noncommunicable diseases , including type 2 diabetes mellitus ( t2 dm ) , are considered the leading cause of death in the world and , in brazil , constitute the main cause of diseases .
t2 dm assumes an important role in this context given that it is considered a worldwide epidemic disease ; in 2011 it appeared among the ten leading causes of death in the world and it is prospected that number of cases will continue to increase .
the ones most frequently being discussed are the increase in population life expectancy , changes in lifestyle ( including unbalanced diet and physical inactivity ) , and obesity .
diabetes can be defined as a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion , insulin action , or both .
the underlining cause of t2 dm can be attributed to a combination of resistance to the action of the hormone , increased production of insulin in a compensatory manner , and inadequate secretory response . on the other hand , according to a study conducted by kaprio et al .
, the heredity has an input around 47% in susceptibility to t2 dm ; thus , genetic factors play an important role in the development of the pathology .
some facts corroborate the importance of heritability in t2 dm : the greater concordance between monozygotic twins than among dizygotic twins and a wide variation in the prevalence of t2 dm in epidemiological studies with different ethnic groups as well as positive results in numerous other genetic studies . in this regard
, it should be noted that even as more than 30 genes associated with t2 dm have been identified , the contribution of each individual gene in the disease susceptibility is very small .
additionally , most of these genes identified are related to dysfunction of pancreatic  cells .
several reports suggest that the characteristics of each individual , including genetic polymorphisms , may confer differences in the occurrence of diabetes and other complex diseases such as cancer and heart disease .
withal , in most cases , a positive association between polymorphisms of these genes and t2 dm are not reproducible in the analysis of a different population .
two polymorphisms in the promoter region of the tnfa gene have been described , one present at position -308 . in this
regard , swaroop et al .   demonstrated an association between the adipocytokine tnf- and development of insulin resistance .
this systematic review was conducted to provide a comprehensive assessment of the association between the polymorphism in the gene tnfa -308g / a and the presence of t2 dm .
the literature search was made through the virtual health library ( vhl ) which uses as bibliographic databases the publications found in sources such as lilacs , medline , and other information bases such as open educational resources , websites , and scientific events .
any publications with case - control studies , on january 21 , 2016 , that show the relationship between polymorphisms of tnfa gene -308g / a and susceptibility to type 2 diabetes mellitus ( t2 dm ) were surveyed .
the search terms used were as follows :  diabetes  and  tnf  or  tumor necrosis factor  , and  polymorphism  .
the filters are selected in accordance with the main subjects of the following terms :  type 2 diabetes mellitus  ,  tumor necrosis factor alpha  ,  single nucleotide polymorphism  , and  genetic polymorphism  .
the filter base on the type of study included solely the term  case - control study  .
inclusion criteria were as follows : ( 1 ) the study must have been case - control ; ( 2 ) the study should have assessed type 2 diabetes mellitus and -308g / a polymorphism of tnfa gene , even if associated with other comorbidities ; and ( 3 ) the study should have provided sufficient data , including the number or frequency of alleles and genotypes .
studies were excluded if ( 1 ) there were commentaries , case reports , or non - case - control or meta - analyses studies ; ( 2 ) they did not report sufficient data ; ( 3 ) they presented data from other types of diabetes or did not specify what kind patients had ; and ( 4 ) they showed polymorphism in another coding region of the tnfa gene or ( 5 ) if the sample was composed of only dm patients .
data from eligible studies were extracted independently in accordance with the inclusion and exclusion criteria . for each study
the following characteristics were collected : the authors , the study title , the year of publication , where it was published , the sample size , the tnfa -308g / a genotypes with their corresponding simple frequencies and percentages for the control and the case group , and the study 's p value and odds ratio , when calculated .
the literature search found articles published starting from 2000 , given that the year the complete mapping of the human genome was made available .
advances in molecular biology technology since this project have been quick and , thus , increasing the number of genetic studies published for the association of certain genetic polymorphisms with various pathologies . in the case of literature search for articles with case studies that related polymorphism position -308 of the tnfa gene with diabetes ,
the result presented forty - three publications between the years 2003 and 2015 , ten of which met the criteria inclusion .
thirteen studies presented results for other types of diabetes ; eleven related to type 1 diabetes and two to gestational diabetes .
two others did not specify what type of diabetes had patients in the case group .
two of these studies did not show enough genetic data for analysis . in relation to tnfa gene ,
seven studies presented polymorphisms in region other than the -308 position and three publications had single nucleotide polymorphism in a gene that was not tnfa .
other studies were excluded due to different methodological designs in their inclusion criteria : two meta - analysis , one being observational and the other prospective and , relative to the sample .
furthermore , there was a publication that presented data of diabetic patient 's polymorphisms in both the control and the case group .
the number and homogeneity of the included studies presented were too limited to allow a meta - analysis .
relate the polymorphism in gene studied with t2 dm and coronary heart disease , while another two ( buraczynska et al . ,
dabhi and mistry ) relate association frequencies in diabetic patients with nephropathy or renal failure .
finally , five studies reported data that directly relate polymorphism in question with t2 dm ( shiau et al . , bouhaha et al . , guzmn - flores et al .
one of which also relates it with obese t2 dm patients ( bouhaha et al . ) .
the general characteristics of the studies included in this review are summarized in table 1 . in three studies conducted in spain , hungary , and
morocco significant associations between the tnfa -308g / a polymorphism and the risk of t2 dm were identified [ 11 , 17 , 20 ] : two of them in patients with other comorbidities such as coronary heart disease   and atherosclerosis . in the present study , therefore , we infer that although there was no evidence of heterogeneity in the association between polymorphisms in the tnfa -308g / a gene and increased risk for development of t2 dm , the presence of positive results may mean that few studies have not been enough to clarify this relationship , and besides there is no documented evidence in various ethnic groups .
due to contradictory results , this systematic review is aimed at providing a comprehensive assessment of the association between tnfa -308g / a and phenotype involving type 2 diabetes .
the concern regarding the quantification and qualification of the genetic impact on phenotypic characteristics started after the first complete human sequence after genomic era . as a consequence ,
health research delved into the genetic information as a way to find answers to complex disease questions .
this type of research has shown high prevalence and increasing prospects in a number of cases , such as diabetes . for this purpose , various portions of the human genome are now analyzed in search for genetic variations among individuals that could explain these diseases .
studies seeking interactions between these variations , in particular , have been very promising . in the case of diabetes , a syndrome whose etiology is complicated and involves several risk factors for its development and progression , some studies on single nucleotide polymorphisms were suggested as causing the phenotypic characteristics and responsible for the increased risk of developing pathology [ 2527 ] . to study the risk factors for a disease is to study the possibility of a certain event happening . within the epidemiological concepts ,
the term is used to predict the likelihood of healthy individuals , exposed to certain factors , developing a given disease .
this does not necessarily mean that it would occur ; nevertheless the presence of these factors makes the individual more vulnerable to manifest the disease . a risk factor 
x  may be the trigger of various diseases , and several risk factors can cooperate for the genesis of a common disease .
environmental factors such as eating habits [ 2931 ] and physical inactivity [ 3234 ] , in addition to the concomitant presence of diverse mutations in many genes , need to be considered so that the contribution of each of them is understood .
linkage research studies genetic markers and specific polymorphisms in a family group that has the disease .
this , thus , allows the researchers a way to better study the regions of a chromosome that is affected .
after the connection is made to the chromosome , one can test for association of polymorphisms for identifying a genotype specific to a given disease in groups of people who have the targeted disease [ 34 , 35 ] .
several association studies have discussed the importance of clarifying the relationship between genetic polymorphisms and the development of type 2 diabetes .
the search for candidate genes was initially focused on possible genes encoding proteins directly involved in the pathophysiology of t2 dm : related encoders , for example , production , secretion or activity of insulin , or development of the pancreas [ 3638 ] .
gradually , however , emerging studies suggested that several other factors could contribute to the development of t2 dm , as the expression of proinflammatory cytokines and other molecules that act in the inflammatory process and that appear to play a critical role in the development of chronic complications of dm .
several studies have shown the influence of various polymorphisms in proinflammatory cytokines genes as a risk of development of obesity , diabetes , and metabolic syndrome .
one of these cytokines , tumor necrosis factor ( tnf- ) , has been investigated since diabetics have elevated levels of it circulating .
tnf- has also been implicated as an insulin resistance - causing factor associated with the pathogenesis of t2 dm .
tnf- is a proinflammatory cytokine that acts in the regulation of cell proliferation , differentiation , and apoptosis . among the various polymorphisms describing the tnfa gene , the -308g > a variant located in the promoter region excels by affecting the expression of its gene .
the presence of the a allele at nucleotide -308 increases transcription of tnfa gene approximately twofold , therefore increasing the production of this cytokine . under this circumstance
, it is expected that the polymorphic genotype may be associated with an increased frequency of diabetes and , for the proper association , of case - control studies can be used . in this review ,
several studies with the frequency of genotypes in control and case group were observed for a better understanding of the population genetic profile and a possible association between polymorphism of tnfa gene and t2 dm in groups with different ethnicities .
the influence of genetic polymorphisms on certain diseases may be found in a population and yet not in another ; this may impact the frequencies and distribution of a given polymorphism in distinct population .
the difference in influence may be due to racial variantion as well as other factors . .
in addition , some studies have included a proportionally small sample size in relation to the country 's population and most of them define the case of groups in t2 dm patients who have concomitant comorbidities .
case - control studies were selected in this review and were made with the people of spain , taiwan , poland , india , tunisia , mexico , hungary , and morocco ; nonetheless a positive association was only found in the spanish , hungarian , and moroccan population .
sefri et al .   in their meta - analysis , which considers 21 case - control studies published until august 2013 , argue that no significant associations were found between the polymorphism in the studied region of the tnfa gene and risk of developing t2 dm .
their finding was consistent with a previous meta - analysis , which included data from 18 association studies .
in these studies , publications with different ethnic groups were included ; among them were africans , asians , caucasians , and other populations .
so , when comparing the frequencies of polymorphic genotypes ( ga and aa ) in the groups of case - control study ( described in table 1 ) , it is possible to observe that these genotypes are presented more frequently in the group that has the disease .
the exceptions to this were the studies in tunisia and india ; the most frequent genotype in type 2 diabetic patients was the gg . in all other countries
this evidence supports the assumption that polymorphisms in the tnfa gene and its association with other aspects , both genetic and environmental , may represent an important risk factor for type 2 diabetes mellitus .
risk factors not modifiable or irreversible in nature , such as genetic profiles , refer to the individual characteristics .
even though these factors may not be changed , the identification of their presence in individuals and families may enable health professionals to advise change in the lifestyle of these patients , avoiding early manifestation of t2 dm .
 diabetes mellitus ( dm ) is considered to be a worldwide epidemic disease and its type 2 form comprises more than 95% of all cases . 
 tumor necrosis factor - alpha ( tnf- ) is a proinflammatory cytokine . 
 its dysregulation has been implicated in a variety of human diseases , including type 2 diabetes mellitus ( t2 dm ) . 
 the control of expression of this cytokine is associated with insulin resistance and has a strong genetic influence . in order to understand this relationship 
 , the literature from all case - control studies since 2000 to date was reviewed . 
 the genotypes frequency results presented in ten publications with different ethnicities were compared . 
 the correlation between the tnfa promoter genotypes and the risk of developing t2 dm remains controversial due to the many discrepancies between the different studies available . 
 ethnic differences may play a role in these conflicting results , since the distribution of tnfa promoter polymorphisms is distinctive between individuals of dissimilar racial origin . 
 hence , although the relationship between t2 dm incidence and presence of polymorphisms at position -308 of the tnfa gene is not entirely clear , the results of these studies suggest the need for further investigation . 
1. Introduction
2. Material and Methods
3. Results
4. Discussion
5. Conclusion