multiple myeloma ( mm ) is a plasma cell neoplasm characterized by the production of a monoclonal protein , bone destruction and susceptibility to infections . most infections in myeloma patients are caused by bacteria , and this susceptibility to infection is mostly due to the reduction in the production of normal immunoglobulins , typical of the disease . the conditioning regimen for the autologous stem cell transplantation ( asct ) further increases patients vulnerability to infections . high levels of proinflammatory cytokines such as il-6 and tnf- are related to mm pathogenesis , and have a relationship with the immune response and the susceptibility to infections . single nucleotide polymorphisms ( snps ) in the promoter region of cytokines genes are responsible for altering their levels of expression , thereby affecting the immune response . specifically , the snp 174g > c ( rs1800795 ) has been correlated with higher levels of il-6 , and the 308g > a ( rs1800629 ) is associated with higher serum levels of soluble tnf- . gene interactions have been successfully used to detect susceptibility to complex diseases , and it is possible that gene interactions may influence the outcome in patients with multiple myeloma . therefore , we aimed to evaluate the association of these snps with bacteremia in mm patients submitted to asct . moreover , as il-6 and tnf- cytokines are known to biologically interact in immune response pathways , we also performed gene we studied 148 mm patients submitted to asct from the bone marrow transplantation unit of federal university of rio de janeiro , rio de janeiro , brazil , from march 1997 to may 2007 . the study was approved by the ethics research committee of the medicine school of ribeiro preto , university of so paulo , and the federal university of rio de janeiro . all patients received melphalan - based conditioning regimen and peripheral blood stem cells ( pbsc ) after mobilization with granulocyte colony - stimulating factor ( g - csf ) with or without cyclophosphamide . until 2006 since then , all patients received ciprofloxacin ( 500  mg orally twice a day ) , started concomitantly with the conditioning regimen , and was maintained until bone marrow recovery or fever . in case of fever , blood cultures were obtained , and the patients were immediately started on intravenous cefepime blood cultures were repeated in case of persistent or recurrent fever , or as clinically indicated . modifications in the empirical antibiotic regimen were performed according to the results of cultures and the clinical course of the patient . genotyping was carried out for the snps il-6 ( 174g > c ) and tnf- ( 308g / a ) using pcr followed by restriction length fragment polymorphism ( pcr - rflp ) . clinical and genotypic database and genotypic analysis were performed with the statistical package for the social sciences version 15 ( spss inc . , we used mdr to combine multilocus genotypes into high risk and low risk cells , which were evaluated for the ability to predict bacteremia through cross - validation and permutation testing . we considered as the best model of interaction the one that had the maximum testing accuracy and the maximum cross - validation consistency ( cvc ) . permutation testing was performed to assess the statistical significance of the testing accuracy of the best model . bivariate analysis ( logstic regression ) was performed to evaluate the impact of the use of quinolones on the risk of bacteremia . we evaluated 148 mm patients , 87 women and 61 men , age range 2969 years , 58 of whom developed bacteremia during the early post - transplant period ( table 1 ) . we did not observe any statistically significant association between the genotypes of tnf- and il-6 polymorphisms and bacteremia ( table 2 ) . however , analyzing the association between bacteremia and the interaction of polymorphisms , we found a significant interaction between tnf- 308g > a and il-6 174g > c polymorphisms , with a cvc of 10/10 and balanced accuracy of 0.6021 ( p=0.04 ) . using this method , we could identify two risk groups : the high risk group comprised patients with wild genotype of tnf- 308g > a and mutated genotype of il-6 174g > c , wild genotype of tnf- 308g > a and heterozygous genotype of il-6 174g > c , and heterozygous for both genes ( dark gray cells in fig . 1 ) . the low - risk group comprised all other combinations ( light gray cells in fig . as shown in table 3 , the frequency of bacteremia overall ( 50.7% vs. 29.6% , p=0.009 ) and of gram - positive bacteremia ( 34.3% vs. 12.5% , p=0.002 ) was significantly higher in the high risk group compared with the low risk group . the frequency of bacteremia was significantly lower in patients receiving quinolone prophylaxis ( 16.7% vs. 43.5% in patients not receiving quinolones , p=0.01 ) . we then run a bivariate analysis to evaluate the influence of quinolone use and the interaction of polymorphisms on the occurrence of bacteremia . receipt of quinolones decreased the risk of bacteremia ( odds ratio [ or ] 0.25 , 95% confidence interval [ 95% ci ] 0.080.81 , p=0.02 ) while the high risk group ( as defined by the analysis of interaction of polymorphisms ) was associated with an increased risk of bacteremia ( or 2.47 , 95% ci 1.244.94 , p=0.01 ) . therefore , the high risk group was associated with an increased risk of bacteremia independent of quinolone use . in the present study , we reported for the first time the possible association of tnf- 308g > a and il-6 174g > c genotypes with bacteremia in mm patients submitted to asct . interestingly , these analyses suggest that the interaction of polymorphisms may be more important than the effects of single polymorphisms for the immune response associated with the susceptibility to infection in asct . the patterns of high risk and low risk cells shown in fig . 1 differ across each of the different multilocus dimensions , which may be interpreted as evidence of epistasis , or gene tnf - stimulates the secretion of il-6 in bone marrow stromal cells , which are associated with a worst prognosis in mm patients . the analysis of gene interaction efficiently discriminated two risk groups , with very different incidences of bacteremia . furthermore , the association of the interaction of polymorphisms and bacteremia was still present after controlling for the use of quinolones . the present findings must be replicated in populations with different genetic backgrounds . moreover , as they focused only on tnf- and il-6 polymorphisms , further studies should be conducted to examine whether interactions between polymorphisms in other genes may affect the infection status in mm patients . likewise , the association between these polymorphisms and gram - negative and gram - positive bacteremia needs to be evaluated in a larger number of patients . the present findings are relevant as they may contribute to the search for genetic markers associated with infection in mm patients submitted to asct , which may be potentially translate into clinical application , with appropriate preventive measures for high - risk patients . the present findings are relevant as they may contribute to the search for genetic markers associated with infection in mm patients submitted to asct , which may be potentially translate into clinical application , with appropriate preventive measures for high - risk patients .
stem cell transplantation affects patients vulnerability to infections due to immunological changes related to chemotherapy . 
 multiple myeloma is characterized by susceptibility to infections , and il-6 and tnf- increased levels affect immune response ( ir ) . 
 polymorphisms in promoter region of cytokine genes may alter expression levels and affect ir . 
 we performed interaction analysis of il-6 ( 174g / c ) and tnf- ( 308g / a ) polymorphisms with infection susceptibility in 148 patients classified accordingly to infection status and found an interaction when compared groups with and without bacteremia ( p=0.0380 ) 
 . the interaction may be more important than single effects for the ir associated with the infection susceptibility in asct .