title: Association of a functional IRF7 variant with systemic lupus erythematosus.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  We genotyped one KIAA1542 SNP (rs4963128) and one IRF7 SNP (rs1131665 [Q412R]) in an Asian population (1,302 cases, 1,479 controls), to assess their association with SLE. Subsequently, rs1131665 was further genotyped in independent panels of Chinese subjects (528 cases, 527 controls), European American subjects (446 cases, 461 controls), and African American subjects (159 cases, 115 controls) by TaqMan genotyping assay, to seek confirmation of association in various ethnic groups. A luciferase reporter assay was used to assess the effect of Q412R polymorphism on the activation of IRF-7.
  
  
  RESULTS
  Consistent association of rs1131665 (Q412R) with SLE was identified in Asian, European American, and African American populations (total 2,435 cases and 2,582 controls) (P(meta) = 6.18 × 10(-6) , odds ratio 1.42 [95% confidence interval 1.22-1.65]). Expression of the IRF7 412Q risk allele resulted in a 2-fold increase in interferon-stimulated response element transcriptional activity compared with expression of IRF7 412R (P = 0.0003), suggesting that IRF7 412Q confers elevated IRF-7 activity and may therefore affect a downstream interferon pathway.
  
  
  CONCLUSIONS
  These findings show that the major allele of a nonsynonymous SNP, rs1131665 (412Q) in IRF7, confers elevated activation of IRF-7 and predisposes to the development of SLE in multiple ethnic groups. This result provides direct genetic evidence that IRF7 may be a risk gene for human SLE.
authors.affiliation: University of California, Los Angeles, and Joint Molecular Rheumatology Laboratory of Institute of Health Sciences and Shanghai Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institutes for Biological Sciences, and Chinese Academy of Sciences, Shanghai, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Fu
authors.forename: Jian
authors.initials: J
authors.lastname: Zhao
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Qian
authors.forename: Jonathan L H
authors.initials: JL
authors.lastname: Wong
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Kaufman
authors.forename: C Yung
authors.initials: CY
authors.lastname: Yu
authors.forename: Mo Yin
authors.initials: MY
authors.lastname: Mok
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
authors.forename: Joel M
authors.initials: JM
authors.lastname: Guthridge
authors.forename: Yeong Wook
authors.initials: YW
authors.lastname: Song
authors.forename: Soo-Kyung
authors.initials: SK
authors.lastname: Cho
authors.forename: Sang-Cheol
authors.initials: SC
authors.lastname: Bae
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Grossman
authors.forename: Bevra H
authors.initials: BH
authors.lastname: Hahn
authors.forename: Frank C
authors.initials: FC
authors.lastname: Arnett
authors.forename: Nan
authors.initials: N
authors.lastname: Shen
authors.forename: Betty P
authors.initials: BP
authors.lastname: Tsao
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics / Q000706:statistics & numerical data; D000595:Amino Acid Sequence; D044466:Asian People / Q000235:genetics / Q000706:statistics & numerical data; D005006:Ethnicity / Q000235:genetics* / Q000706:statistics & numerical data; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D050839:Interferon Regulatory Factor-7 / Q000235:genetics* / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000208:ethnology* / Q000235:genetics* / Q000276:immunology; D008297:Male; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D044465:White People / Q000235:genetics / Q000706:statistics & numerical data
chemical_list: C494234:IRF7 protein, human; D050839:Interferon Regulatory Factor-7