Genetic determinants of lupus pathogenesis. Genome-wide association studies are confirming previous data identifying genetic variants that are statistically associated with systemic lupus erythematosus and are finding new lupus-associated genes. Most lupus-associated genes represent common variants, but several (C2, C4, C1q and TREX1) are characterized by rare mutations. We suggest that lupus-associated genes contribute to one or more essential mechanisms that must be implemented to generate lupus susceptibility. Some genetic variants will facilitate innate immune system activation, particularly type I IFN production; other genetic variants will result in increased availability of self-antigen; and other genetic variants will alter the threshold for activation or regulation of cells of the adaptive immune response, resulting in production of autoantibodies. Additional genetic variants might promote inflammation and damage to target organs or fail to protect those organs from proinflammatory mediators. The lupus-associated genetic variants prepare the immune system and target organs to be responsive to exogenous or endogenous triggers. Lupus-associated genes are shown in red.