title: Analysis of gender differences in genetic risk: association of TNFAIP3 polymorphism with male childhood-onset systemic lupus erythematosus in the Japanese population.
abstract: BACKGROUND
  Systemic lupus erythematosus (SLE) is a systemic multisystem autoimmune disorder influenced by genetic background and environmental factors. Our aim here was to replicate findings of associations between 7 of the implicated single nucleotide polymorphisms (SNPs) in IRF5, BLK, STAT4, TNFAIP3, SPP1, TNIP1 and ETS1 genes with susceptibility to childhood-onset SLE in the Japanese population. In particular, we focused on gender differences in allelic frequencies.
  
  
  RESULTS
  The 7 SNPs were genotyped using TaqMan assays in 75 patients with childhood-onset SLE and in 190 healthy controls. The relationship between the cumulative number of risk alleles and SLE manifestations was explored in childhood-onset SLE. Logistic regression was used to test the effect of each polymorphism on susceptibility to SLE, and Wilcoxon rank sum testing was used for comparison of total risk alleles. Data on rs7574865 in the STAT4 gene and rs9138 in SPP1 were replicated for associations with SLE when comparing cases and controls (corrected P values ranging from 0.0043 to 0.027). The rs2230926 allele of TNFAIP3 was associated with susceptibility to SLE in males, but after Bonferroni correction there were no significant associations with any of the other four SNPs in IRF5, BLK, TNIP1 and ETS1 genes. The cumulative number of risk alleles was significantly increased in childhood-onset SLE relative to healthy controls (P = 0.0000041). Male SLE patients had a slightly but significantly higher frequency of the TNFAIP3 (rs2230926G) risk allele than female patients (odds ratio [OR] = 4.05, 95% confidence interval [95%CI] = 1.46-11.2 P<0.05).
  
  
  CONCLUSIONS
  Associations of polymorphisms in STAT4 and SPP1 with childhood-onset SLE were confirmed in a Japanese population. Although these are preliminary results for a limited number of cases, TNFAIP3 rs2230926G may be an important predictor of disease onset in males. We also replicated findings that the cumulative number of risk alleles was significantly increased in childhood-onset SLE.
authors.affiliation: Department of Pediatrics, Yokohama City University School of Medicine, Kanazawa-ku, Yokohama, Kanagawa, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kadota
authors.forename: Masaaki
authors.initials: M
authors.lastname: Mori
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Yanagimachi
authors.forename: Takako
authors.initials: T
authors.lastname: Miyamae
authors.forename: Takuma
authors.initials: T
authors.lastname: Hara
authors.forename: Taichi
authors.initials: T
authors.lastname: Kanetaka
authors.forename: Tomo
authors.initials: T
authors.lastname: Nozawa
authors.forename: Masako
authors.initials: M
authors.lastname: Kikuchi
authors.forename: Ryoki
authors.initials: R
authors.lastname: Hara
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Imagawa
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Kaneko
authors.forename: Shumpei
authors.initials: S
authors.lastname: Yokota
mesh_terms: D017668:Age of Onset; D000483:Alleles; D044466:Asian People / Q000235:genetics*; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics*; D003710:Demography; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D007564:Japan; D016015:Logistic Models; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D012727:Sex Characteristics; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
references.citation: J Biol Chem. 2009 Mar 27;284(13):8217-21
references.pmid: 19008218
references.citation: Lupus. 2010 Feb;19(2):119-29
references.pmid: 19946032
references.citation: Science. 2000 Feb 4;287(5454):860-4
references.pmid: 10657301
references.citation: Am J Med. 2002 Jun 15;112(9):726-9
references.pmid: 12079714
references.citation: Lupus. 2011 Oct;20(10):1090-4
references.pmid: 21700658
references.citation: Arthritis Rheum. 2008 Mar;58(3):826-34
references.pmid: 18311811
references.citation: Gend Med. 2004 Aug;1(1):12-7
references.pmid: 16115579
references.citation: Ann Rheum Dis. 2011 Jan;70(1):151-6
references.pmid: 20881011
references.citation: Arthritis Res Ther. 2010;12(5):R174
references.pmid: 20849588
references.citation: Arthritis Rheum. 2008 Feb;58(2):556-62
references.pmid: 18240232
references.citation: Nat Rev Rheumatol. 2010 Sep;6(9):538-46
references.pmid: 20683438
references.citation: Blood. 2004 Feb 15;103(4):1376-82
references.pmid: 14592838
references.citation: Immunol Rev. 2002 Dec;190:169-81
references.pmid: 12493014
references.citation: Nat Genet. 2008 Sep;40(9):1062-4
references.pmid: 19165919
references.citation: Nat Genet. 2009 Nov;41(11):1234-7
references.pmid: 19838193
references.citation: Ann Rheum Dis. 2012 May;71(5):694-9
references.pmid: 22110124
references.citation: Rheumatology (Oxford). 2005 May;44(5):602-6
references.pmid: 15705633
references.citation: Arthritis Rheum. 1997 Sep;40(9):1725
references.pmid: 9324032
references.citation: Bioinformatics. 2007 Mar 1;23(5):644-5
references.pmid: 17267436
references.citation: Autoimmun Rev. 2011 Jun;10(8):439-43
references.pmid: 21296190
references.citation: N Engl J Med. 2008 Feb 28;358(9):900-9
references.pmid: 18204098
references.citation: J Biomed Biotechnol. 2011;2011:802581
references.pmid: 22131818
references.citation: Arthritis Res Ther. 2008;10(5):R113
references.pmid: 18803832
references.citation: Arthritis Res Ther. 2011;13(6):R186
references.pmid: 22087647
references.citation: Arthritis Rheum. 1982 Nov;25(11):1271-7
references.pmid: 7138600
references.citation: Genes Immun. 2009 Jul;10(5):487-94
references.pmid: 19339987
references.citation: J Hum Genet. 2011 Jul;56(7):503-7
references.pmid: 21562514
references.citation: PLoS Genet. 2010 Feb 12;6(2):e1000841
references.pmid: 20169177
references.citation: PLoS Genet. 2008 May 30;4(5):e1000084
references.pmid: 18516230
references.citation: Arthritis Rheum. 2009 Feb;60(2):553-8
references.pmid: 19180478
references.citation: Trends Immunol. 2009 Aug;30(8):383-91
references.pmid: 19643665
references.citation: J Biomed Biotechnol. 2010;2010:207578
references.pmid: 20617138
references.citation: PLoS One. 2008 Mar 12;3(3):e0001757
references.pmid: 18335026
references.citation: Arthritis Rheum. 2005 Feb;52(2):539-47
references.pmid: 15692970
references.citation: Nat Genet. 2008 Sep;40(9):1059-61
references.pmid: 19165918