease; lupus nephritis; outcomes