Authors: ElHelou OC, Berbari EF, Brown RA, Gralewski JG, Osmon DR, Razonable RR
Title: Relationship Between the G2408A Polymorphism in TollLike Receptor (TLR) 2 and Prosthetic Joint Infections (PJI) Due to Staphylococcus Aureus
Institution: Mayo Clinic Rochester, MN
Purpose: Experimental models implicate TLR2, a peptidoglycan sensor, in S. aureus immunopathogenesis. The clinical relevance of these observations is poorly defined. We assessed the association between the TLR2 G2408A polymorphism and the risk of S aureus PJI
Methods: An unmatched single center casecontrol study design was used to determine the potential relationship between TLR2 G2408A singlenucleotide polymorphism (SNP) and PJI due to S aureus. Genomic DNA from 77 patients with S aureus PJI and 208 noninfected control subjects were extracted from paraffinembedded tissue samples and subsequently tested for the presence of the TLR2 G2408A SNP by realtime polymerase chain reaction and, in randomly selected cases, by genetic sequencing. A multivariate logistic regression model using a stepwise method was used to identify factors independently associated with PJI caused by S aureus.
Results: The PJI cases and noninfected control subjects were comparable in terms of age (mean ? standard deviation, 67 ? 13 and 70 ? 10 years, respectively), gender (male, 52% and 48%, respectively) and race (Caucasian, 88% and 92%, respectively). The wildtype GG, heterozygous GA, and homozygous AA variant were present in 70%, 8% and 22% of S aureus PJI cases and 61%, 12% and 27% of control subjects, respectively. Significant variables associated with the outcome of S aureus PJI in a multivariate model were American Society of Anesthesia score (Odds Ratio [OR]: 1.77; 95%CI: 1.01, 3.12; p = 0.047), wound drainage (OR: 23.87; 95%CI: 7.32, 77.8; p & .001), and distant organ infection (OR: 4.85; 95%CI: 2.45, 9.57; p = 0.007). After controlling for these clinical variables, the presence of homozygous AA (OR: 0.66; 95%CI: 0.31, 1.41; p = 0.288) and heterozygous GA (OR: 0.64; 95%CI: 0.22, 1.83; p = 0.406) mutation had a lower risk of PJI due to S aureus, compared to the wildtype GG; however, these differences were not statistically significant.
Discussion and Conclusion: In this clinical study, the G2408A SNP which results in functional R753Q mutation in TLR2 was not significantly associated with PJI due to S aureus. While this lack of significant association could be due to the small number of subjects, it may also imply that a single mutation in TLR2 gene alone may not be sufficient to account for an association with S. aureus infections. We theorize that other immune response genes, including other members of the TLR family, may act in combination to provide a comprehensive defense mechanism against S aureus infections.