Journal
NATURE GENETICS
Volume 49, Issue 3, Pages 433-437Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3782
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Funding
- US National Institutes of Health [R01AR043814, R21AR065626, R01AR056360, R01AR063124, U19AI082714, R01AR043274, R01DE015223, R01DE018209, R01AR050782, R01AR065953, P50AR0608040, P60AR062755]
- Lupus Foundation of America
- Alliance for Lupus Research
- Sjogren's Syndrome Foundation
- Korea Healthcare Technology R&D Project of the Ministry for Health and Welfare in the Republic of Korea [HI13C2124, HI15C3182]
- National Basic Research Program of China (973 program) [2014CB541902]
- Key Research Program of Bureau of Frontier Sciences and Education Chinese Academy of Sciences grant [QYZDJ-SSW-SMC006]
- Key Research Program of the Chinese Academy of Sciences grant [KJZD-EW-L01-3]
- State Key Laboratory of Oncogenes and Related Genes grant [91-14-05]
- National Natural Science Foundation of China [31630021]
- Strategic Priority Research Program of the Chinese Academy of Sciences grant [XDA12020107]
- Clinical and Translational Science Institute (CTSI) grants [UL1RR033176, UL1TR000124, UL1TR001450]
- Spaulding-Paolozzi Autoimmunity Center of Excellence (MUSC)
- Endowment for Inflammation Research
- SmartState(R) Center of Economic Excellence in Inflammation and Fibrosis Research
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Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a strong genetic component characterized by autoantibody production and a type 1 interferon signatures. 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 lmmunochip 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(2), predisposes to SLE (odds ratio (OR) = 3.47 in Asians (P-meta = 3.1 x 10(-104)), OR = 2.61 in European Americans, OR = 2.02 in African Americans) and other autoimmune diseases, including primary Sjogren'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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