type 2 diabetes mellitus ( t2 dm ) is a group of metabolic disorders with insulin secretion deficiency or insulin resistance ( ir ) and characterized by hyperglycemia . the prevalence of diabetes increases significantly in recent decades , affecting about 6% of adult population globally . t2 dm is a heterogeneous and polygenic disease associated with increased risk of several complications , such as cardiovascular disease , ischemic heart disease , and diabetic retinopathy . over the past decades , great achievements have been made in clinical diagnosis and interventions as well as elucidating the underlying pathogenesis of diabetes . obesity , food intake , and energy expenditure have long been recognized as important key factors in the etiology of diabetes . besides , genetic factors also play a pivotal role in the development of diabetes and identified multiple t2dm - associated genes , providing additional insights into the disease mechanisms . leptin is a hormone protein important in regulating food intake and energy expenditure for energy balance , fertility , and metabolism , which are mediated by the cell surface leptin receptor ( lepr ) [ 5 , 6 ] . it is suggested that there is a connection between energy metabolism and obesity . under normal condition notably , leptin is also known to facilitate glucose utilization and improves insulin sensitivity [ 8 , 9 ] . apart from its role in obesity , recent studies have drawn attention to the role of leptin in the pathogenesis of t2 dm and insulin resistance . several functional variants with possible biological effects on metabolism regulation have been extensively investigated for the genetic predispositions on diabetes and its complications . these gene polymorphisms include rs1137101 ( p.arg223gln or p.r223q ) , rs1137100 ( p.arg109lys or p.r109k ) , rs8179183 ( p.lys656asn or p.k656n ) , rs62589000 ( p.pro1019pro or p.p1019p ) , 3-untranslated region ( utr ) ins / del , rs1805134 ( p.ser343ser or p.s343s ) , and rs2228301 ( p.asn567asn or p.n567n ) [ 1023 ] . although many studies have elucidated the association between t2 dm and lepr gene , the conclusion is still controversial because of small sample size in each study and lack of robust replication . we therefore conducted a systematic review and meta - analysis to evaluate the genetic impacts of lepr gene polymorphisms on the risk of t2 dm . a comprehensive literature search was conducted in online databases , medline ( medical literature analysis and retrieval system online ) and embase ( via ovid ) engines up to july 2015 . the following medical subject headings and keywords were used for search strategy :  leptin  ,  leptin receptor  ,  lep  ,  lepr  , gene(s )  ,  polymorphism(s )  ,  mutation(s )  ,  variant(s )  ,  diabetes  ,  diabetic  ,  dm  , and references lists of the retrieved articles and reviews were also screened for additional articles not captured by electronic search . eligible studies were defined as the following criteria : ( 1 ) case - control study ; ( 2 ) investigating the association between t2 dm and lepr polymorphisms ; ( 3 ) sufficient genotype distribution data in case and control groups ; ( 4 ) study samples being unrelated individuals drawn from clearly defined populations ; ( 5 ) written in english . the exclusion criteria were defined as studies on animals , case reports , reviews , abstracts , editorial comments , and reports with incomplete data . the following information was extracted from each study : first author , year of publication , country of studies , ethnicity , sample size , age , gender , allele / genotypic frequencies , and body mass index ( bmi ) . if the test for hardy - weinberg equilibrium ( hwe ) was not reported , it was tested by the genotype data . the quality of studies was evaluated independently by two investigators ( m. m. yang and j. wang ) according to the newcastle - ottawa scale ( nos ) . uncertainties were resolved by discussions or by consensus with a third reviewer ( j. j. fan ) . nos evaluated studies with a star - rating system ranging from 0 ( lowest ) to 9 ( highest ) stars , which was based on three study components , including selection , comparability , and outcome assessment . studies with more than 5 points were evaluated as qualified . pooled odds ratios ( ors ) and corresponding 95% confidence intervals ( ci ) were used to estimate the association strength between lepr polymorphisms and t2 dm risk . the regression coefficients and the associated standard errors ( se , 95% ci ) were combined using meta - analytic software . the combined ors were , respectively , calculated by four genetic models ( allele , dominant , recessive , and homozygous ) . hwe among controls was evaluated by  test and p < 0.05 was considered as significant disequilibrium . both cochran 's q statistic testing degree of heterogeneity across studies and the index i statistic quantifying the proportion of heterogeneity between studies were calculated ; p  value less than 0.10 for the q - test and i above 50% were considered as statistically significant . if there was significant heterogeneity , the random effects model would be used to analyze the pooled ors ; otherwise , the fixed effects model would be applied . we used univariate random effects metaregression to investigate the potential sources of heterogeneity , such as , ethnicity , sample size , source of control , and publication years . sensitivity analysis was used to assess the stability of results by systematically removing each study and reassessing the significance , whereas funnel plot and egger 's test were used to assess the potential publication bias . statistical analyses were conducted by review manager ( version 5.3 , copenhagen : the nordic cochrane centre , the cochrane collaboration , 2014 ) . the search and selection process of included studies was presented in figure 1 . according to our searching strategy , 199 potentially relevant studies were retrieved initially ; after screening , 14 studies and 30 extracted snp outcomes met the inclusion criteria and were used for the meta - analysis . the detailed information of the corresponding pooled odds ratios and p  values of each snp were presented in table 2 . the nos results showed that the methodological quality was generally good ( data not shown ) . eleven studies , containing 3649 t2 dm cases and 2381 controls , were eligible for pooling of genetic effects of p.r223q on t2 dm . the allele model ( r versus q ) yielded a pooled or of 1.27 ( 95% ci : 1.131.42 ) with minimal heterogeneity ( pq = 0.13 , i = 38% ) . our result demonstrated a positive correlation between r allele of p.r223q and t2 dm risk . significant association was also observed under other genetic models ( dominant : or = 1.19 , 95% ci 1.051.35 ; homozygote : or = 1.82 , 95% ci 1.382.39 ; and recessive : or = 1.75 , 95% ci 1.352.28 , resp . ) the pooled analysis showed that r109k had no significant association with t2 dm susceptibility for all genetic models : allele ( or = 1.02 , 95% ci 0.921.12 ) , dominant model ( or = 1.04 , 95% ci 0.911.19 ) , homozygote model ( or = 1.15 , 95% ci 0.811.65 ) , and recessive model ( or = 1.17 , 95% ci 0.821.66 ) ( figure 3 ) . the ors for all genetic effects were homogeneous across all studies ( i = 0% ) except mild heterogeneity in the dominant model ( i = 27% ) . the association between p.k656n and t2 dm has been examined in five studies , including 2018 cases and 1641 controls . the genetic effects were homogeneous across studies ( i  25% , figure 4 ) . three studies were carried out to assess the association of p.p1019p with susceptibility to t2 dm , involving 753 cases and 767 controls . only dominant genotype data can be extracted from the original study by takahashi - yasuno et al . . overall , the recessive and homozygote model showed homogeneity and the fixed effects pooled ors were found to be significant ( or = 1.75 , 95% ci = 1.122.72 , and or = 1.86 , 95% ci = 1.143.02 , resp . ) . the allele and dominant model yielded a strong heterogeneity between studies ( i  67% ; p = 0.001 ) , and the random effect model was therefore used but no significant association was observed ( or = 1.49 , 95% ci = 0.892.50 , and or = 1.28 , 95% ci = 0.841.96 , resp . ) ( figure 5 ) . regarding the association of 3utr ins / del , variable results were observed across different models , whose significant association was detected between 3utr ins / del and t2 dm under allele and dominant models with no evidence of heterogeneity , but lack of significant association in other genetic models . moreover , the ors yielded strong heterogeneity among the studies ( i = 66% and 69% in homozygote and recessive model , resp . ) two variants of rs1805134 ( p.s343s ) and rs22283014 ( p.n567n ) were reported by only one article by kyong et al . with 775 cases and 688 healthy controls . this study found no significant association between these two polymorphisms and risk of t2 dm . in order to examine the influence of each study set to the pooled ors , sensitivity analysis was performed by omitting one study in each time . for the variants , rs1137101 ( p.r223q ) , rs1137100 ( p.r109k ) , and rs8179183 ( p.k656n ) , the ors were not significantly influenced by individual data , indicating that our results were statistically stable and robust . metaregression was performed to detect the source of heterogeneity for the significant finding of rs1137101 ; the results indicated that sample size ( p = 0.015 ) and source of control ( p = 0.029 ) contributed heterogeneity , while ethnicity ( p = 0.648 ) and publication year ( p = 0.429 ) did not . regarding rs62589000 ( p.p1019p ) , the sensitivity analysis showed that the data from lu et al . apparently influenced the overall results ; therefore , the pooled ors need be taken into account . for 3utr ins / del , only two studies were performed in finland and mexican populations ; among the two included articles , the results in one study performed by nannipieri et al . were overweight and significantly influenced the overall results . publication bias was investigated by funnel plot and egger 's test ; for all snps , funnel plot shapes did not reveal any evidence of obvious asymmetry ( figure 7 ) . egger 's test also suggested no publication bias ( p = 0.524 for rs1137101 ) . in recent years , numerous studies have been conducted to evaluate the genetic influence of leptin to t2 dm susceptibility . while the reports in different ethnic groups often yielded contradictory results , the inconsistencies could be due to the lack of power in each individual study with limited sample size as well as the heterogeneous data and methods . to confirm the association of lepr and t2 dm , we , for the first time , conducted a systematic review and meta - analysis to examine the associations of lepr polymorphisms with t2 dm risk . for this meta - analysis , five of the most commonly investigated lepr snps were analyzed . among them , p.r223q was found to be significantly associated with t2 dm , which remained significant even after sensitivity analysis . genetic effect with allele r showed a positive association with t2 dm from 1.19- to 1.82-fold under different genetic models . this result provides robust evidence for the genetic impact of leptin on diabetes , which will lead to further biological function investigation . it is well known that obesity is a major link to t2 dm , especially characterized by insulin resistance . as leptin has long been linked with obesity , recent studies have depicted the role of leptin in t2 dm and insulin resistance . leptin can facilitate glucose utilization and improve insulin sensitivity , which has been implicated in the development of diabetes . meanwhile , lower leptin expression in the adipose tissue and serum leptin levels were observed in t2 dm patients . the lepr p.r223q ( g > a polymorphism , rs1137101 ) leads to an amino acid alteration from arg to gln located in the regulatory domain of the lepr protein . study by murugesan et al . found that the levels of leptin , insulin , and body mass index ( bmi ) were significantly increased with homozygous and heterozygous variants of p.r223q and showed significant difference between cases and controls . these results were consistent with findings of yiannakouris et al . suggesting that the p.r223q polymorphism is associated with obesity and predicts a small percentage of body weight and body composition variability in a genetically homogeneous population . regarding this snp , majority of studies were conducted in asian populations ; this is because some studies in other ancestries were excluded during the process of narrowing the studies ; additionally , the maf of this polymorphism is similar across different populations . therefore , this significant association reported in the present study is more likely to be predictive of diabetes in overall population . for other two functional variants , p.r109q and p.k656n , no significant associations were found with t2 dm under any genetic models , implying that these two variants might not contribute to the risk of t2 dm . with regard to p.p1019p and 3utr ins / del , significant association was identified with t2 dm , but the results were largely influenced by particular article and a limited number of studies were available . therefore , these associations should be carefully interpreted , and further examinations in larger cohorts are warranted . the number is not enough for every variant in the meta - analysis , such as p.p1019p and 3utr ins / del . secondly , the small sample size conferred limited statistical power for exploring real association , especially for the subgroup analysis . thirdly , as a multifactorial disease , a more precise analysis on t2dm - related factors should be conducted , such as bmi , age , and environmental exposure ; however , some studies did not provide the detailed information . to the best of our knowledge , this is the first meta - analysis to investigate the association of lepr gene with t2 dm . our results suggested that the polymorphism rs1137101 ( p.r223q ) has strong association with t2 dm susceptibility . more studies in larger cohort and functional analyses of lepr are required to reinforce the results and elucidate its biological roles in diabetes .
leptin is a hormone protein regulating food intake and energy expenditure . 
 a number of studies have evaluated the genetic effect of leptin ( lep ) and leptin receptor ( lepr ) genes on t2 dm . 
 this study aimed to investigate the association between these gene polymorphisms and t2 dm by a systematic review and meta - analysis . 
 published studies were identified through extensive search in pubmed and embase . 
 a total of 5143 t2 dm cases and 5021 controls from 14 articles were included in this study . 
 five functional variants in lepr were well evaluated . 
 meta - analysis showed that rs1137101 ( p.r223q ) was significantly associated with t2 dm in all genetic models : allele model ( or = 1.27 , 95% confidence interval ( ci ) = 1.131.42 ) , dominant model ( or = 1.19 , 95% ci = 1.051.35 ) , homozygote model ( or = 1.82 , 95% ci = 1.382.39 ) , and recessive model ( or = 1.75 , 95% ci = 1.352.28 ) , with minimal heterogeneity and no indication of publication bias . 
 similar associations with t2 dm were also found for rs62589000 ( p.p1019p ) and 3utr ins / del , although the data was obtained from a small number of studies . 
 for the other two polymorphisms rs1137100 ( p.r109k ) and rs8179183 ( p.k656n ) , they were not significantly associated with t2 dm . our results provide robust evidences for the genetic association of rs1137101 ( p.r223q ) in lepr with t2 dm susceptibility .