Systemic lupus erythematosus (SLE) is a common autoimmune disease. Recent findings have shown that a major single nucleotide variant predi_ LE is associated with low production of reactive oxygen species (ROS). A variant amino frequent NCF1 allele causing deficient ROS production leads to an exaggerated type I interferon (IFN) response, earlier disease onset, and higher susceptibility to SLE. It is the so far strongest identified single nucleotide variant, with an odds ratio (OR) of amp;gt;3 and an allele frequency of amp;gt;10%. Its functional role is in sharp contrast to the earlier belief that excessive ROS production is exclusively pathogenic rather than protective. It opens new possibilities to understand the pathogenesis of SLE and to develop novel diagnostics and treatment strategies.