title: Association of an activity-enhancing variant of IRAK1 and an MECP2-IRAK1 haplotype with increased susceptibility to rheumatoid arthritis.
abstract: OBJECTIVE
  To investigate whether a human X chromosome locus of IRAK1 and MECP2 is associated with susceptibility to rheumatoid arthritis (RA), an autoimmune disease that predominantly affects women.
  
  
  METHODS
  A total of 2,334 unrelated Korean participants (including 1,318 patients with RA) were genotyped for 5 tag single-nucleotide polymorphisms (SNPs) and 3 additional SNPs in an Xq28 region harboring MECP2 and IRAK1. Twenty-nine additional neighboring SNPs were imputed using the Korean HapMap Project data. All 37 SNPs were statistically tested for association with RA susceptibility, and 2 SNPs associated with RA were examined for their functional effects.
  
  
  RESULTS
  RA susceptibility was associated with multiple SNPs in a 79-kb linkage disequilibrium block harboring both MECP2 and IRAK1. The most significant association was for MECP2 SNP rs1734792 (P = 0.00089), but 2 nonsynonymous IRAK1 SNPs, rs1059702 (P = 0.0034) and rs1059703 (P = 0.0042), which were in strong linkage disequilibrium with the MECP2 SNP (D' = 0.87 and 0.91, respectively) affected IRAK1 protein activity. The major haplotype of the 2 nonsynonymous SNPs was associated with a 1.7-fold increase in RA susceptibility versus the minor haplotype (P = 0.0082), and with increased IRAK1 activity, which was demonstrated by a 1.7-fold increase in the intracellular activity of transcription factor NF-κB.
  
  
  CONCLUSIONS
  Our findings indicate that RA susceptibility is associated with multiple SNPs in MECP2 and IRAK1, but high linkage disequilibrium between them does not allow for further localization. Therefore, both genes remain candidates. Nevertheless, the major haplotype of the 2 nonsynonymous IRAK1 SNPs encoding for pPhe196Ser and pSer532Leu confers enhanced IRAK1 activity and, consequently, enhanced susceptibility to RA, as compared to the minor haplotype.
authors.affiliation: Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
authors.forename: Tae-Un
authors.initials: TU
authors.lastname: Han
authors.forename: Soo-Kyung
authors.initials: SK
authors.lastname: Cho
authors.forename: Taehyeung
authors.initials: T
authors.lastname: Kim
authors.forename: Young Bin
authors.initials: YB
authors.lastname: Joo
authors.forename: Sang-Cheol
authors.initials: SC
authors.lastname: Bae
authors.forename: Changwon
authors.initials: C
authors.lastname: Kang
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000453:epidemiology / Q000235:genetics*; D001402:B-Lymphocytes / Q000166:cytology / Q000502:physiology; D016022:Case-Control Studies; D002461:Cell Line, Transformed; D041321:Chromosomes, Human, X / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D056910:Republic of Korea / Q000453:epidemiology
chemical_list: C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases