ABIN1 Dysfunction as a Genetic Basis for Lupus Nephritis

The genetic factors underlying the pathogenesis of lupus nephritis associated with systemic lupus erythematosus are largely unknown, although animal studies indicate that nuclear factor (NF)-k Bi s involved. WereportedpreviouslythataknockinmouseexpressinganinactiveformofABIN1(ABIN1[D485N])develops lupus-like autoimmune disease and demonstrates enhanced activation of NF-kB and mitogen-activated protein kinases in immune cells after toll-like receptor stimulation. In the current study, we show that ABIN1[D485N] mice develop progressive GN similar to class III and IV lupus nephritis in humans. To investigate the clinical relevance of ABIN1 dysfunction, we genotyped five single-nucleotide polymorphisms in the gene encoding ABIN1, TNIP1, in samples from European-American, African American, Asian, Gullah, and Hispanic participants in the Large Lupus Association Study 2. Comparing cases of systemic lupus erythematosuswithnephritisandcasesofsystemiclupuserythematosuswithoutnephritisrevealedstrongassociations with lupus nephritis at rs7708392 in European Americans and rs4958881 in African Americans. Comparing cases of systemic lupus erythematosus with nephritis and healthy controls revealed a stronger association at rs7708392inEuropeanAmericansbutnotatrs4958881inAfricanAmericans.Ourdatasuggestthatvariantsin theTNIP1geneareassociatedwiththeriskforlupusnephritisandcouldbemechanisticallyinvolvedindisease