title: Juvenile idiopathic arthritis subtype- and sex-specific associations with genetic variants in the PSMA6/PSMC6/PSMA3 gene cluster.
abstract: BACKGROUND
  The ubiquitin proteasome system plays an exceptional biological role in the antigen processing and immune response and it could potentially be involved in pathogenesis of many immunity-related diseases, including juvenile idiopathic arthritis (JIA).
  
  
  METHODS
  The PSMB5 (rs11543947), PSMA6 (rs2277460, rs1048990), PSMC6 (rs2295826, rs2295827), and PSMA3 (rs2348071) proteasomal genes were genotyped on JIA subtype- and sex-specific association; plasma proteasome levels was measured in patients having risk and protective four-locus genotypes and eventual functional significance of allele substitutions was evaluated in silico.
  
  
  RESULTS
  Loci rs11543947 and rs1048990 were identified as disease neutral and other loci as disease susceptible (p < 0.05). The rs2277460, rs2295826, and rs2295827 loci had the strongest association with oligoarthritis [odds ratio (OR) = 2.024, 95% confidence interval (CI) 1.101-3.722; OR = 2.371, 95% CI 1.390-4.044; OR = 2.183, 95% CI 1.272-2.737, respectively), but the rs2348071 locus was associated with polyarthritis in females (OR = 3.438, 95% CI 1.626-7.265). A strong (p < 0.001) association was detected between the rs2277460/rs2295826/rs2295827/rs2348071 four-locus genotypes and the healthy phenotype when all loci were homozygous on common alleles (OR 0.439, 95% CI 0.283-0.681) and with the disease phenotype when the rs2348071 and the rs2295826 and/or rs2295827 loci were represented by risk genotypes simultaneously (OR 4.674, 95% CI 2.096-10.425). Rarely observed in controls, the double rs2277460/rs2348071 heterozygotes were rather frequent in affected males and more strongly associated with polyarthritis (p < 0.05). Haplotypes carrying the rare rs2295826/rs2295827 and rs2277460 alleles showed a strong (p < 0.001) association with oligo- and polyarthritis, respectively. The plasma proteasome level was found to be significantly higher in females having four-locus risk genotypes compared with protective genotypes (p < 0.001). Sequence affinity to transcription factors and similarity to splicing signals, microRNAs and/or hairpin precursors potentially depend on allele substitutions in disease susceptible loci.
  
  
  CONCLUSIONS
  We demonstrate for the first time evidence of a sex-specific association of PSMA6/PSMC6/PSMA3 genetic variants with subtypes of JIA and plasma proteasome concentrations. Theoretical models of the functional significance of allele substitutions are discussed.
authors.affiliation: Institute of Biology, University of Latvia, Salaspils, Latvia. Electronic address: tanja@email.lubi.edu.lv.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Sjakste
authors.affiliation: Institute of Biology, University of Latvia, Salaspils, Latvia.
authors.forename: Natalia
authors.initials: N
authors.lastname: Paramonova
authors.affiliation: Faculty of Medicine, University of Latvia, Riga, Latvia.
authors.forename: Ingrida
authors.initials: I
authors.lastname: Rumba-Rozenfelde
authors.affiliation: Latvian Institute of Organic Synthesis, Riga, Latvia.
authors.forename: Ilva
authors.initials: I
authors.lastname: Trapina
authors.affiliation: Institute of Biology, University of Latvia, Salaspils, Latvia.
authors.forename: Olga
authors.initials: O
authors.lastname: Sugoka
authors.affiliation: Faculty of Medicine, University of Latvia, Riga, Latvia; Latvian Institute of Organic Synthesis, Riga, Latvia.
authors.forename: Nikolajs
authors.initials: N
authors.lastname: Sjakste
mesh_terms: D001171:Arthritis, Juvenile / Q000145:classification* / Q000201:enzymology / Q000235:genetics*; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D005810:Multigene Family; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D046988:Proteasome Endopeptidase Complex / Q000097:blood / Q000235:genetics*
chemical_list: C488165:PSMA3 protein, human; C465641:PSMA6 protein, human; D046988:Proteasome Endopeptidase Complex
keywords: PSMA3; PSMA6; PSMC6; genotype–sex interaction; juvenile idiopathic arthritis; plasma proteasome; polymorphism