Taken together, we have conclusively demonstrated the association of two SNPs near DGUOK/DGUOK-AS1 with SLE, established transcriptional regulatory mechanisms and protein-binding effects of the risk alleles, and laid out potential downstream signaling pathways, mediated primarily through mitochondrial OxPhos activity and phagocytosis, and separately through competition with the function of myriad immune-involved microRNAs and Xist, the principal determinant of X chromosome inactivation and autoimmune sex bias. Here, XIST is linked to systemic lupus erythematosus.