Gene 563 (2015) 76–82

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Research paper

Genetic susceptibility to prosthetic joint infection following total joint arthroplasty: A systematic review Xindie Zhou a, Mumingjiang Yishake b, Jin Li d, Lifeng Jiang d, Lidong Wu d, Ruiping Liu c,⁎, Nanwei Xu a,⁎ a

Department of Orthopedics Surgery, Affiliated Hospital of Nanjing Medical University, Changzhou Second People's Hospital, Changzhou 213003, China Department of Orthopedics Surgery, Zhongshan Hospital, Fudan University, Shanghai 200000, China Department of Orthopedic Trauma, Affiliated Hospital of Nanjing Medical University, Changzhou Second People's Hospital, Changzhou 213003, China d Department of Orthopedics Surgery, The Second Affiliated Hospital of Medical College, Zhejiang University, Hangzhou 310000, China b c

a r t i c l e

i n f o

Article history: Received 21 November 2014 Received in revised form 3 March 2015 Accepted 4 March 2015 Available online 5 March 2015 Keywords: Prosthetic joint infection Total joint arthroplasty Systematic review Polymorphism SNP

a b s t r a c t Background: Prosthetic joint infection (PJI) is the most common cause of total joint arthroplasty failure and revision surgery. Genetic polymorphisms could be determinant factors for PJI. Methods: We performed a systematic research of Medline, Pubmed, Embase, Cochrane Library, and Google Scholar, and identified 11 studies with 34 kinds of gene polymorphisms, were included in the synthesis. Results: Our data suggest that the C allele and genotype C/C for MBL-550 SNP, genotype A/A for MBL-54 SNP and G allele for MBL-221 SNP increase the risk of PJI, while G allele and genotype G/G for MBL-550 SNP decrease the risk of PJI in Caucasian populations. Several other genes reported by single-center studies also contribute to the genetic susceptibility to septic PJI. No definitive conclusions could be achieved due to the small amount of data in the included studies. Conclusion: Several genes contribute to the genetic susceptibility to PJI following total joint arthroplasty. Further studies will enhance the understanding of PJI, and may inform and direct early interventions. © 2015 Elsevier B.V. All rights reserved.

1. Introduction Total joint arthroplasty (TJA) is a very effective procedure that substantially improves the quality of life in patients with end-stage joint affections, including osteoarthritis and rheumatoid arthritis. It is now estimated that millions of patients worldwide have received total joint replacements annually. Prosthetic implants relieve symptoms and improve quality of life, but some of these benefits are time limited. Prosthetic joint infection (PJI) is a feared complication threatening of total joint replacement regardless of the site. Numerous risk factors contributing to PJI have been identified in epidemiological studies such as rheumatoid arthritis, diabetes mellitus, revision arthroplasty, higher individual risk scores for anesthesia, and wound complications including superficial infections (Jamsen et al., 2009; Pedersen et al., 2010). Despite careful management and preventative measures, PJI can exhibit in up to 1.7% of primary hip arthroplasties and 2.5% of primary knee arthroplasties, dependent on anatomical localization of the arthroplasty (Cataldo et al., 2010). Majority of PJI is tightly linked to Abbreviations: PJI, Prosthetic joint infection; TJA, Total joint arthroplasty; OR, Odds ratio; CI, Confidence intervals; OPG, Osteoprotegerin; SNP, Single nucleotide polymorphism; MBL, Mannose-binding lectin; TLR, Toll-like receptor; VDR, Vitamin D receptor; CXCL-1, CXC chemokine-ligand-1; CXCR2, Chemokine C-X-C motif receptor 2; IL, Interleukin; TNF, Tumor necrosis factor; MMPs, Matrix metalloproteinases. ⁎ Corresponding authors. E-mail addresses: [email protected] (R. Liu), [email protected] (N. Xu).

http://dx.doi.org/10.1016/j.gene.2015.03.005 0378-1119/© 2015 Elsevier B.V. All rights reserved.

intraoperative contamination of prosthesis implantation. It was repeatedly demonstrated that any medical implanted device impairs local innate host response facilitating development of infection (Klouche et al., 2010). PJI usually requires revision surgery and, apart from detrimental effects on patients, multiplies the overall cost of TJA in affected individuals (Mrazek et al., 2013). To diminish intraoperative microbial exposure and increase the likelihood that the host immune response together with antibiotics will tackle remaining bacterial load, rigorous preventative measures have been introduced into clinical practice (Jamsen et al., 2010). To try to identify preventive measures, possible biophysical, physical and biological factors have been investigated. At present, it is thought that susceptibility to PJI results from a combination of environmental and genetic factors. Environmental factors such as type of bacteria (Hall-Stoodley et al., 2004), prosthesis (Lima et al., 2013), material (Malchau et al., 1993), BMI (Somayaji et al., 2013), age (Meehan et al., 2014), diabetes mellitus (Malinzak et al., 2009), operative time (Naranje et al., 2014), malnutrition (Lima et al., 2013), HIV infection at an advanced stage (Issa et al., 2013), presence of distant infectious foci (Gerometta et al., 2012), and antecedents of arthroscopy or infection in previous arthroplasty (Lima et al., 2013; Le et al., 2014) have been widely studied, and investigations on genetic factors may well give a newly answer to this issue. Interindividual variability in cytokine and protein production has been observed, and these variations are suspected to be genetically determined, most frequently via the effects

X. Zhou et al. / Gene 563 (2015) 76–82

of polymorphisms within regulatory regions of the corresponding genes. Accordingly, relevant functional polymorphisms in the cytokine, receptor and protein genes may be implicated in the pathogenesis of PJI for example via impairing the effector phase of the innate immune response (Danis et al., 1995; Del Buono et al., 2012). Genetic polymorphisms are genetic variations that are considered biologically normal and can be found in at least 1% of the population (Del Buono et al., 2012). These variations may influence protein transcription, expression of related factors, immunoreaction and contribute towards individual susceptibilities to certain pathological conditions (Goodman et al., 1992). To date, some studies (Malik et al., 2006, 2007a, 2007b; Osmon et al., 2008; El-Helou et al., 2011; Malik et al., 2012; Navratilova et al., 2012a, 2012b, 2014; Stahelova et al., 2012; Mrazek et al., 2013) focusing on the role of heritable factors in individual susceptibility to PJI had been published, including the mutation of proteins, receptors, intracellular mediators, cytokines and enzymes. In the present study, we therefore performed a systematic review to investigate whether or not the gene polymorphisms are associated with PJI. 2. Materials and methods 2.1. Search strategy We performed a systematic research of Medline, Pubmed, Embase, Cochrane Library, and Google Scholar to identify published epidemiological studies through March 2014 that were related to gene polymorphisms and prosthetic joint infection. The medical subject headings and free-text words of “polymorphism”, “SNP”, “gene”, “genetic”, “arthroplasty”, “joint replacement”, “prosthesis”, “infection” and “prosthetic joint infection” were combined for free research. No language or other restrictions were placed on the search. Full-texts were obtained if the abstracts did not allow us to include or exclude the studies.

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Furthermore, the reference lists of all the related papers were examined to identify any initially omitted studies. 2.2. Inclusion and exclusion criteria To be eligible for inclusion in the present study, the following items were established: (1) observational studies that addressed patients with PJI and healthy controls with aseptic TJA; (2) studies that evaluated the association between gene polymorphisms and susceptibility to PJI; (3) studies had sufficient genetic frequency for extraction; (4) case– control, cross-sectional cohort and prospective cohort studies were included; and (5) studies in abstract form, which the full paper could not be acquired, were also included. Exclude strategies are followed: (1) studies on patients who were not experienced joint replacement surgery were excluded; (2) cadavers, literature reviews, technical notes, biomechanical reports, case reports, in vitro, studies on animals and instructional course were excluded; (3) studies carried out on patients, who were pregnant, with cancer or other diseases were excluded; (4) overlapping study populations, interim analyses and comparisons of laboratory methods were excluded. Any publications with questionable were discussed and disagreements were resolved by consensus. 2.3. Study selection Four reviewers independently screened the titles and abstracts. When there was uncertainty about any of the above vital information, the full article was retrieved for further scrutiny, or the authors of individual trials were contacted directly to provide further information when necessary. Subsequently, the literature was further reviewed to determine the final inclusion. Two of the reviewers independently evaluated the methodological quality of the included studies by

Fig. 1. A flowchart shows the results of the literature search and selection for this study.

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Table 1 Characteristics of included studies. Study and year

Country Race

Study design Subgroups

Eligible subjects (n)

Genotyping Genotype method

QAS

PCR

11

Septic Aseptic Malik_2006

UK

US US Czech

Caucasian Case–control Malik_2006_1 63 Malik_2006_2 62 Malik_2006_3 62 Malik_2006_4 62 Caucasian Case–control Malik_2007_a_1 62 Malik_2007_a_2 61 Malik_2007_a_3 62 Malik_2007_a_4 62 Caucasian Case–control Malik_2007_b_1 62 Malik_2007_b_2 62 Malik_2007_b_3 62 Malik_2007_b_4 63 Malik_2007_b_5 63 Caucasian Case–control 286 Caucasian Case–control 76 Caucasian Case–control 89

150 149 147 144 145 148 148 144 148 148 147 148 149 209 208 214

Malik_2007_a

UK

Malik_2007_b

UK

Douglas_2008a El-Helou_2011 Stahelova_2012

PCR PCR PCR

Malik_2012a Navratilova_2012_a

UK Czech

Caucasian Case–control Caucasian Case–control

71 98

150 253

PCR PCR-SSP

Navratilova_2012_b Czech

Caucasian Case–control

112

245

Navratilova_2014 Mrazek_2013

Caucasian Case–control Caucasian Case–control

98 98

251 252

PCR-SSP, PCR PCR-SSP PCR

Czech Czech

PCR

PCR

OPG-163 OPG-245 OPG + 1181 RANK + 575 MBL-221 MBL-550 MBL codon 52 MBL codon 54 MMP1-1 (rs5854) MMP1-3 (rs2397776) MMP1-4 (rs470747) VDR-T, VDR-L IL6-174 TLR9-1486, TLR9-1237 TLR2 R753Q IL-1B-511 (rs16944), IL-1B + 3962 (rs1143634), TNF-308 (rs1800629), TNF-238 (rs361525), IL6-174 (rs1800795), IL-6nt565 (rs1800797) OPG-163, OPG-245, OPG + 1181, RANK + 575 IL-17A (rs2275913), IL-17F (rs763780), IL-4 (rs22432597), IL-12A (rs583911), IL-12B (rs3212227), IL-12B (rs17860508), IL-23R (rs7517847), CXCL1 (rs4074), CXCL5 (rs425535), CXCR2 (rs2230054) MBL2 − 550 (rs11003125), MBL2 − 221 (rs7096206), MBL2 + 54 (rs1800450) OPG-163 (rs3102735) TLR2 R753Q (rs5743708), TLR4 D299G (rs4986790), TLR4 T399I (rs4986791)

11

11

7 11 10

7 10

10 10 11

OPG, osteoprotegerin; MBL, mannose-binding lectin; MMP, matrix metalloproteinase; VDR, vitamin D receptor; IL, interleukin; TLR, toll-like receptors; and TNF, tumor necrosis factor. a Abstract only.

applying an 11-item quality checklist (Zhou et al., 2013), derived from the STROBE (von Elm et al., 2007) (Strengthening the Reporting of Observational Studies in Epidemiology) and STREGA (Little et al., 2009) (Strengthening the Reporting of Genetic Association Studies) checklists. Studies, which had sufficient genetic frequency for extraction, were included. Disagreements were resolved by reaching a consensus through discussion. If controversy remained, disagreements were resolved by consultation with the senior reviewer. 2.4. Date extraction Three of the authors independently extracted the following data from each selected study. Information was extracted on the first name of the first author, year of publication, study design, country and ethnicity of study population, size of the study, genetic testing method, names of gene polymorphisms, and genotype frequency in cases and controls. 2.5. Statistical analysis Data were checked independently and analyzed using Review Manager 5.0 (The Cochrane Collaboration, Oxford, UK) by different reviewers. To determine the strength of genetic association between

gene polymorphism and PJI, a pooled odds ratio (OR) was calculated for each gene variant and a 95% confidence intervals (CI) established under the dominant (BB + AB vs. AA), recessive (BB vs. AB + AA), and allelic (B vs. A) genetic models respectively (B represented minor allele, A represented major allele). For each study, tests for heterogeneity were performed with significance set at p ≤ 0.1, and the degree of heterogeneity was measured using the I2 value. The Mantel–Haenszel method for fixed effects and the Der-Simonian and Laird method for random effects were used to estimate pooled effects. Fixed effect analysis was used for comparing trials without showing heterogeneity, whereas random effect analysis was used for comparing trials showing heterogeneity. p-Values less than 0.05 were considered to indicate significance. 3. Results The computer search yielded 14,864 citations, and following application and refinement of the literature search strategy, 11 independent trials (Malik et al., 2006, 2007a, 2007b; Osmon et al., 2008; El-Helou et al., 2011; Malik et al., 2012; Navratilova et al., 2012a, 2012b, 2014; Stahelova et al., 2012; Mrazek et al., 2013), with 34 kinds of gene polymorphisms, were included in synthesis, and ten of them (Malik et al.,

Fig. 2. Forest plot shows that PJI was significantly more prevalent in the allele C compared with the allele G of MBL-550 polymorphism in Caucasian populations.

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Fig. 3. Forest plot shows that PJI was significantly more prevalent in the genotype CC of MBL-550 polymorphism in Caucasian populations.

2006, 2007a, 2007b; Osmon et al., 2008; El-Helou et al., 2011; Navratilova et al., 2012a, 2012b, 2014; Stahelova et al., 2012; Mrazek et al., 2013), containing 33 kinds of genes, were included in systematic review. The flowchart of reviews which showed the detailed process of selection could be found in Fig. 1. All of the included studies investigated the relationship between gene polymorphisms and susceptibility to PJI in Caucasian population. Of these, three studies (Malik et al., 2006, 2007a, 2007b) contained data on four or five different groups, with different number of eligible subjects. Two of them (Osmon et al., 2008; Malik et al., 2012) are abstracts only, while only one (Osmon et al., 2008) provided the detailed data. A summary of outcomes of included studies is detailed in Table 1. 3.1. Proteins, receptors and intracellular mediators The osteoprotegerin (RANK/RANKL/OPG) system plays an important role in osteolysis associated with inflammatory arthritis and tumor-mediated bone loss (Malik et al., 2006). The expression of RANK, RANKL, and OPG in the interface membrane of both aseptic and septic loosened total hip replacements has implicated this system as being central to the mechanism of bone loss (Gehrke et al., 2003). However, the outcome of two studies (Malik et al., 2006; Navratilova et al., 2012c) showed no significant difference in frequency of OPG-163 in septic group when compared with aseptic group. Besides, Malik et al. (2006) also reported that no statistically significant relationship was observed among septic failure and the OPG-245, OPG + 1181, or RANK + 575 SNPs. The association between mannose-binding lectin (MBL) deficiency associated with SNPs at codons 52 and 54 and at promoter positions550 and -221 and the development of infection around TJAs has been investigated in two case–control studies (Malik et al., 2007a; Navratilova et al., 2012a). MBL is a liver-derived serum protein, which participates in the opsonization of bacteria, increases during the acute-phase response to infection and mediates complement activation (Sullivan et al., 1996). The C allele (OR 1.64; 95% CI 1.23–2.19; p = 0.0007; Fig. 2) and the genotype C/C (OR 1.64; 95% CI 1.07–2.52; p = 0.02; Fig. 3) for the 550 SNP were highly associated with PJI compared with controls. Meanwhile, the G allele (OR 0.61; 95% CI 0.46–0.81; p = 0.0007; Fig. 4) and the genotype G/G (OR 0.45; 95% CI 0.28–0.74; p = 0.002; Fig. 5) were highly inverse associated with aseptic TJA. The G allele (OR 2.37; 95% CI 1.85–3.04; p b 0.00001; Fig. 6) for the promoter 221 and the genotype A/A (OR 18.59; 95% CI 5.76–59.99; p b 0.00001; Fig. 7) for codon 54 SNP were highly associated with PJI compared with aseptic TJA. No significant relationship was noted between septic

failure and the genotype of promoter 221, allele of codon 54 SNPs, or codon 52 SNPs. Five polymorphisms for toll-like receptor (TLR) were investigated in three included studies (Osmon et al., 2008; El-Helou et al., 2011; Mrazek et al., 2013) concentrating on severe infection and TJA failure. TLRs are evolutionary cellular proteins, and involved in the first line of the host's anti-infectious defense. They initiate intracellular molecular pathways responsible for inflammation and immune response (Kawai and Akira, 2011). Several structural variants of the genes encoding for TLRs that modify their function have already been associated with the predisposition to infections in humans (Netea and van der Meer, 2011; Park et al., 2011; Noreen et al., 2012). The authors hypothesized that SNPs in TLRs are made in association with the risk of PJI. Osmon et al. (2008) reported that when compared to wild-type T/T, the heterozygous T/C (OR: 2.13; 95% CI 1.3, 3.49; p = 0.003) and the homozygous C/C (OR: 1.98; 95% CI 0.95–4.14; p = 0.069) variants at TLR9-1486 were significantly or marginally associated with an increased risk of PJI. In contrast, the TLR91237, TLR2 R753Q, TLR4 D299G and TLR4 T399I variants were not significantly associated with PJI. In a study on 211 Britain Caucasian patients undergoing TJA, Malik et al. (2007b) investigated two polymorphisms (VDR-L and VDR-T) in codon 1 of the VDR (vitamin D receptor) gene. These results in a shorter product of translation and may cause a change in the biological activity of the protein (Arai et al., 1997). The VDR-L SNPs proved to be monomorphic in all groups. But the T allele (OR = 1.76; 95% CI 1.16–2.66; p = 0.007) and T/T (p = 0.028) genotype for VDR-T were significantly associated with osteolysis owing to deep infection as compared with aseptic TJA. Navratilova et al. (2012b) investigated the possible influence of the functional CXCL1 (CXC chemokine-ligand-1), CXCL5 and CXCR2 (chemokine C-X-C motif receptor 2) polymorphisms in 351 patients with TJA. Both CXCL1 and CXCL4 encode a member of the CXC chemokine family. Protein encoded by CXCL1 is a secreted growth factor that signals through the G-protein coupled receptor, CXC receptor 2. This protein plays a role in inflammation and as a chemoattractant for neutrophils (Dhawan and Richmond, 2002). Chemokine encoded by CXCL4 is released from the alpha granules of activated platelets in the form of a homotetramer which has high affinity for heparin and is involved in platelet aggregation (Schenk et al., 2002). This protein is chemotactic for numerous other cell types and also functions as an inhibitor of hematopoiesis, angiogenesis and T-cell function. CXCR2 encoded a receptor for interleukin 8 (IL8), a member of the G-proteincoupled receptor family. This receptor mediates neutrophil migration

Fig. 4. Forest plot shows that PJI was significantly less prevalent in the allele G compared with the allele C of MBL-550 polymorphism in Caucasian populations.

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Fig. 5. Forest plot shows that PJI was significantly less prevalent in the genotype GG of MBL-550 polymorphism in Caucasian populations.

to sites of inflammation (Acosta et al., 2008). None of these polymorphisms are related to the septic PJI. 3.2. Cytokines In three case–control studies (Malik et al., 2007b; Navratilova et al., 2012b; Stahelova et al., 2012) of 866 patients, 13 SNPs in 9 genes encoding inflammatory cytokines and cytokine receptors (IL-1β, TNF, IL-6, IL-17A, IL-17B, IL-4, IL-12A, IL-12B and IL-23R) were investigated. The data of allele and genotype for the IL6-174 SNP were presented in two studies (Malinzak et al., 2009; Stahelova et al., 2012), however, neither allele nor genotype is associated with the infection after TJA. In a study on 351 patients, Navratilova et al. (2012b) investigated 7 SNPs of 6 genes. However, the outcomes of this study showed that none of the examined polymorphisms in IL17A, IL17F, IL4, IL12A, IL12B, and IL23R genes were found to be risk factors for PJI in Czech patients. Common polymorphisms in the genes encoding the pro-inflammatory IL-1, TNF and IL-6 family cytokines were genotyped in 303 patients after implantation of TJA (Stahelova et al., 2012). 89 patients were included in the septic PJI group, and 214 in the aseptic TJA group of patients who showed no evidence of infection. Stahelova et al. (2012) reported that the proportion of carriers of the less common IL-1β-511 T allele was significantly higher for PJI patients than in those that did not develop PJI (OR = 2.06, 95% CI 1.22–3.47; p = 0.006). Similarly, the allelic frequency of IL-1β-511 T tended to be higher in the group of PJI patients by comparison to those with aseptic TJA (p = 0.052). The alleles and genotypes of the other investigated cytokine gene polymorphisms were similarly distributed in both of the two groups. 3.3. Enzymes Malik et al. (2007b) investigated the role of four common polymorphisms of MMP1, namely MMP1-1, MMP1-2, MMP1-3 and MMP1-4. MMP1 is a protease that breaks down the interstitial collagens, and its gene variation has also proved to be associated with increased transcription factor production and metastasis (Ye, 2000). The effect of MMP1 may be produced by the direct degradation of the extracellular organic matrix. Degradation products of collagen and matrix components are chemotactic for monocytes. Local production and activation of MMP1 and its subsequent action on substrates involved in inflammation and neovacularization may suggest its role in the development of deep sepsis around TJA (Malik et al., 2007b; Del Buono et al., 2012). Malik et al. reported that the MMP1-2 SNPs proved to be monomorphic

in two groups. No statistically significant relationship was observed between septic failure and MMP1-1, MMP1-3, or MMP1-4 SNPs.

4. Discussion Prosthetic joint infection, or periprosthetic infection, is defined as infection involving the joint prosthesis and adjacent tissue. Advances in the understanding of the diagnosis, treatment, epidemiology and prevention of PJI over the last few years have led to improvement in outcomes for this challenging infection (Tande and Patel, 2014). Many factors have been associated with an increased risk of hip or knee PJI in unadjusted models or in selected studies. These factors include diabetes, rheumatoid arthritis, exogenous immunosuppressive medications, malignancy, arthroplasty revision surgery, smoking and antecedent bacteremia (Pulido et al., 2008). Recently demonstrated associations between gene polymorphisms and a higher risk of PJI have suggested an interesting new area of research in the era of individualized medicine. Pro-inflammatory mediators are implicated in PJI. Individual susceptibility to PJI is determined by patient-related factors other than demographic characteristics or co-morbidities. This condition has a genetic susceptibility component that likely includes contributions by many polymorphisms and gene encoding cytokines. According to our study and other reported studies, the MBL-550 C allele and C/C genotype, MBL-221G allele, MBL codon 54 A/A genotype, TLR9-1486 T/C and C/C genotypes, VDR-TT allele and T/T genotype and IL-1β-511 T allele supposedly predispose to PJI. The top signal identified in this study was the MBL gene, also known as MBL2. MBL gene SNPs, at the chromosomal location 10q11.2, are known to affect MBL protein production. MBL is a pattern recognition receptor, which functions by binding to carbohydrates on the surface of microorganisms. This process enhances phagocytosis by opsonizing microbial antigens and inducing complement-system-mediated death. MBL insufficiency is determined largely genetically. Importantly, low MBL protein levels were shown to be associated with an increased occurrence of infections. Our study identified three SNPs of MBL that increase the risk of PJI in carriers, and MBL-550 SNP was of the highest importance among them. Both the C allele and genotype C/C of the MBL-550 SNP increase the risk of PJI by almost 64%. However, we also found that the G allele and genotype G/G for the MBL-550 SNP could decrease the risk of PJI by almost 39% and 55%, respectively, indicating that the G allele and genotype G/G of MBL-550 have a protective effect in carriers. A similar phenomenon was also observed for the MBL-221 SNP, with the G allele increasing the risk of PJI by 137%. Another

Fig. 6. Forest plot shows that PJI was significantly more prevalent in the allele G compared with the allele C of MBL-221 polymorphism in Caucasian populations.

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Fig. 7. Forest plot shows that PJI was significantly more prevalent in the genotype AA of MBL-54 polymorphism in Caucasian populations.

important finding in our study concerned the genotype A/A of MBL-54. Twenty-two of one hundred and seventy-four patients who carried the genotype A/A of MBL-54 underwent total joint arthroplasty that developed to PJI, compared with 3 of 389 patients who did not carry the genotype, indicating that carriers of MBL-54 with the A/A genotype had a 17 fold higher risk of deep bacterial infection than patients without this genotype. However, because of this association with PJI limited to one study out of two performed and several limitations of the study, such as the sample size, population stratification, and statistical methods used, definitive conclusions could not be reached. Several other studies have also reported significant associations between PJI and gene SNPs. No significant associations with OPG-163, IL6174, and TLR2 R753Q could be found based on the results of our study. Osmon et al. (2008) reported that compared with the wild-type T/T genotype, the heterozygous T/C and homozygous C/C variants at TLR91486 were significantly or marginally associated with an increased risk of PJI. However, when the calculations and analyses were performed using the dominant or recessive model, the outcomes were not significant. Nevertheless, most of the data originated from single center studies. Thus, the mechanisms of gene regulation and activation remain unclear, and key elements are yet to be identified. Additional multi-center, prospective studies are necessary to confirm the validity of the findings reported. Additionally, the interaction of biomaterials and the environment may also be associated with related genes and genetic polymorphisms. Therefore, further study in this field will lead to a better understanding of the mechanisms of PJI and improve the outcome of TJA. The primary limitations of this study included the following: (1) few individuals and studies were included, particularly, only two studies were included in each analysis of related gene SNPs; (2) the small sample size makes definitive conclusions regarding the genetics of PJI less reliable, and the statistical efficacy may be inadequate; (3) because only Caucasian populations were included, further studies of other racial/ethnic groups are needed due to ethnic differences in gene polymorphisms; (4) Due to the small number of included studies and the relative paucity of raw data of individual patients extracted from the original studies, we could not conduct a sensitivity analysis or subgroup analysis for some confounding factors, including environment, gender and age. Additionally, publication bias could not be evaluated. In conclusion, our data suggest that the C allele and genotype C/C of the MBL-550 SNP, genotype A/A of the MBL-54 SNP, and G allele of the MBL-221 SNP increase the risk of PJI, whereas the G allele and genotype G/G of the MBL-550 SNP decrease the risk of PJI in Caucasian populations. Several other genes reported by single-center studies also contribute to the genetic susceptibility to septic PJI. No definitive conclusions could be reached due to the small amount of data in the included studies. Genetic studies in the field of PJI will further enhance our understanding of prosthesis failure and may inform and direct pharmaceutical interventions. With increased knowledge and the availability of newer forms of prophylaxis, it should be possible to identify patients scheduled for arthroplasty who are at greater risk of infection, enabling improved planning and more individualized treatment for early intervention. Prospective studies with larger samples are required to improve the validity of the findings and further evaluate the relationships between gene SNPs and the development of PJI following arthroplasty.

Conflict of interest statement The authors declare that they have no conflict of interests. Author contributions Conceived and designed the study: Nanwei Xu and Xindie Zhou. Performed the study: Jin Li, Lifeng Jiang. Analyzed the data: Xindie Zhou, Lidong Wu. Contributed reagents/materials/analysis tools: Xindie Zhou, Ruiping Liu. Wrote the paper: Xindie Zhou, Ruiping Liu. Critical review of the manuscript: Xindie Zhou, Ruiping Liu, and Mumingjiang Yishake. Acknowledgments This study was supported in part by the National Natural Science Foundation of China (81371927) and the Changzhou Foundation for Applied Basic Research (CJ20130027). References Acosta, J.C., O'Loghlen, A., Banito, A., Guijarro, M.V., Augert, A., Raguz, S., Fumagalli, M., Da Costa, M., Brown, C., Popov, N., Takatsu, Y., Melamed, J., d'Adda di Fagagna, F., Bernard, D., Hernando, E., Gil, J., 2008. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133, 1006–1018. Arai, H., Miyamoto, K., Taketani, Y., Yamamoto, H., Iemori, Y., Morita, K., Tonai, T., Nishisho, T., Mori, S., Takeda, E., 1997. A vitamin D receptor gene polymorphism in the translation initiation codon: effect on protein activity and relation to bone mineral density in Japanese women. J. Bone Miner. Res. 12, 915–921. Cataldo, M.A., Petrosillo, N., Cipriani, M., Cauda, R., Tacconelli, E., 2010. Prosthetic joint infection: recent developments in diagnosis and management. J. Infect. 61, 443–448. Danis, V.A., Millington, M., Hyland, V.J., Grennan, D., 1995. Cytokine production by normal human monocytes: inter-subject variation and relationship to an IL-1 receptor antagonist (IL-1Ra) gene polymorphism. Clin. Exp. Immunol. 99, 303–310. Del Buono, A., Denaro, V., Maffulli, N., 2012. Genetic susceptibility to aseptic loosening following total hip arthroplasty: a systematic review. Br. Med. Bull. 101, 39–55. Dhawan, P., Richmond, A., 2002. Role of CXCL1 in tumorigenesis of melanoma. J. Leukoc. Biol. 72, 9–18. El-Helou, O., Berbari, E.F., Brown, R.A., Gralewski, J.H., Osmon, D.R., Razonable, R.R., 2011. Functional assessment of Toll-like receptor 2 and its relevance in patients with Staphylococcus aureus infection of joint prosthesis. Hum. Immunol. 72, 47–53. Gehrke, T., Sers, C., Morawietz, L., Fernahl, G., Neidel, J., Frommelt, L., Krenn, V., 2003. Receptor activator of nuclear factor kappaB ligand is expressed in resident and inflammatory cells in aseptic and septic prosthesis loosening. Scand. J. Rheumatol. 32, 287–294. Gerometta, A., Rodriguez Olaverri, J.C., Bittan, F., 2012. Infection and revision strategies in total disc arthroplasty. Int. Orthop. 36, 471–474. Goodman, S.B., Chin, R.C., Magee, F.P., 1992. Prostaglandin E2 production by the membrane surrounding loose and fixated cemented tibial hemiarthroplasties in the rabbit knee. Clin. Orthop. Relat. Res. 283–287. Hall-Stoodley, L., Costerton, J.W., Stoodley, P., 2004. Bacterial biofilms: from the natural environment to infectious diseases. Nat. Rev. Microbiol. 2, 95–108. Issa, K., Naziri, Q., Rasquinha, V., Maheshwari, A.V., Delanois, R.E., Mont, M.A., 2013. Outcomes of cementless primary THA for osteonecrosis in HIV-infected patients. J. Bone Joint Surg. Am. 95, 1845–1850. Jamsen, E., Huhtala, H., Puolakka, T., Moilanen, T., 2009. Risk factors for infection after knee arthroplasty. A register-based analysis of 43,149 cases. J. Bone Joint Surg. Am. 91, 38–47. Jamsen, E., Furnes, O., Engesaeter, L.B., Konttinen, Y.T., Odgaard, A., Stefansdottir, A., Lidgren, L., 2010. Prevention of deep infection in joint replacement surgery. Acta Orthop. 81, 660–666. Kawai, T., Akira, S., 2011. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34, 637–650. Klouche, S., Sariali, E., Mamoudy, P., 2010. Total hip arthroplasty revision due to infection: a cost analysis approach. Orthop. Traumatol. Surg. Res. 96, 124–132.

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