Lupus Nephritis Linked to Defective Immune Control Gene

Janis C. Kelly

August 26, 2013

A gene in the nuclear factor (NF)-κB pathway, which helps regulate the immune system, is associated with the risk of lupus nephritis, according to a case–control study published online August 22 in the Journal of the American Society of Nephrology. The discovery suggests new targets for diagnosing and treating lupus nephritis, according to Dawn J. Caster, MD, from the Department of Medicine, University of Louisville School of Medicine, Kentucky, and colleagues.

Researchers found that patients with systemic lupus erythematosus (SLE) who develop lupus nephritis were more likely to have variants of the TNP1 gene, which encodes the ABIN1 protein, than patients with SLE but no nephritis. The genetic variants differed by race, according to the authors, with the most common variant in whites occurring at rs 770832 and in blacks at rs4958881.

The researchers first established a connection between lupus nephritis and ABN1 in a knock-in mouse model and then compared TPN1 genotypes in patients with lupus both with and without nephritis.

In the mouse studies, the investigators found that inactivating the ABIN1 protein caused a variety of immune abnormalities and a SLE-like autoimmune disease. "In the present study, we show that ABIN1[D485N] mice develop diffuse proliferative [glomerulonephritis] similar to class III and IV human" lupus nephritis, the authors note.

On the basis of those data, the researchers used 16,999 case and control samples collected as part of the international, multi-institution Large Lupus Association Study 2 to genotype 5 single-nucleotide polymorphisms in TNIP1. They compared the gene profiles of participants with and without lupus nephritis in samples from white, black, Asian, Gullah, and Hispanic participants.

White patients with SLE and lupus nephritis were significantly more likely than those without lupus nephritis to carry a variant at rs7708392 (odds ratio [OR], 1.22; P = 3.66 × 10−4). Conversely, black patients with SLE and lupus nephritis were more likely than their counterparts without kidney disease to carry a variant at rs4958881 (OR, 1.22; P = 8.47 × 10−3).

"Our data suggest that variants in the TNIP1 gene are associated with the risk for lupus nephritis and could be mechanistically involved in disease development via aberrant regulation of NF-κB and mitogen-activated protein kinase activity," the authors conclude.

"Our studies identify genes of the NF-kappaB pathway as a focus for future work understanding the pathogenesis and therapy of lupus nephritis. Understanding the role of genes in the NF-kappaB pathway in the development and severity of lupus nephritis provides the hope that personalized therapy for the condition may be possible," senior author David W. Powell, MD, from the Department of Medicine and the Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, said in a news release.

Lupus nephritis is now treated with immunosuppressive drugs that are effective in only about 50% of cases and are associated with undesirable short- and long-term adverse events.

The study was supported by the National Institutes of Health, the Juvenile Diabetes Research Foundation, the United Kingdom Medical Research Council, the US Department of Veterans Affairs, the Alliance for Lupus Research, the Korea Healthcare Technology R&D project, the Korea Ministry for Health & Welfare, and the Republic of Korea.

J Am Soc Nephrol. Published online August 22, 2013. Abstract

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