title: Association of polymorphism in genes encoding kappaB inhibitors (IkappaB) with susceptibility to and phenotype of Graves' disease: a case-control study.
abstract: BACKGROUND
  Genes related to the nuclear factor-kappaB (NF-kappaB), a key transcription factor involved in regulation of immune responses, are interesting candidates for association studies in autoimmune disorders. The aim of this study was to investigate an association of polymorphisms in two genes encoding NF-kappaB inhibitors: IKBL (encoding inhibitor of kappaB-like) and NFKBIA (encoding kappaB inhibitor alpha), withsusceptibility to and phenotype of Graves' disease (GD).
  
  
  METHODS
  A population-based, case-control association study comprising 481 patients with GD and 455 healthy controls was performed. We analyzed 3 single nucleotide polymorphisms (SNPs) in IKBL [promoter region -62T/A substitution (rs2071592), intron 1 C/T substitution (rs2071591) and exon 4 T/C substitution (rs3130062)] and 3 SNPs in NFKBIA [G/A substitution in 3' untranslated region (rs696) and two promoter region polymorphisms -297C/T (rs2233409) and -826C/T (rs2233406)] by the PCR-restriction fragment length polymorphism (RFLP) method.
  
  
  RESULTS
  The two SNPs in IKBL (rs2071592 and rs2071591) were in a strong linkage disequilibrium (D' = 0.835) and the AT haplotype was associated with susceptibility to GD (p < 10-4, OR = 1.61 [95%CI:1.21-2.14]). Moreover subgroup analysis revealed a gen-gen interaction between the investigated IKBL haplotype and HLA-DRB1*03 allele (p < 10-4). The investigated NFKBIA SNPs were not associated with susceptibility to GD. However, when correlated with phenotype, the -297T (rs2233409) and -826T (rs2233406) alleles were associated with the development of clinically evident ophthalmophaty (p = 0.004, pc = 0.07, OR = 1.65 [95%CI: 1.18-2.38] and p = 0.002, pc = 0.036, OR = 1.67 [95%CI: 1.20-2.36], respectively).
  
  
  CONCLUSIONS
  Our results suggest that SNPs in genes encoding NF-kappaB inhibitors may contribute to the development and clinical phenotype of GD.
authors.affiliation: Department of Endocrinology, Mossakowski Medical Research Center, Polish Academy of Science, Pawinskiego 5, 02-106 Warsaw, Poland. kurylowicz@cmdik.pan.pl.
authors.forename: Alina
authors.initials: A
authors.lastname: Kurylowicz
authors.forename: Piotr
authors.initials: P
authors.lastname: Miśkiewicz
authors.forename: Ewa
authors.initials: E
authors.lastname: Bar-Andziak
authors.forename: Janusz
authors.initials: J
authors.lastname: Nauman
authors.forename: Tomasz
authors.initials: T
authors.lastname: Bednarczuk