Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a strong genetic component characterized by autoantibody production and a type I interferon signature1. Here we report a missense variant (g.74779296G>A; p.Arg90His) in NCF1, encoding the p47phox subunit 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 GTF2IRD1GTF2I 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) production2, 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.

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We thank all subjects for their participation in this study. We thank E. Magdangal and Y. Shi for help with DNA preparation and organization. We also thank A. Lusis for valuable discussion and comments. This work was supported by US National Institutes of Health grants R01AR043814 (B.P.T.), R21AR065626 (B.P.T.), R01AR056360 (P.M.G.), R01AR063124 (P.M.G.), U19AI082714 (P.M.G.), R01AR043274 (K.L.S.), R01DE015223 (K.L.S.), R01DE018209 (K.L.S.), R01AR050782 (K.L.S.), R01AR065953 (C.J.L. and K.L.S.), P50AR0608040 (K.L.S. and C.J.L.), U19AI082714 (K.L.S. and C.J.L.) and P60AR062755 (D.L.K. and G.S.G.), the Lupus Foundation of America (B.P.T.), the Alliance for Lupus Research (B.P.T.), the Sjögren's Syndrome Foundation (K.L.S. and C.J.L.), Korea Healthcare Technology R&D Project of the Ministry for Health and Welfare in the Republic of Korea grants HI13C2124 (S.-C.B.) and HI15C3182 (K.K.), National Basic Research Program of China (973 program) grant 2014CB541902 (N.S.), Key Research Program of Bureau of Frontier Sciences and Education Chinese Academy of Sciences grant QYZDJ-SSW-SMC006 (N.S.), Key Research Program of the Chinese Academy of Sciences grant KJZD-EW-L01-3 (N.S.), State Key Laboratory of Oncogenes and Related Genes grant 91-14-05 (N.S.), National Natural Science Foundation of China grant 31630021 (N.S.), Strategic Priority Research Program of the Chinese Academy of Sciences grant XDA12020107 (N.S.). Clinical and Translational Science Institute (CTSI) grants UL1RR033176 (UCLA), UL1TR000124 (UCLA) and UL1TR001450 (MUSC), and funds from the Spaulding-Paolozzi Autoimmunity Center of Excellence (MUSC), the Richard M. Silver, MD, Endowment for Inflammation Research (B.P.T.) and the SmartState® Center of Economic Excellence in Inflammation and Fibrosis Research (B.P.T.). The funders had no role in study design, data collection, analysis and interpretation, writing of the report, or decision to submit the paper for publication.

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Author notes

    • Jian Zhao
    •  & Jianyang Ma

    These authors contributed equally to this work.


  1. Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.

    • Jian Zhao
    • , Yun Deng
    • , Diane L Kamen
    • , Gary S Gilkeson
    •  & Betty P Tsao
  2. Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.

    • Jian Zhao
    • , Yun Deng
    • , Bevra H Hahn
    • , Jennifer M Grossman
    •  & Betty P Tsao
  3. Shanghai Institute of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

    • Jianyang Ma
    •  & Nan Shen
  4. Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.

    • Jennifer A Kelly
    • , Astrid Rasmussen
    • , Christopher J Lessard
    • , Kathy L Sivils
    •  & Patrick M Gaffney
  5. Department of Biology, Kyung Hee University, Seoul, Republic of Korea.

    • Kwangwoo Kim
  6. Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea.

    • So-Young Bang
    • , Hye-Soon Lee
    •  & Sang-Cheol Bae
  7. Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Quan-Zhen Li
    •  & Edward K Wakeland
  8. 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.

    • Rong Qiu
    •  & Nan Shen
  9. Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China.

    • Mengru Liu
    • , Jianping Guo
    •  & Zhanguo Li
  10. Department of Rheumatology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

    • Wenfeng Tan
  11. Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

    • Christopher J Lessard
    •  & Kathy L Sivils
  12. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

    • Nan Shen
  13. Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

    • Nan Shen
  14. Collaborative Innovation Center for Translational Medicine at Shanghai Jiao Tong University School of Medicine, Shanghai, China.

    • Nan Shen


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J.Z., B.P.T. and N.S. led the study. J.Z., Y.D. and B.P.T. wrote the manuscript. J.Z., J.M., Y.D. and R.Q. performed the experiments. J.Z., J.M., Y.D., J.A.K. and K.K. analyzed the data and performed statistical analysis. S.-Y.B., H.-S.L., Q.-Z.L., E.K.W., M.L., J.G., Z.L., W.T., A.R., C.J.L., K.L.S., B.H.H., J.M.G., D.L.K., G.S.G., S.-C.B. and P.M.G. contributed primarily to sample collection and/or genotyping. All authors reviewed the final manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Jian Zhao or Nan Shen or Betty P Tsao.

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  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–7 and Supplementary Tables 1–11

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    Supplementary Data

    Raw TaqMan data for the R90H variant in NCF1.

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