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Adrianto, Indra,Wang, Shaofeng,Wiley, Graham B.,Lessard, Christopher J.,Kelly, Jennifer A.,Adler, Adam J.,Glenn, Stuart B.,Williams, Adrienne H.,Ziegler, Julie T.,Comeau, Mary E.,Marion, Miranda C.,Wa Wiley Subscription Services, Inc., A Wiley Company 2012 Vol.64 No.11
<P><B>Abstract</B></P><P><B>Objective</B></P><P>Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and altered type I interferon expression. Genetic surveys and genome‐wide association studies have identified >30 SLE susceptibility genes. One of these genes, <I>TNIP1</I>, encodes the ABIN1 protein. ABIN1 functions in the immune system by restricting NF‐κB signaling. The present study was undertaken to investigate the genetic factors that influence association with SLE in genes that regulate the NF‐κB pathway.</P><P><B>Methods</B></P><P>We analyzed a dense set of genetic markers spanning <I>TNIP1</I> and <I>TAX1BP1</I>, as well as the <I>TNIP1</I> homolog <I>TNIP2</I>, in case–control populations of diverse ethnic origins. <I>TNIP1</I>, <I>TNIP2</I>, and <I>TAX1BP1</I> were fine‐mapped in a total of 8,372 SLE cases and 7,492 healthy controls from European‐ancestry, African American, Hispanic, East Asian, and African American Gullah populations. Levels of <I>TNIP1</I> messenger RNA (mRNA) and ABIN1 protein in Epstein‐Barr virus–transformed human B cell lines were analyzed by quantitative reverse transcription–polymerase chain reaction and Western blotting, respectively.</P><P><B>Results</B></P><P>We found significant associations between SLE and genetic variants within <I>TNIP1</I>, but not in <I>TNIP2</I> or <I>TAX1BP1</I>. After resequencing and imputation, we identified 2 independent risk haplotypes within <I>TNIP1</I> in individuals of European ancestry that were also present in African American and Hispanic populations. Levels of <I>TNIP1</I> mRNA and ABIN1 protein were reduced among subjects with these haplotypes, suggesting that they harbor hypomorphic functional variants that influence susceptibility to SLE by restricting ABIN1 expression.</P><P><B>Conclusion</B></P><P>Our results confirm the association signals between SLE and <I>TNIP1</I> variants in multiple populations and provide new insight into the mechanism by which <I>TNIP1</I> variants may contribute to SLE pathogenesis.</P>