A missense variant in NCF1 is associated with susceptibility to multiple autoimmune diseases

Jian Zhao, Jianyang Ma, Yun Deng, Jennifer A. Kelly, Kwangwoo Kim, So Young Bang, Hye Soon Lee, Quan Zhen Li, Edward K. Wakeland, Rong Qiu, Mengru Liu, Jianping Guo, Zhanguo Li, Wenfeng Tan, Astrid Rasmussen, Christopher J. Lessard, Kathy L. Sivils, Bevra H. Hahn, Jennifer M. Grossman, Diane L. KamenGary S. Gilkeson, Sang Cheol Bae, Patrick M. Gaffney, Nan Shen, Betty P. Tsao

Research output: Contribution to journalArticlepeer-review

116 Scopus citations


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 p47 phox 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) production, predisposes to SLE (odds ratio (OR) = 3.47 in Asians (P meta = 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.

Original languageEnglish (US)
Pages (from-to)433-437
Number of pages5
JournalNature genetics
Issue number3
StatePublished - Mar 1 2017

ASJC Scopus subject areas

  • Genetics


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