title: Variations in the TNFα gene and their interactions with the IL4R and IL10 genes in relation to hand osteoarthritis.
abstract: BACKGROUND
  The development of osteoarthritis (OA) involves inflammation, but the evidence for participation of genes propagating or inhibiting inflammation in the OA process is inconsistent. We investigated the associations of common variants in the TNFα gene, and their interactions with other cytokine genes, with hand OA among Finnish women.
  
  
  METHODS
  This cross-sectional study was based on bilateral hand radiographs of 542 female dentists and teachers which were classified according to the presence of OA (radiographic K-L score ≥ 2 in ≥ 3 joints) using reference images. The genotypes were determined by PCR-based methods. The degree of pairwise linkage disequilibrium (LD) and haplotypes were constructed and analyzed by the SNPStats software. The associations between four TNFα SNPs and hand OA were tested using logistic regression adjusting for age, occupation, and BMI, and fitting a log-additive model of inheritance. Gene-gene interactions of TNFα SNPs with IL4R and IL10 SNPs were examined by stratified logistic regression analyses. Possible interactions of the TNFα SNPs with variants in the previously reported IL1β and IL6 genes in influencing hand OA were also explored.
  
  
  RESULTS
  Two TNFα polymorphisms ("-1031" and "-863") were associated with hand OA (OR = 1.45, 95% CI 1.01-2.07 and 1.55, 1.06-2.25, respectively). These associations retained when adjusting further for IL1β "3954" and IL6 "174". The TNFα G-A-G haplotype was associated with an increased risk of hand OA (1.61, 1.10-2.37, p = 0.01). Interactions were observed between TNFα "-1031" and IL4R Ser503Pro, TNFα "-1031" and IL10 "-1082", and TNFα "-863" and IL10 "-1082" SNPs with regard to hand OA (p = 0.012, p = 0.0068, and p = 0.02, respectively). The carriage of the TNFα "-1031" minor allele doubled the risk (2.01, 1.26 - 3.22) only in women with the IL4R Ser/Ser genotype. Similarly, the TNFα "-1031" and "-863" minor alleles were associated with an increased risk of hand OA only in IL10 G/G or A/A homozygotes (2.54, 1.45-4.47 and 2.60, 1.46-4.62, respectively) but not in heterozygotes (G/A).
  
  
  CONCLUSIONS
  Our results suggest that the TNFα gene variants play a role in the etiology of hand OA. In addition, the findings are suggestive of a gene-gene interaction of the TNFα with IL4R and IL10 genes.
authors.affiliation: Finnish Institute of Occupational Health, Centre of Expertise for Health and Work Ability, Topeliuksenkatu 41 a A, FI-00250 Helsinki, Finland. satu.hamalainen@ttl.fi.
authors.forename: Satu
authors.initials: S
authors.lastname: Hämäläinen
authors.forename: Svetlana
authors.initials: S
authors.lastname: Solovieva
authors.forename: Tapio
authors.initials: T
authors.lastname: Vehmas
authors.forename: Päivi
authors.initials: P
authors.lastname: Leino-Arjas
authors.forename: Ari
authors.initials: A
authors.lastname: Hirvonen
mesh_terms: D003430:Cross-Sectional Studies; D004843:Epistasis, Genetic / Q000235:genetics*; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D006225:Hand / Q000000981:diagnostic imaging; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics*; D053662:Interleukin-4 Receptor alpha Subunit / Q000235:genetics*; D008875:Middle Aged; D010003:Osteoarthritis / Q000000981:diagnostic imaging / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011859:Radiography; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: C508609:IL10 protein, human; C504000:IL4R protein, human; D053662:Interleukin-4 Receptor alpha Subunit; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10