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GG-04 A missense mutation in neutrophil cytosolic factor 1 (NCF1) is associated with susceptibility to multiple autoimmune diseases
  1. Jian Zhao**1,2,
  2. Jianyang Ma**3,
  3. Yun Deng1,2,
  4. Jennifer A Kelly4,
  5. Kwangwoo Kim5,
  6. So-Young Bang5,
  7. Hye-Soon Lee7,
  8. Quan-Zhen Li8,
  9. Edward K Wakeland8,
  10. Kathy Moser Sivils4,7,
  11. Bevra H Hahn1,
  12. Jennifer M Grossman1,
  13. Sang-Cheol Bae5,
  14. Patrick M Gaffney4,
  15. Nan Shen3,8,9,10,11 and
  16. Betty P Tsao1,2
  1. 1Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA
  2. 2Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA
  3. 3Shanghai Institute of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China
  4. 4Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA
  5. 5Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, Korea
  6. 6Department of Immunology, University of Texas Southwestern Medical Centre, Dallas, Texas 75235, USA
  7. 7Department of Pathology, University of Oklahoma Health Sciences Centre, Oklahoma City, Oklahoma 73104, USA
  8. 8Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS) and Shanghai Jiao Tong University School of Medicine (SJTUSM), Chinese Academy of Sciences (CAS), Shanghai 200025, China
  9. 9State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200001, China
  10. 10The Centre for Autoimmune Genomics and Aetiology (CAGE), Cincinnati Children’s Hospital Medical Centre, Cincinnati, Ohio 45229, USA
  11. 11Collaborative Innovation Centre for Translational Medicine at Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
  12. **These authors contributed equally to this work


Background Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a strong genetic component. Dozens of SLE-associated loci have been identified by genome-wide associated studies (GWAS) and included in the ImmunoChip for fine-mapping.

Materials and methods Using ImmunoChip, we assessed case-control subjects including Chinese, European Americans (EA) and African Americans (AA) for association with SLE. Subsequently, we carried out trans-ancestral mapping and resequenced the complex GTF2IRD1-GTF2I-NCF1 region on 7q11.23 to identity underlying causal variant.

Results The strongest association signal in Chinese was unexpectedly detected at rs73366469 (OR = 2.88, P = 3.6×10–29) within the GTF2IRD1-GTF2I intergenic region on 7q11.23 rather than SLE-associated GWAS loci. This association was confirmed in EA (OR = 1.37, P = 2.5×10–3) but not in AA. By trans-ancestral mapping and sequencing, we identified R90H of NCF1, a neighbouring gene of GTF2I encoding the p47phox subunit of NADPH oxidase, as a highly plausible causal variant. R90H was associated with SLE in East Asians (OR = 3.47, P meta = 3.0×10–105), EA (OR = 2.11, P meta = 7.0×10–8) and AA (OR = 1.91, P = 7.2×10–3), and in conditional test R90H eliminated SLE-associated signals within the GTF2IRD1-GTF2I region including rs73366469. Furthermore, R90H was dose-dependently associated with early age of onset in Korean (P = 0.011) and EA (P = 0.012) patients with SLE. In addition to SLE, R90H was associated with seropositive rheumatoid arthritis (RA) in Koreans (OR = 1.66, P = 1.2×10–8) and primary Sjögren’s syndrome (SS) in EA (OR = 1.72, P = 5.8×10–3). The conserved arginine 90 to histidine substitution located in the PX-?binding domain of p47phox is predicted deleterious, which is supported by a report showing R90H results in reduced reactive oxygen species (ROS) production.

Conclusions We identified R90H of NCF1 as a novel risk variant for multiple autoimmune diseases, highlighting the pathogenic role of reduced ROS production in developing autoimmune diseases.

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