title: Epistatic interactions between HLA-DRB1 and interleukin 4, but not interferon-gamma, increase susceptibility to giant cell arteritis.
abstract: OBJECTIVE
  To assess the roles of the interleukin 4 (IL-4) and interferon-g (IFN-g) gene polymorphisms in a series of patients with biopsy-proven giant cell arteritis (GCA).
  
  
  METHODS
  Eighty-two patients with biopsy-proven GCA and 102 ethnically matched controls from the Lugo region (Northwest Spain) were studied. The following single nucleotide polymorphisms (SNP) were assessed: IL-4 (SNP1: rs2070874, SNP2: rs2227284, SNP3: rs2227282, SNP4: rs2243266, and SNP5: rs2243267) and IFN-g (SNP1: rs1861494, SNP2: rs1861493, and SNP3: rs2069718).
  
  
  RESULTS
  Significant differences in allele and genotype frequencies were observed for the IL-4 SNP between HLA-DRB1*04 negative patients and controls. Epistatic interaction between SNP2 (rs2227284) with HLA-DRB1 showed a significant interaction (p = 0.001) and carriage of the SNP2*T allele in the absence of HLA-DRB1*04 resulted in a 4-fold risk of developing GCA (OR 4.2, 95% CI 1.1-15.6). Also, a significant increase in the frequency of the T-T-C-A-C IL-4 haplotype was observed in HLA-DRB1*04 negative GCA patients compared to the controls (p = 0.02; OR 2.0, 95% CI 1.0-3.9). Similar distributions of allele and genotype frequencies were observed for the IFN-g polymorphisms in both GCA patients and controls.
  
  
  CONCLUSIONS
  Our results suggest an association with IL-4 gene polymorphism that is dependent on HLA-DRB1 genotype in GCA susceptible individuals. These data indicate an interaction between HLA-DRB1 and IL-4 that contributes to pronounced disease susceptibility.
authors.affiliation: Centre for Integrated Genomic Medical Research, School of Epidemiology and Health Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Mahsa M
authors.initials: MM
authors.lastname: Amoli
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Gonzalez-Gay
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Zeggini
authors.forename: Fiona
authors.initials: F
authors.lastname: Salway
authors.forename: Carlos
authors.initials: C
authors.lastname: Garcia-Porrua
authors.forename: William E R
authors.initials: WE
authors.lastname: Ollier
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D016022:Case-Control Studies; D016001:Confidence Intervals; D005260:Female; D020022:Genetic Predisposition to Disease; D013700:Giant Cell Arteritis / Q000175:diagnosis / Q000235:genetics*; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics*; D015847:Interleukin-4 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D016017:Odds Ratio; D016133:Polymerase Chain Reaction / Q000379:methods; D011110:Polymorphism, Genetic; D011336:Probability; D012016:Reference Values
chemical_list: D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D015847:Interleukin-4; D007371:Interferon-gamma