An autoimmune disease called systemic lupus erythematosus (SLE) that occur 10 times more often in women than in men, is influenced by X-linked gene known as interleukin-1 receptor-associated kinase 1 (IRAK1). This gene significantly influences 2 key genetic loci for SLE development. The study was conducted in collaboration among institutions in the United States and Puerto Rico, Canada, South Korea, and the United Kingdom. The test involved 5337 patients with adult-onset SLE, 769 patients with childhood-onset SLE, and 5317 healthy control participants. In each group Blacks, Asian-Americans, Hispanic-Americans, and whites were represented. The case-control study looked for IRAK1 single nucleotide polymorphisms (SNPs) associated with SLE susceptibility. Of 13 SNPs tested, 5 were significantly associated with SLE in more than one ethnic group. A guanine (GGGG) haplotype based on the 4 SNPs most highly associated with adult-onset SLE (individual P values, 2.56 × 10-9 to 5.04 × 10-10) was strongly associated with SLE in 3 of the 4 racial groups. Thus, the presence of guanine rather than adenine (A) at all 4 SNP loci was associated with SLE, while the AAAA haplotype was associated with protection. The investigators then used laboratory mice to elucidate the mechanisms underlying the IRAK1–SLE association. In mice bred to develop spontaneous lupus, Sle1 and Sle3 have been identified as the most critical genes for SLE development. The z alleles of both these genes (Sle1z and Sle3z) create a murine model of lupus. When IRAK1-knockout mice were bred to homozygous Sle1z mice, the offspring had reduced levels of autoantibodies, smaller spleens, and lower B cell and CD4+ T-cell counts compared with IRAK1-positive control mice. Similarly, Sle3z mice with no IRAK1 activity showed reduced antibody levels, milder renal disease, and fewer splenocytes (including T- and B-cells) relative to IRAK1-positive control mice. Overall, the effects of Sle1z and Sle3z were reduced or normalized in the absence of IRAK1 activity.