title: A missense variant in NCF1 is associated with susceptibility to multiple autoimmune diseases.
abstract: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a strong genetic component characterized by autoantibody production and a type I interferon signature. Here we report a missense variant (g.74779296G>A; p.Arg90His) in NCF1, encoding the p47phoxsubunit of the phagocyte NADPH oxidase (NOX2), as the putative underlying causal variant that drives a strong SLE-associated signal detected by the Immunochip in the GTF2IRD1-GTF2I region at 7q11.23 with a complex genomic structure. We show that the p.Arg90His substitution, which is reported to cause reduced reactive oxygen species (ROS) production, predisposes to SLE (odds ratio (OR) = 3.47 in Asians (Pmeta= 3.1 × 10-104), OR = 2.61 in European Americans, OR = 2.02 in African Americans) and other autoimmune diseases, including primary Sjögren's syndrome (OR = 2.45 in Chinese, OR = 2.35 in European Americans) and rheumatoid arthritis (OR = 1.65 in Koreans). Additionally, decreased and increased copy numbers of NCF1 predispose to and protect against SLE, respectively. Our data highlight the pathogenic role of reduced NOX2-derived ROS levels in autoimmune diseases.
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.|Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Shanghai Institute of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Jianyang
authors.initials: J
authors.lastname: Ma
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.|Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Kelly
authors.affiliation: Department of Biology, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Kwangwoo
authors.identifier: http://orcid.org/0000-0001-8926-6216
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea.
authors.forename: So-Young
authors.initials: SY
authors.lastname: Bang
authors.affiliation: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea.
authors.forename: Hye-Soon
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Quan-Zhen
authors.initials: QZ
authors.lastname: Li
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Edward K
authors.initials: EK
authors.lastname: Wakeland
authors.affiliation: Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences (SIBS), University of Chinese Academy of Sciences, Chinese Academy of Sciences (CAS), Shanghai, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Qiu
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.
authors.forename: Mengru
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.
authors.forename: Zhanguo
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Rheumatology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Tan
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
authors.forename: Astrid
authors.initials: A
authors.lastname: Rasmussen
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.|Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lessard
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.|Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Sivils
authors.affiliation: Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Bevra H
authors.initials: BH
authors.lastname: Hahn
authors.affiliation: Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Grossman
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Diane L
authors.initials: DL
authors.lastname: Kamen
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Gilkeson
authors.affiliation: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea.
authors.forename: Sang-Cheol
authors.initials: SC
authors.lastname: Bae
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Gaffney
authors.affiliation: Shanghai Institute of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.|Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences (SIBS), University of Chinese Academy of Sciences, Chinese Academy of Sciences (CAS), Shanghai, China.|State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.|Collaborative Innovation Center for Translational Medicine at Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Shen
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.|Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Betty P
authors.initials: BP
authors.lastname: Tsao
mesh_terms: D001741:Black or African American / Q000235:genetics; D044466:Asian People / Q000235:genetics; D001327:Autoimmune Diseases / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics; D008297:Male; D019255:NADPH Oxidases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012859:Sjogren's Syndrome / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: D017382:Reactive Oxygen Species; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1