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Guthridge, Joel M.,Lu, R.,Sun, H.,Sun, C.,Wiley, Graham B.,Dominguez, N.,Macwana, Susan R.,Lessard, Christopher J.,Kim-Howard, X.,Cobb, Beth L.,Kaufman, Kenneth M.,Kelly, Jennifer A.,Langefeld, Carl D University of Chicago Press [etc.] 2014 American journal of human genetics Vol.94 No.4
Efforts to identify lupus-associated causal variants in the FAM167A/BLK locus on 8p21 are hampered by highly associated noncausal variants. In this report, we used a trans-population mapping and sequencing strategy to identify a common variant (rs922483) in the proximal BLK promoter and a tri-allelic variant (rs1382568) in the upstream alternative BLK promoter as putative causal variants for association with systemic lupus erythematosus. The risk allele (T) at rs922483 reduced proximal promoter activity and modulated alternative promoter usage. Allelic differences at rs1382568 resulted in altered promoter activity in B progenitor cell lines. Thus, our results demonstrated that both lupus-associated functional variants contribute to the autoimmune disease association by modulating transcription of BLK in B cells and thus potentially altering immune responses.
Han, S.,Kim-Howard, X.,Deshmukh, H.,Kamatani, Y.,Viswanathan, P.,Guthridge, J. M.,Thomas, K.,Kaufman, K. M.,Ojwang, J.,Rojas-Villarraga, A.,Baca, V.,Orozco, L.,Rhodes, B.,Choi, C.-B.,Gregersen, P. K. Oxford University Press 2009 Human Molecular Genetics Vol.18 No.6
<P>We recently identified a novel non-synonymous variant, rs1143679, at exon 3 of the ITGAM gene associated with systemic lupus erythematosus (SLE) susceptibility in European-Americans (EAs) and African-Americans. Using genome-wide association approach, three other studies also independently reported an association between SLE susceptibility and ITGAM or ITGAM-ITGAX region. The primary objectives of this study are to assess whether single or multiple causal variants from the same gene or any nearby gene(s) are involved in SLE susceptibility and to confirm a robust ITGAM association across nine independent data sets (n = 8211). First, we confirmed our previously reported association of rs1143679 (risk allele 'A') with SLE in EAs (P = 1.0 x 10(-8)) and Hispanic-Americans (P = 2.9 x 10(-5)). Secondly, using a comprehensive imputation-based association test, we found that ITGAM is one of the major non-human leukocyte antigen susceptibility genes for SLE, and the strongest association for EA is the same coding variant rs1143679 (log(10)Bayes factor=20, P = 6.17 x 10(-24)). Thirdly, we determined the robustness of rs1143679 association with SLE across three additional case-control samples, including UK (P = 6.2 x 10(-8)), Colombian (P = 3.6 x 10(-7)), Mexican (P = 0.002), as well as two independent sets of trios from UK (P(TDT) = 1.4 x 10(-5)) and Mexico (P(TDT) = 0.015). A meta-analysis combing all independent data sets greatly reinforces the association (P(meta) = 7.1 x 10(-50), odds ratio = 1.83, 95% confidence interval = 1.69-1.98, n = 10 046). However, this ITGAM association was not observed in the Korean or Japanese samples, in which rs1143679 is monomorphic for the non-risk allele (G). Taken together along with our earlier findings, these results demonstrate that the coding variant, rs1143679, best explains the ITGAM-SLE association, especially in European- and African-derived populations, but not in Asian populations.</P>
Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus
Adrianto, Indra,Wen, Feng,Templeton, Amanda,Wiley, Graham,King, Jarrod B,Lessard, Christopher J,Bates, Jared S,Hu, Yanqing,Kelly, Jennifer A,Kaufman, Kenneth M,Guthridge, Joel M,Alarc처n-Riquelme, Mart Nature Publishing Group, a division of Macmillan P 2011 Nature genetics Vol.43 No.3
Systemic lupus erythematosus (SLE, MIM152700) is an autoimmune disease characterized by self-reactive antibodies resulting in systemic inflammation and organ failure. TNFAIP3, encoding the ubiquitin-modifying enzyme A20, is an established susceptibility locus for SLE. By fine mapping and genomic re-sequencing in ethnically diverse populations, we fully characterized the TNFAIP3 risk haplotype and identified a TT>A polymorphic dinucleotide (deletion T followed by a T to A transversion) associated with SLE in subjects of European (P = 1.58 ? 10<SUP>??8</SUP>, odds ratio = 1.70) and Korean (P = 8.33 ? 10<SUP>??10</SUP>, odds ratio = 2.54) ancestry. This variant, located in a region of high conservation and regulatory potential, bound a nuclear protein complex composed of NF-觀B subunits with reduced avidity. Further, compared with the non-risk haplotype, the haplotype carrying this variant resulted in reduced TNFAIP3 mRNA and A20 protein expression. These results establish this TT>A variant as the most likely functional polymorphism responsible for the association between TNFAIP3 and SLE.
Association of a functional IRF7 variant with systemic lupus erythematosus
Fu, Qiong,Zhao, Jian,Qian, XiaoXia,Wong, Jonathan L. H.,Kaufman, Kenneth M.,Yu, C. Yung,Mok, Mo Yin,Harley, John B.,Guthridge, Joel M.,Song, Yeong Wook,Cho, Soo-Kyung,Bae, Sang-Cheol,Grossman, Jennife Wiley (John WileySons) 2011 Vol.63 No.3
<P>A previous genome-wide association study conducted in a population of European ancestry identified rs4963128, a KIAA1542 single-nucleotide polymorphism (SNP) 23 kb telomeric to IRF7 (the gene for interferon regulatory factor 7 [IRF-7]), to be strongly associated with systemic lupus erythematosus (SLE). This study was undertaken to investigate whether genetic polymorphism within IRF7 is a risk factor for the development of SLE.</P>
Kim-Howard, Xana,Sun, Celi,Molineros, Julio E.,Maiti, Amit K.,Chandru, Hema,Adler, Adam,Wiley, Graham B.,Kaufman, Kenneth M.,Kottyan, Leah,Guthridge, Joel M.,Rasmussen, Astrid,Kelly, Jennifer,Sá Oxford University Press 2014 Human Molecular Genetics Vol.23 No.6
<P>Recent reports have associated <I>NCF2</I>, encoding a core component of the multi-protein NADPH oxidase (NADPHO), with systemic lupus erythematosus (SLE) susceptibility in individuals of European ancestry. To identify ethnicity-specific and -robust variants within <I>NCF2</I>, we assessed 145 SNPs in and around the <I>NCF2</I> gene in 5325 cases and 21 866 controls of European-American (EA), African-American (AA), Hispanic (HS) and Korean (KR) ancestry. Subsequent imputation, conditional, haplotype and bioinformatic analyses identified seven potentially functional SLE-predisposing variants. Association with non-synonymous rs17849502, previously reported in EA, was detected in EA, HS and AA (<I>P</I><SUB>EA</SUB> = 1.01 × 10<SUP>−54</SUP>, <I>P</I><SUB>HS</SUB> = 3.68 × 10<SUP>−10</SUP>, <I>P</I><SUB>AA</SUB> = 0.03); synonymous rs17849501 was similarly significant. These SNPs were monomorphic in KR. Novel associations were detected with coding variants at rs35937854 in AA (<I>P</I><SUB>AA</SUB> = 1.49 × 10<SUP>−9</SUP>), and rs13306575 in HS and KR (<I>P</I><SUB>HS</SUB> = 7.04 × 10<SUP>−7</SUP>, <I>P</I><SUB>KR</SUB> = 3.30 × 10<SUP>−3</SUP>). In KR, a 3-SNP haplotype was significantly associated (<I>P</I> = 4.20 × 10<SUP>−7</SUP>), implying that SLE predisposing variants were tagged. Significant SNP–SNP interaction (<I>P</I> = 0.02) was detected between rs13306575 and rs17849502 in HS, and a dramatically increased risk (OR = 6.55) with a risk allele at each locus. Molecular modeling predicts that these non-synonymous mutations could disrupt NADPHO complex assembly. The risk allele of rs17849501, located in a conserved transcriptional regulatory region, increased reporter gene activity, suggesting <I>in vivo</I> enhancer function. Our results not only establish allelic heterogeneity within <I>NCF2</I> associated with SLE, but also emphasize the utility of multi-ethnic cohorts to identify predisposing variants explaining additional phenotypic variance (‘missing heritability’) of complex diseases like SLE.</P>