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Lupus Risk Variant Increases pSTAT1 Binding and Decreases ETS1 Expression
Lu, X.,Zoller, Erin E.,Weirauch, Matthew T.,Wu, Z.,Namjou, B.,Williams, Adrienne H.,Ziegler, Julie T.,Comeau, Mary E.,Marion, Miranda C.,Glenn, Stuart B.,Adler, A.,Shen, N.,Nath, Swapan K.,Stevens, An University of Chicago Press [etc.] 2015 American journal of human genetics Vol.96 No.5
Genetic variants at chromosomal region 11q23.3, near the gene ETS1, have been associated with systemic lupus erythematosus (SLE), or lupus, in independent cohorts of Asian ancestry. Several recent studies have implicated ETS1 as a critical driver of immune cell function and differentiation, and mice deficient in ETS1 develop an SLE-like autoimmunity. We performed a fine-mapping study of 14,551 subjects from multi-ancestral cohorts by starting with genotyped variants and imputing to all common variants spanning ETS1. By constructing genetic models via frequentist and Bayesian association methods, we identified 16 variants that are statistically likely to be causal. We functionally assessed each of these variants on the basis of their likelihood of affecting transcription factor binding, miRNA binding, or chromatin state. Of the four variants that we experimentally examined, only rs6590330 differentially binds lysate from B cells. Using mass spectrometry, we found more binding of the transcription factor signal transducer and activator of transcription 1 (STAT1) to DNA near the risk allele of rs6590330 than near the non-risk allele. Immunoblot analysis and chromatin immunoprecipitation of pSTAT1 in B cells heterozygous for rs6590330 confirmed that the risk allele increased binding to the active form of STAT1. Analysis with expression quantitative trait loci indicated that the risk allele of rs6590330 is associated with decreased ETS1 expression in Han Chinese, but not other ancestral cohorts. We propose a model in which the risk allele of rs6590330 is associated with decreased ETS1 expression and increases SLE risk by enhancing the binding of pSTAT1.
Zhao, Jian,Wu, Hui,Khosravi, Melanie,Cui, Huijuan,Qian, Xiaoxia,Kelly, Jennifer A.,Kaufman, Kenneth M.,Langefeld, Carl D.,Williams, Adrienne H.,Comeau, Mary E.,Ziegler, Julie T.,Marion, Miranda C.,Adl Public Library of Science 2011 PLoS genetics Vol.7 No.5
<▼1><P>Systemic lupus erythematosus (SLE), a complex polygenic autoimmune disease, is associated with increased complement activation. Variants of genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) within the chromosome 1q32 locus linked to SLE, have been associated with multiple human diseases and may contribute to dysregulated complement activation predisposing to SLE. We assessed 60 SNPs covering the <I>CFH</I>-<I>CFHRs</I> region for association with SLE in 15,864 case-control subjects derived from four ethnic groups. Significant allelic associations with SLE were detected in European Americans (EA) and African Americans (AA), which could be attributed to an intronic <I>CFH</I> SNP (rs6677604, in intron 11, <I>P</I><SUB>meta</SUB> = 6.6×10<SUP>−8</SUP>, OR = 1.18) and an intergenic SNP between <I>CFHR1</I> and <I>CFHR4</I> (rs16840639, <I>P</I><SUB>meta</SUB> = 2.9×10<SUP>−7</SUP>, OR = 1.17) rather than to previously identified disease-associated <I>CFH</I> exonic SNPs, including I62V, Y402H, A474A, and D936E. In addition, allelic association of rs6677604 with SLE was subsequently confirmed in Asians (AS). Haplotype analysis revealed that the underlying causal variant, tagged by rs6677604 and rs16840639, was localized to a ∼146 kb block extending from intron 9 of <I>CFH</I> to downstream of <I>CFHR1</I>. Within this block, the deletion of <I>CFHR3</I> and <I>CFHR1</I> (<I>CFHR3-1</I>Δ), a likely causal variant measured using multiplex ligation-dependent probe amplification, was tagged by rs6677604 in EA and AS and rs16840639 in AA, respectively. Deduced from genotypic associations of tag SNPs in EA, AA, and AS, homozygous deletion of <I>CFHR3-1</I>Δ (<I>P</I><SUB>meta</SUB> = 3.2×10<SUP>−7</SUP>, OR = 1.47) conferred a higher risk of SLE than heterozygous deletion (<I>P</I><SUB>meta</SUB> = 3.5×10<SUP>−4</SUP>, OR = 1.14). These results suggested that the <I>CFHR3-1</I>Δ deletion within the SLE-associated block, but not the previously described exonic SNPs of <I>CFH</I>, might contribute to the development of SLE in EA, AA, and AS, providing new insights into the role of complement regulators in the pathogenesis of SLE.</P></▼1><▼2><P><B>Author Summary</B></P><P>Systemic lupus erythematosus (SLE) is a complex autoimmune disease, associated with increased complement activation. Previous studies have provided evidence for the presence of SLE susceptibility gene(s) in the chromosome 1q31-32 locus. Within 1q32, genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) may contribute to the development of SLE, because genetic variants of these genes impair complement regulation and predispose to various human diseases. In this study, we tested association of genetic variants in the region containing <I>CFH</I> and <I>CFHRs</I> with SLE. We identified genetic variants predisposing to SLE in European American, African American, and Asian populations, which might be attributed to the deletion of <I>CFHR3</I> and <I>CFHR1</I> genes but not previously identified disease-associated exonic variants of <I>CFH</I>. This study provides the first evidence for consistent association between <I>CFH/CFHRs</I> and SLE across multi-ancestral SLE datasets, providing new insights into the role of complement regulators in the pathogenesis of SLE.</P></▼2>
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>
Kaufman, Kenneth M,Zhao, Jian,Kelly, Jennifer A,Hughes, Travis,Adler, Adam,Sanchez, Elena,Ojwang, Joshua O,Langefeld, Carl D,Ziegler, Julie T,Williams, Adrienne H,Comeau, Mary E,Marion, Miranda C,Glen British Medical Association 2013 Annals of the Rheumatic Diseases Vol.72 No.3
<P>The Xq28 region containing IRAK1 and MECP2 has been identified as a risk locus for systemic lupus erythematosus (SLE) in previous genetic association studies. However, due to the strong linkage disequilibrium between IRAK1 and MECP2, it remains unclear which gene is affected by the underlying causal variant(s) conferring risk of SLE.</P>
Zhao, Jian,Giles, Brendan M,Taylor, Rhonda L,Yette, Gabriel A,Lough, Kara M,Ng, Han Leng,Abraham, Lawrence J,Wu, Hui,Kelly, Jennifer A,Glenn, Stuart B,Adler, Adam J,Williams, Adrienne H,Comeau, Mary E H. K. Lewis 2016 Annals of the rheumatic diseases Vol.75 No.1
<P><B>Objectives</B></P><P>Systemic lupus erythematosus (SLE; OMIM 152700) is characterised by the production of antibodies to nuclear antigens. We previously identified variants in complement receptor 2 (<I>CR2/CD21</I>) that were associated with decreased risk of SLE. This study aimed to identify the causal variant for this association.</P><P><B>Methods</B></P><P>Genotyped and imputed genetic variants spanning <I>CR2</I> were assessed for association with SLE in 15 750 case-control subjects from four ancestral groups. Allele-specific functional effects of associated variants were determined using quantitative real-time PCR, quantitative flow cytometry, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP)-PCR.</P><P><B>Results</B></P><P>The strongest association signal was detected at rs1876453 in intron 1 of <I>CR2</I> (p<SUB>meta</SUB>=4.2×10<SUP>−4</SUP>, OR 0.85), specifically when subjects were stratified based on the presence of dsDNA autoantibodies (case-control p<SUB>meta</SUB>=7.6×10<SUP>−7</SUP>, OR 0.71; case-only p<SUB>meta</SUB>=1.9×10<SUP>−4</SUP>, OR 0.75). Although allele-specific effects on B cell <I>CR2</I> mRNA or protein levels were not identified, levels of complement receptor 1 (<I>CR1/CD35)</I> mRNA and protein were significantly higher on B cells of subjects harbouring the minor allele (p=0.0248 and p=0.0006, respectively). The minor allele altered the formation of several DNA protein complexes by EMSA, including one containing CCCTC-binding factor (CTCF), an effect that was confirmed by ChIP-PCR.</P><P><B>Conclusions</B></P><P>These data suggest that rs1876453 in <I>CR2</I> has long-range effects on gene regulation that decrease susceptibility to lupus. Since the minor allele at rs1876453 is preferentially associated with reduced risk of the highly specific dsDNA autoantibodies that are present in preclinical, active and severe lupus, understanding its mechanisms will have important therapeutic implications.</P>