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 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) 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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
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.
Integrated supplementary information
About this article
Frontiers in Immunology (2019)