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Paper text:
stroke is a complex multifactorial disorder and a leading cause of mortality and morbidity worldwide .
growing evidence has shown that inflammation appears to play crucial roles in the pathogenesis of is through the promotion of atherosclerosis .
clinically , the incidence and outcome of is are influenced by systemic inflammatory processes , and stroke patients with systemic inflammation portend poorer outcomes [ 24 ] .
experimentally , focal ischemic injury with acute and chronic inflammation induces production of proinflammatory mediators and recruitment of inflammatory cells , including neutrophils , t cells , and monocyte / macrophages [ 57 ] .
in addition to some known risk factors , such as inflammation , advanced age , hypertension , and diabetes , genetic variants have been reported to contribute to the development of is [ 810 ] .
identification of susceptibility genes is of great value to clarify the aetiology and improve prognostication , therapy , and prevention .
subsequently , it was identified as a proinflammatory cytokine that is a 67  kd precursor protein consisting of 631 amino acids .
il-16 is produced by activated cd8-positive ( cd8 + ) t cells   and activates cd4 + t cells , monocytes , macrophages , and dendritic cells by binding to the cd4 molecular [ 16 , 17 ] .
in addition to the activation of cd4 + t cells , il-16 can promote the secretion of inflammatory cytokines such as tumour necrosis factor ( tnf )  , interleukin-1 , and interleukin-6 ( il-6 ) .
all of these cytokines are key elements in the ischemic cascade after cerebral ischemia [ 1922 ] . in 2000 , nakayama and colleagues found a -295t - to - c polymorphism in the promoter region of il-16 , which is related to different levels of gene expression .
the polymorphism was reported to be associated with a series of inflammatory or autoimmune diseases , including crohn 's disease , allergic contact dermatitis , endometriosis , asthma , graves ' disease , and systemic lupus erythematosus ( sle ) .
recently , another two functional polymorphisms ( i.e. , rs11556218 and rs4072111 ) were identified to be associated with sle   and coronary artery disease ( cad ) [ 30 , 31 ] . to date , no data exist regarding the contribution of the il-16 polymorphisms to is . in this study , we aimed to assess the prevalence of the il-16 polymorphisms in is .
the study was approved by the zhejiang hospital institutional review board for human subjects research , and written informed consent was obtained from all individuals .
the study population comprised 434 unrelated chinese subjects who visited the zhejiang hospital between march 2010 and september 2012 . among them , 198 were patients with is ( 122 men and 76 women ) and 236 were healthy controls ( 155 men and 81 women ) .
is was determined by the presence of a focal or global neurological deficit with symptoms and signs lasting more than 24  h. computed tomography and/or magnetic resonance image scanning of the brain was used to ascertain the diagnosis of is .
hypertension was defined as having a systolic blood pressure 140  mmhg and/or a diastolic blood pressure 90  mmhg .
diabetes mellitus was diagnosed if the fasting plasma glucose level 7.0  mmol / l or the plasma glucose 11.1  mmol / l 2 hours after a 75  g oral glucose tolerance test .
mmol / l , and hypertriglyceridemia was determined by a fasting serum triglyceride level > 2.3 
we used hospital - based controls that were age , gender , and ethnicity matched , without a history of is .
il-16 polymorphisms were genotyped by performing polymerase chain reaction - restriction fragment length polymorphism ( pcr - rflp ) assay .
randomly selected pcr products were examined by dna sequencing , and the results were 100% concordant .  
all data were analyzed using the spss software ( version 19.0 , spss inc . ,
, hardy - weinberg equilibrium was tested with a goodness - of - fit  test .
demographic and clinical data between cases and controls were compared using the  test for dichotomous covariates and unpaired student 's t - test for continuous covariates .
a binary logistic regression analysis was used to compute adjusted odds ratio ( or ) and 95% confidence intervals ( ci ) for evaluating the association of the il-16 polymorphisms with is .
the genotype and allele frequencies of the rs4778889 t / c , rs11556218 t / g , and rs4072111 c / t polymorphisms in il-16 gene are summarized in table 2 .
the genotype distributions of the three polymorphisms in controls were consistent with the hardy - weinberg equilibrium .
the genotype frequencies of the rs11556218 t / g polymorphism were significantly different between cases and controls .
the tg genotype of the rs11556218 t / g polymorphism was associated with a significantly increased risk of is compared with the tt genotype ( adjusted or = 1.88 ; 95% ci , 1.153.07 ) .
similarly , the g allele of the rs11556218 t / g polymorphism was associated with a significantly increased risk of is compared with the t allele ( adjusted or = 1.54 ; 95% ci , 1.052.27 ) .
however , there were no significant differences in the genotype and allele frequencies of il-16 rs4778889 t / c and rs4072111 c / t polymorphisms between the two groups , even after stratification analyses by age , gender , and the presence or absence of hypertension , diabetes mellitus , hypercholesterolemia , and hypertriglyceridemia .
  clinical and experimental data have demonstrated that inflammation plays fundamental roles in the pathogenesis of is [ 27 ] .
an increased level of il-16 mrna and protein was observed in patients with inflammatory or autoimmune diseases , and the high expression of il-16 mrna correlated with increased numbers of cd4 + cells in acute skin lesions [ 36 , 37 ] .
ischemic stroke patients had a high risk for systemic infections , and anti - inflammatory agents may be a promising approach to treating is [ 6 , 38 , 39 ] .   
based on the key roles of il-16 in inflammatory disorders , the association between il-16 polymorphism and the risk of inflammatory diseases has attracted widespread attention over the past decades . some authors reported that the rs4778889 polymorphism was associated with increased risks of developing allergic contact dermatitis , graves ' disease , sle , and endometriosis .
in contrast , some researchers reported that the rs4778889 polymorphism was not related to the risk of periodontitis   and cad [ 30 , 31 ] . in this study
, we failed to find any association between the rs4778889 polymorphism and the risk of is .
these findings suggest that the rs4778889 polymorphism may have different roles in different diseases .  
recently , another two nonsynonymous polymorphisms were identified ( rs11556218 t / g and rs4072111 c / t ) .
the two polymorphisms were reported to be associated with increased risks of developing sle   and cad [ 30 , 31 ] . in conformity with the results , we found that the frequency of the rs11556218tg genotype in is group was significantly higher than that in the control group , indicating that the il-16 rs11556218 polymorphism may be used as a genetic marker for is .  
although the mechanism of il-16 as an inflammatory mediator is still not fully known , there is evidence that il-16 participates in the inflammatory disorder through the activation of t lymphocytes and the secretion of inflammatory cytokines [ 41 , 42 ] . in the early stages following an ischemic stroke ,
t lymphocytes were activated , released reactive oxygen species , and finally contributed to brain injury . in the later stages
depletion of t lymphocytes can reduce stroke size during the acute phase of ischemia , and the protective effect against stroke lasted in the later stages of infarct development .
this evidence may explain the possible role of il-16 gene polymorphism in is .   in conclusion
, this study provides the first evidence for associations of il-16 gene polymorphisms with risk of is in the chinese population .
the tg genotype and g allele of the rs11556218 polymorphism may have a promoting effect on is .
however , further studies are warranted in order to shed more light on the molecular mechanism .
clinical and experimental data have demonstrated that inflammation plays fundamental roles in the pathogenesis of ischemic stroke . 
 interleukin-16 ( il-16 ) is identified as a proinflammatory cytokine that is a key element in the ischemic cascade after cerebral ischemia . 
 we aimed to examine the relationship between the il-16 polymorphisms and the risk of ischemic stroke in a chinese population . 
 a total of 198 patients with ischemic stroke and 236 controls were genotyped using polymerase chain reaction - restriction fragment length polymorphism ( pcr - rflp ) and dna sequencing method . 
 we found that the rs11556218tg genotype and g allele of il-16 were associated with significantly increased risks of ischemic stroke ( tg versus tt , adjusted or  =  1.88 ; 95% ci , 1.153.07 ; g versus t , adjusted or  =  1.54 ; 95% ci , 1.052.27 , resp . ) . 
 however , there were no significant differences in the genotype and allele frequencies of il-16 rs4778889 t / c and rs4072111 c / t polymorphisms between the two groups , even after stratification analyses by age , gender , and the presence or absence of hypertension , diabetes mellitus , hypercholesterolemia , and hypertriglyceridemia . 
 these findings indicate that the il-16 polymorphism may be related to the etiology of ischemic stroke in the chinese population .