title: Association of a functional polymorphism in the 3'-untranslated region of SPI1 with systemic lupus erythematosus.
abstract: OBJECTIVE
  SPI1, also referred to as PU.1, is an Ets family transcription factor that interacts with IRF2, IRF4, and IRF8. In view of the significance of the type I interferon pathway in systemic lupus erythematosus (SLE), this study was undertaken to investigate a possible association between SPI1 polymorphisms and SLE.
  
  
  METHODS
  A case-control association study was performed using 6 tag single-nucleotide polymorphisms (SNPs), as well as a SNP located upstream of SPI1 previously found to be associated with acute myelogenous leukemia, in 400 Japanese patients with SLE and 450 healthy controls. Resequencing of all exons and known regulatory regions was performed to identify functional polymorphisms. Association of genotype and SPI1 expression was examined using the GENEVAR database and reporter assays.
  
  
  RESULTS
  A significant association was detected in 2 SNPs in intron 2 (rs10769258 and rs4752829) (P = 0.005 and P = 0.008, respectively, under the dominant model). The association was stronger in patients with nephropathy. Resequencing identified a potentially functional polymorphism in the 3'-untranslated region (3'-UTR), rs1057233, which was in strong linkage disequilibrium with the SNPs in intron 2. The number of risk alleles at rs1057233 was strongly correlated with SPI1 messenger RNA (mRNA) level in the database analysis (P = 0.0002), and was confirmed by a reporter assay. Interestingly, rs1057233 alters a target sequence for microRNA hsa-miR-569 (miR-569). Transfection experiments demonstrated that miR-569 inhibits expression of a reporter construct with the 3'-UTR sequence containing the nonrisk allele but not the risk allele.
  
  
  CONCLUSIONS
  Our findings indicate that a SNP in the 3'-UTR of SPI1 is associated with elevated SPI1 mRNA level and with susceptibility to SLE.
authors.affiliation: University of Tsukuba, Tsukuba, Japan.
authors.forename: Koki
authors.initials: K
authors.lastname: Hikami
authors.forename: Aya
authors.initials: A
authors.lastname: Kawasaki
authors.forename: Ikue
authors.initials: I
authors.lastname: Ito
authors.forename: Minori
authors.initials: M
authors.lastname: Koga
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ito
authors.forename: Taichi
authors.initials: T
authors.lastname: Hayashi
authors.forename: Isao
authors.initials: I
authors.lastname: Matsumoto
authors.forename: Akito
authors.initials: A
authors.lastname: Tsutsumi
authors.forename: Makio
authors.initials: M
authors.lastname: Kusaoi
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Takasaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hashimoto
authors.forename: Tadao
authors.initials: T
authors.lastname: Arinami
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sumida
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Tsuchiya
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000328:Adult; D044466:Asian People / Q000235:genetics* / Q000706:statistics & numerical data; D005260:Female; D017930:Genes, Reporter / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008180:Lupus Erythematosus, Systemic / Q000208:ethnology* / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012307:Risk Factors; D015534:Trans-Activators / Q000235:genetics*; D014162:Transfection; D055815:Young Adult; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1