title: Regulatory polymorphisms in EGR2 are associated with susceptibility to systemic lupus erythematosus.
abstract: Systemic lupus erythematosus (SLE) is an autoimmune disease induced by the combinations of environmental and genetic factors. Recently, mice in which the early growth response 2 (EGR2) gene, a zinc-finger transcription factor, is conditionally knocked out in CD2(+) T cells have been shown to develop a lupus-like autoimmune disease. Here, we evaluated if polymorphisms in the EGR2 gene influence SLE susceptibility in humans. We first analyzed the effect of SNPs in the EGR2 region on EGR2 expression, and a significant positive correlation with expression was identified in an SNP located at the 5' flanking region of EGR2 (rs10761670, R=0.23, P=0.00072). We then performed a case-control association study using three sets of SLE cohorts by genotyping 14 tag SNPs in the EGR2 gene region. A peak of association with SLE susceptibility was observed for rs10761670 [Pooled: OR = 1.23 (95% CI 1.10-1.37), P=0.00023). This SNP was also associated with susceptibility to rheumatoid arthritis (RA) [OR = 1.15 (95% CI 1.05-1.26), P = 0.0019), suggesting that EGR2 is a common risk factor for SLE and RA. Among the SNPs in complete linkage disequilibrium with rs10761670 (r(2) = 1.0), two SNPs (rs1412554 and rs1509957) affected the binding of transcription factors and transcriptional activity in vitro, suggesting that they may be candidates of causal regulatory variants in this region. Therefore, EGR2 is a genetic risk factor for SLE, in which increased gene expression may contribute to SLE pathogenesis.
authors.affiliation: Laboratory for Autoimmune Diseases, Center for Genomic Medicine, RIKEN, Tokyo 113-0033, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Myouzen
authors.forename: Yuta
authors.initials: Y
authors.lastname: Kochi
authors.forename: Kenichi
authors.initials: K
authors.lastname: Shimane
authors.forename: Keishi
authors.initials: K
authors.lastname: Fujio
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Okamura
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Okada
authors.forename: Akari
authors.initials: A
authors.lastname: Suzuki
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Atsumi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ito
authors.forename: Kazuki
authors.initials: K
authors.lastname: Takada
authors.forename: Akio
authors.initials: A
authors.lastname: Mimori
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegawa
authors.forename: Ryo
authors.initials: R
authors.lastname: Yamada
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D016022:Case-Control Studies; D051767:Early Growth Response Protein 2 / Q000235:genetics* / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: C497326:EGR2 protein, human; D051767:Early Growth Response Protein 2