This study examined (1) the interrelationships among 5-HTTLPR genotype, perceived parental rejection, and impulsivity, and (2) meditational models in which perceived paternal/maternal rejection mediates the relationship between the 5-HTTLPR genotype and impulsive behaviour. Participants included 403 adults  who provided genetic data and a set of the questionnaires . Using SEM , we evaluated 3 models for both direct and indirect relationships between 5-HTTLPR (5HTT) and Impulsivity (IMP), via maternal/fraternal rejection (MAT/FAT). In model 1, the direct path from 5HTT and IMP was not significant across the mother’s and father’s analysis. Models 2 and 3 assessed the indirect influence of 5HTT on IMP through MOT/FAT. The paths of models 2 and 3 were all significant and showed a good fit between the hypothesized model and data. Furthermore, the effects of the 5-HTTLPR genotype on impulsiveness in this Japanese sample were particularly accounted for by perceived rejection from the mother or father. The effects from the parents appeared to be robust especially among males. These results may help elucidate the specific pathways of risk in relation to genetic and environment influences on impulsive phenotypes. Violence is one of the international issues that researchers have set a task to prevent. There have been concerns about how we solve problems relating to violent, aggressive, and impulsive behaviour, such as DV, child maltreatment, neglect, and adolescent delinquency. Impulsivity is treated as one of the symptoms that cuts across psychiatric disorders, and social, biological, and psychological etiologies of treatment are necessary. Moeller et al The serotonin transporter (5HT) is a key regulator of serotonin neurotransmission. 5-HTTLPR (serotonin transporter linked polymorphic region) consists of two common alleles differing by 44 pairs, short (S) and long (L) variants, where the S allele has lower transcription efficiency than the L allele It is now well known that early experiences with a caregiver influence psychological development in later life e.g. , as it iResearch into gene - environmental interactions is relatively new in the field of psychiatry, psychology, and neuroscience. It has been generally accepted that genetics and the environment contribute to personality and behaviour. However, subsequent studies of gene -environment interactions at 5-HTTLPR and personality or behaviour are still inconsistent. Munafo et al The serotonergic system is said to behave differently depending on gender. Some studies suggested gender differences in the effects of 5-HTTLPR on behaviour. It was shown that females with the S allele and males with the L allele were at the highest psychological risk In summary, genotype/personality studies are notoriously difficult to interpret, and their results are often controversial. Despite early studies suggesting the 5-HTTLPR genotype as a player in social behaviour, neurobiological factors contributing to behavioural problems in humans remain poorly understood. A few studies have reported the influence of the serotonin system on impulsive behaviour and perceived parental rearing in a non-referred sample. Furthermore, we sought to address the question of whether perceived fraternal/maternal rejection mediates 5-HTTLPR and impulsive behaviour in adults drawn from the general population. Therefore, the aims of the present study were to: (1) examine the interrelationships among 5-HTTLPR, perceived parental rejection, and impulsivity, and (2) test a meditational model in which perceived paternal/maternal rejection mediates the relationship between the 5-HTTLPR genotype and impulsive behaviour. In the light of findings reported about associations between the serotoninergic system and social behaviour, we hypothesize that the relationship between the 5-HTTLPR genotype and impulsive behaviour is mediated by rejection from the mother or father.Participants for the present study included 403 individuals who provided both genetic data and questionnaires , from a total sample of 741 adults who provided a set of questionnaires at the University  and Vocational College in Nagasaki city .The study protocol was approved by Nagasaki University, and all participants provided written informed consent after receiving a full explanation of the study. Questionnaires and saliva sample collection containers were administrated during lectures. In addition, students and staff distributed questionnaires to their friends and neighbours in order to obtain a more diverse range of ages. After an explanation of the present study, participants provided informed consent, a saliva sample for DNA analyses, and a series of self-report measures of demographics, perceived parenting, and impulsive behaviour. It took approximately 30–40 minutes for the whole procedure. A saliva sample was not collected from all participants due to the class schedule. From a total sample of 741 adults who provided the questionnaires, data from 403 individuals who provided saliva samples and questionnaires were used for the present study.BIS11 EMBU (Egna Minnen av Bätraffande Uppfostran – My memories of upbringing 5′-GGCGTTGCCGCTCTGAATGC-3′) and reverse primer (5′-GAGGGACTGAGCTGGACAACCAC-3′). For PCR, 10 ng of genomic DNA was used in a 25-µL reaction mixture containing 0.5 U of KOD FX Neo  and 10 pmoles of each primer in PCR buffer for KOD FX Neo . Cycling conditions were as follows: denaturation (94°C for 2 min) and 30 cycles of amplification . PCR products were separated by electrophoresis in a 3% agarose gel and visualized by UV after ethidium bromide staining. A 484 bp band was observed for the S allele, and a 528 bp band for the L allele; heterozygous samples showed both alleles. Two investigators scored allele sizes independently and any inconsistencies were reviewed and rerun.Genomic DNA was extracted from oral mucosa collected from participants using the QIAamp DNA Micro Kit . This study was performed using ethnically homogeneous individuals (only of Japanese descent). The serotonin transporter gene (5-HTTLPR) of the 5-HTT gene regulatory region was amplified by polymerase chain reaction (PCR) with a forward primer  version 17.0 The GFI (Goodness of Fit Index) is considered a reasonable statistic index for evaluating a model and assesses the fit between a hypothesized model and the data. AMOS calculates all measures that capture model evaluation that were selected based on different theoretical perspectives such as: CMIN/df  = 2.20, p<.05), Overprotection (t (322) = -13.5, p<.001), and Emotional Warmth (t (322) = −10.65, p<.001).Of the 403 participants, 273 (67.7%) were homozygous for the short allele, 111 (27.5%) carried the heterogeneous genotype, and 19 (4.7%) were homozygous for the long allele. 5-HTTLPR groups did not differ significantly in regard to gender. To test whether levels of maternal parenting differed from paternal rearing, we conducted a pair samples t-test. Results showed that ratings of mothers were significantly higher than ratings of fathers in regard to all EMBU scales; Rejection  = 7.36, Eta2 = .03, p<.005, suggesting that individuals who perceived their mother as less loving tended to report more Non-planning Impulsivity than those who reported more maternal warmth. There was a gene -mother interaction on Motor Impulsivity, F  = 3.68, Eta2 = .025, p<.005 suggesting that SS carriers with low maternal warmth reported more Motor Impulsivity than SS carriers with high maternal warmth. Regarding Emotional Warmth Father, an effect of fraternal warmth was shown on Non- planning Impulsivity, F  = 5.98, Eta2 = .025, p<.005. There was a gene - father interaction on Attention Impulsivity, F  = 5.95, Eta2 = .025, p<.005, and Motor Impulsivity, F  = 5, Eta2 = .025, p<.005, suggesting that SS with low warmth from fathers tended to report more Attention and Motor Impulsivities than the SS type with more fraternal warmth.Regarding scales of Emotional Warmth, a univariate F-test showed a significant effect of  maternal rejection on Attention Impulsivity, F  = 4.24, Eta2 = .03, p<.005, Motor Impulsivity F  = 4.24, Eta2 = .03, p<.005, and Total Impulsivity F  = 4.24, Eta2 = .03, p<.005, indicating that individuals who perceived their mother as rejecting tended to report more Attention, Motor, and Total Impulsivities than those who reported less maternal rejection. There were no significant effects on genotype or gene - father interaction. There were no significant main effects on father’s rejection, genotype, or gene - father interaction.Regarding the scale of Rejection, a univariate F-test showed a significant effect ofr = .150, p<.001), but not with Rejection Father. Rejection from both the mother and father was associated with Motor Impulsivity  and Total Impulsivity .Before testing models, intercorrelations among factors were analysed. Correlations between the scales of BIS11, and perceived rejection and other variables are presented in The following strategy was used to test mediation. First, a model was estimated with only the predictor (i.e. 5HTT) and outcome variable (i.e. IMP) included, assessing the direct effect exclusive of any mediator variables. In the first model, both father and mother and genotype were included as a predictor in the model. Parent rejection (PAR) as mediating the relationship between 5HTT and IMP showed a relatively good fit , but the pathway did not evaluate a shared variance of variables for 5HTT, PAR, and IMP.p>.05); however, the direct pathway from 5HTT to IMP was not significant when analysing neither the father’s nor mother’s rejection.Second, we investigated the model analysis for mother and father separately, and included a direct path from 5HTT to IMP in the context of the meditational model to determine whether a significant bivariate relationship between predictor and outcome exists. Model 1 was explored in the model illustrated in p<.001). The relationships between all constructs and their indicators were positive and significant (p<.001). Indices of goodness of fit indicated an acceptable fit between model 2 and the data (X2(4) = 1.63,CMIN/df = .399, CFI = 1.00, RMSEA = .000; see p<.001 and p<.05). Indices of goodness of fit showed acceptable fits: X2(4) = .2.45,CMIN/df = .171, CFI = 1.00, RMSEA = .000 for males, and X2(4) = .71,CMIN/df = 2.45, CFI = 1.00, RMSEA = .000 for females  = 1.60, CMIN/df = .40, CMIN = 1.84, CFI = 1.00, RMSEA = .000. This model reached an adequate fit across gender; X2(4) = 2.13,CMIN/df = .53, CMIN = 1.60, CFI = 1.00, RMSEA = .000 for males, and X2(4) = .68, CMIN/df = .17, CMIN = .684, CFI = 1.00, RMSEA = .000 for females. All paths  were significant among males (p<.05), but not among females. Despite the significant path between 5HTT and FAT (p<.05), the path linking FAT and IMP was not significant among females.Finally, The present study examined a meditational model in which perceived paternal/maternal rejection mediates the relationship between the 5-HTTLPR genotype and impulsive behaviour. The main result was that the effects of the 5-HTTLPR genotype on impulsiveness in this Japanese sample can be particularly accounted for by perceived parental rejection, especially from the mother. The effects from the parents appeared to be robust especially among males.We evaluated two models regarding both direct and indirect relationships between 5-HTTLPR and impulsivity via perceived rejection. Model 1 provided a reasonable fit with the data. However, the direct path from 5HTT and IMP was not significant. This may reflect results from earlier studies The path of model 2 was all significant and showed a good fit between the hypothesized model and data across males and females. Perceived parenting formed as rejection from the father or mother interacted with genotype in relation to self-reported impulsive behaviours. This result is in line with results from studies that showed associations between the 5-HTTLPR genotype, low maternal care and loneliness Despite the power analysis, which showed no significant gender effect or gene - gender interaction, the result of SEM analysis showed a better model fit on rejection from both the mother and father among males than females. Similarly, rejection from the mother seems to play an important role in impulsivity as the model fit of the mother was better than rejection from the father. As seen in a comparison of the ratings for the mother and father on EMBU, it was shown that mother’s scores of all four factors  were significantly higher than those rating fathers. It may reflect the traditional Japanese childrearing style where the mother is regarded as the one to take care of the children. However, results showed that it is necessary to consider not only the mother’s, but also the father’s rearing when analysing problem behaviour in addition to the genotype.It is important to note the limitations of the present study. First, the present study was designed as cross-sectional and hence does not provide directions or causal effects. It is equally plausible that a higher degree of impulsivity was contributed to negative perceived parenting and genes, or impulsive individuals elicited negative evaluations from their surroundings. Second, generalization of our findings may be limited due to a low sample size because of the large number of excluded participants as a consequence of a lack of a DNA sample, and there were more females than males. Power analysis indicated in the present study may have been underpowered to detect effects or associations with 5-HTTLPR. It should also be mentioned that SL and LL genotypes were combined in the MANOVA analysis. Further study in a larger population from both clinical and non-clinical samples is needed to avoid stratification artifacts. Third, measurements are solely based on self-reports that involve a risk for information bias from recall and interpretation of past behaviour Despite these limitations, the present study shows some evidence that the 5-HTTLPR genotype influences impulsive behaviour, and that this influence depends on the environment in which the individual was raised, or at least on his/her perception of the environment in which he/she was raised. The seemingly infinite complexities of social behaviour, difficulties in “measuring” it, influence of environment, interactions with genes, and influence of epigenetic phenomena may be amongst the confounding factors that present an apparently insurmountable obstacle to understanding the causal links between genetics and social behaviour. To advance understanding of these complexities, further research needs to be applied in a more controlled way, e.g. matching experimental set-ups with population-based and clinical samples with a sufficient sample size.


A total of 13 studies were included in this meta-analysis, including the entire Danish population, 5,107,506 other participants and more than 2,206 cases of brain tumors. In the analysis of these 13 studies, we observed that diabetic individuals had a similar risk of brain tumors as non-diabetic individuals . There was significant evidence of heterogeneity among these studies . Sub-group analysis revealed that diabetic females had a 24.2% increased risk of brain tumors , which was not observed in diabetic males. No significant publication bias was found in this study. The findings of this meta-analysis indicate that diabetic individuals have a similar risk of brain tumors as non-diabetic individuals. However, a significant positive correlation between the risk of brain tumors and diabetes mellitus was revealed in females, but not in males.Accumulating evidence suggests that a history of diabetes may be involved in the occurrence of various types of cancer. However, the association of diabetes with the risk of brain tumors remains unclear. We identified relevant studies by performing a literature search of PubMed and EMBASE (through to 24 May 2012) and by searching the reference lists of pertinent articles. All data were extracted independently by two investigators using a standardized data abstraction tool. Summary relative risks (SRRs) with 95% confidence intervals (CIs) were calculated using a random-effects model. Inter-study heterogeneity was assessed using the Cochran’s Q and I Cancer of the brain and central nervous system results in an estimated 142,000 mortalities per year, worldwide . HoweverDiabetes mellitus (DM) is a serious and growing health problem worldwide and is associated with severe acute and chronic complications that negatively influence the quality of life and survival of affected individuals . DM has Due to inconsistent reports on the correlation between diabetes and brain tumor risk –26, the The electronic databases of PubMed and Embase were searched  using the following search terms: ‘diabetes’, ‘diabetes mellitus’, ‘DM’, ‘brain’, ‘CNS’, ‘Central Nervous System’, ‘cancer’, ‘neoplasm’, ‘tumor’, ‘incidence’, ‘risk’, ‘occurrence’, ‘mortality’ and combinations of these terms. All indexed studies were retrieved and we also reviewed the reference lists of the identified publications to discover additional pertinent studies. No language restrictions were imposed. The literature search was carried out independently by two investigators.The selection criteria were that the study: i) was published as an original article; ii) had DM as the exposure of interest; iii) had brain tumor incidence or mortality as the outcome of interest; iv) provided relative risk (RR), odds ratio (OR), hazard ratio (HR) or standardized incidence/mortality rate (SIR/SMR) with the corresponding 95% confidence intervals (CIs), or presented original data from which to calculate them; and v) at least took age as a confounding factor into consideration in the calculation of RR and corresponding 95% CIs. When there was overlap in the study populations between published papers, only the most recent or complete study was included.The following data from each included study were extracted using a standardized data-collection protocol: the first author’s name, country of origin, publication year, numbers of cases and subjects, sample size, definition of the study population, ascertainment of exposure and outcome, type of DM, participant characteristics (gender composition), duration of follow-up and variables adjusted for in the analysis. When several risk estimates were presented, we used those adjusted for the largest number of potential confounding factors. Data abstraction was performed independently by two investigators and then cross-checked.2 statistic . Furthermore, positive associations were observed between diabetes and brain tumor risk in the diabetes assessment by self-report and by blood glucose level groups . However, no differences were found in brain tumor risk with diabetes between strata in the geographic region, types of diabetes, the number of cases, population size, duration of follow-up and level of confounding factors  but not in males , and there was clear heterogeneity in the analysis of female subjects  our meta-analysis was based on 13 studies, the majority of which were prospective studies, thereby minimizing the possibility of recall or selection bias; ii) all included studies evaluated multiple potential confounding factors, some of which were considered to be risk factors for cancer, such as alcohol use, smoking and body mass index; iii) the varied populations of the studies expanded on prior observational studies by permitting additional subgroup evaluation .As with any meta-analysis of observational studies, there are several potential limitations to the results of this meta-analysis. Firstly, significant heterogeneity existed across studies, throwing some doubt on the reliability of the summary RR estimates. Although we found the main source of heterogeneity to be one study, we are unable to account for how this study differed from the others. Secondly, the majority of studies included in this meta-analysis did not distinguish between type 1 and type 2 DM. This non-differential misclassification may distort the magnitude of the association between DM and the risk of brain tumors. Thirdly, the history of DM may also reflect other factors associated with an unhealthy lifestyle, such as smoking, heavy alcohol consumption and obesity. Such unhealthy lifestyles have generally been associated with an increased risk of cancer. However, some authors did not adjust for those risk factors. Fourthly, the status of DM was self-reported in some studies. This may contribute to bias in the diabetes assessments. Additionally, the majority of studies did not consider the role of anti-diabetic drugs on the occurrence and mortality of brain tumors. This role may also contribute to bias. Finally, as in any meta-analysis, it is possible that an observed association is the result of publication bias, since small studies with null results tend not to be published. However, the results obtained from the funnel plot analysis and formal statistical tests did not provide evidence for such bias.In summary, the results of this meta-analysis suggest a non-significant association between diabetes and the risk of brain tumors. However, compared with non-diabetic patients, diabetic females may have a slightly increased risk of brain tumors, whereas this was not the case in diabetic males. It should be noted that this meta-analysis does not provide firm evidence of any association between DM and brain tumor risk. Future studies are required to determine the role of a history of DM in brain tumor incidence or mortality.


APOE and FOXO3A associated with longevity; other genes show inconsistent results. Genome-wide association scans (GWAS) of centenarians vs. younger controls reveal only APOE as achieving genome-wide significance (GWS); however, analyses of combinations of SNPs or genes represented among associations that do not reach GWS have identified pathways and signatures that converge upon genes and biological processes related to aging. The impact of these SNPs, which may exert joint effects, may be obscured by gene-environment interactions or inter-ethnic differences. GWAS and whole genome sequencing data both show that the risk alleles defined by GWAS of common complex diseases are, perhaps surprisingly, found in long-lived individuals, who may tolerate them by means of protective genetic factors. Such protective factors may ‘buffer’ the effects of specific risk alleles. Rare alleles are also likely to contribute to healthy aging and longevity. Epigenetics is quickly emerging as a critical aspect of aging and longevity. Centenarians delay age-related methylation changes, and they can pass this methylation preservation ability on to their offspring. Non-genetic factors, particularly lifestyle, clearly affect the development of age-related diseases and affect health and lifespan in the general population. To fully understand the desirable phenotypes of healthy aging and longevity, it will be necessary to examine whole genome data from large numbers of healthy long-lived individuals to look simultaneously at both common and rare alleles, with impeccable control for population stratification and consideration of non-genetic factors such as environment.Longevity and healthy aging are among the most complex phenotypes studied to date. The heritability of age at death in adulthood is approximately 25 %. Studies of exceptionally long-lived individuals show that heritability is greatest at the oldest ages. Linkage studies of exceptionally long-lived families now support a longevity locus on chromosome 3; other putative longevity loci differ between studies. Candidate gene studies have identified variants at  The basis of human longevity and healthy aging, and how to achieve these desirable phenotypes, remain among the principal challenges of biology and medicine. While an understanding of lifestyle and environmental factors will maximize our ability to prevent disease and maximize health in the general population, studying the genetic basis of longevity and healthy aging in exceptional individuals is providing important biological insights. In model organisms it has been possible to demonstrate effects of mutations in genes that can extend lifespan nearly tenfold , longevity , exceptional longevity , or healthy aging . Longevity studies focus on long-lived individuals (LLI), often centenarians aged 100 or more years. One advantage of such studies is the simplicity of phenotype definition. Healthy aging can be defined in various ways, usually with regard to reaching an at least moderately old age in the absence of certain diseases or disabilities, and/or in the presence of desirable traits such as intact cognition or mobility. Both types of studies should be differentiated from the study of the fundamental biological processes of aging .A major difference between longevity and healthy aging studies is that the former focuses on lifespan, whereas the latter is focused on healthspan. Lifespan and healthspan are intimately related, however, and individuals who live exceptionally long also tend to be healthy for much of their lives. A landmark study of the health of supercentenarians (aged 110–119), semisupercentenarians (aged 105–109), centenarians (in this context aged 100–104), nonagenarians, and younger controls found that the older the age group, the greater the delay in onset of major disease  and grew up before the use of antibiotics and vaccines became commonplace. The selective pressures that influenced their mortality are not identical to those experienced by later generations, and this is an important consideration for study design.Phenotype definition is particularly important in genetic studies; it affects the interpretation and meaning of results, and the ability to compare to the results of other studies. Studies of longevity can include extreme longevity (defined as living beyond a specific extreme age) or age at death. Studies of healthy aging may use age to disease onset, successful aging or wellness , or other phenotypes Manolio . LinkageChoice of a comparison group to contrast with exceptionally long-lived or exceptionally healthy elderly individuals is also critical. Health data for LLI can be compared with archived data for deceased individuals of the same birth cohort, but DNA samples from an ideal comparison group (such as their birth cohort) are not available. Case/control molecular genetic studies of long-lived or healthy aged individuals often compare elderly cases to younger controls. Potential pitfalls of such studies include inadequate detection and control for population stratification, particularly for populations that have experienced immigration of different ethnicities over time  isoforms are known risk factors for cardiovascular disease (CVD) and Alzheimer disease (AD), likely due to their involvement in inflammation, elevated lipid levels, and oxidative stress  and APOE2 (p = 1.0 × 10−5) account for the linkage at 19q. The APOE linkage was characterized by absence of APOE4, but enrichment for APOE2 among the nonagenarians. In this study the APOE2 allele is the stronger association, and the authors refer to APOE as a longevity gene.The largest linkage study to date was done in the multi-site European Genetics of Healthy Aging (GEHA) Study, which looked at 2118 European full sib-pairs over 90 years old , with replication in eight population-based cohorts  in 873 LLI and 443 controls, and remained significant upon meta-analysis of 3,619 subjects from four independent samples  on longevity and age-related diseases was reviewed by Polito et al.  of actual variants, and small true effect sizes. Poorly designed or under-powered studies will result in false positives that legitimately fail to replicate. For studies of longevity and healthy aging, in particular, differences in phenotype or type of study will also result in findings that are non-uniform between studies. While larger case/control studies are frequently suggested as a solution to the limitations of present-day association studies, combining data from populations with different lifestyles and genetic backgrounds, even if well-matched for ethnicity, may obscure true association signals.APOE are the only ones to achieve genome-wide significance  in genome-wide association studies (GWAS) of lifespan-related traits. In three GWAS of long-lived individuals vs. younger controls, APOE was significantly associated with longevity at the genome-wide level. The first of these included 763 long lived (94–110 years) and 1,085 control (45–77 years) from German biobanks and replication in an independent set of German samples   with APOE achieved GWS. GWAS of 403 unrelated nonagenarians (average age 94) from longevity families in the LLS vs. 1,670 controls (average age 58) showed similar results , and E4 being deleterious . A third longevity GWAS  was also detectable in the Southern Italian centenarians study (SICS) of 440 LLIs aged 90–109 and 553 young controls aged 18–45  in the Rotterdam study RS1 cohort, with replication in the RS2 cohort and the FHS, found that large common deletions are associated with mortality  at old age  involve absence of specific complex diseases. If GWAS studies of survival to elderly ages are even more confounded by environmental (E) factors than GWAS of diseases, combining studies from different populations in pooled or meta-analyses may complicate the E effects even more. In studies of older individuals, it is particularly hard to control for E factors experienced over many decades of life.APOE, have achieved Bonferroni-corrected levels of GWS in GWAS of longevity. By current standards these GWAS, which involved fewer than 1,000 centenarians, or a few 1,000 nonagenarians, are modest in size. Larger GWAS may in theory allow additional SNPs to achieve this threshold. There are other indications, however, that support the idea that SNPs that do not reach this threshold of GWS may be biologically important, either individually or through their joint effects. Several studies used a variety of techniques to analyze collections of nominally longevity-associated SNPs to determine if they act in concert to affect lifespan.SNPs at only one locus, WRN and FOXO1A, as well as GAPDH, KL, LEPR, PON1, PSEN1, and SOD2 were associated with age at death. Kulminski and Culminskaya  and one TM gene (POT1) were the main determinants of the association.Gene set analysis of GWAS data from the LLS and Rotterdam studies was used to show that genes in the insulin/IGF-1 signaling (IIS) and telomere maintenance TM pathways are associated with longevity Deelen . 1021 anTOMM40 SNP near APOE alone has poor predictive value; removing it from the model reduces specificity and sensitivity by only 1 %. The 281 SNPs include 137 in 130 genes, including LMNA, WRN, SOD2, CDKN2A, SORCS1 and SORCS2, and GIP. This set of 130 genes is highly and significantly enriched for those related to Alzheimer disease (38 genes), 42 related to dementia, 38 to tauopathies, 24 to CAD, and several to neoplasms.Sebastiani et al.  construcp < 10−4  ; examples of buffered genotypes are heterozygotes for deleterious alleles of KLOTHO and LPA. Importantly, Bergman et al. use a cross-sectional study design, with 1,200 subjects in their 6–11th decades of life to show experimental support for the buffering hypothesis; their data support the idea that CETP VV genotype buffers the deleterious effects of an LPA genotype. They show a genetic interaction between CETP genotype and LPA; LPA heterozygotes with the CETP IV/II genotypes monotonically decrease in frequency with age, but those in CETP VV individuals increase from age 70 onward. They argue that case/control analyses are insufficient to reveal this effect because it does not reveal the shape of the allele frequency × age curve.One mechanism for a lack of effect by an undesirable allele is the ‘buffering’ mechanism explored by Barzilai et al. They propose that some individuals who show exceptional longevity may do so despite the presence of unfavorable alleles because those alleles are buffered by favorable alleles in other genes . Somatic mosaicism (heteroplasmy) of the mitochondrial genome also increases over the lifespan (Sondheimer et al. Two recent large-scale analyses of data from GWAS studies have established that mosaicism for large genomic alterations increases with age (Laurie et al. + T cells of a centenarian and a newborn identified differentially methylated regions that were usually hypomethylated and less correlated with methylation of adjacent CpG dinucleotides in the centenarian (Heyn et al. C. elegans (Greer et al. Epigenetics, at the interface between the genome and the environment, is emerging as an important factor in longevity, and has been the subject of recent excellent reviews (Gravina and Vijg RPTOR in the mTOR pathway is differentially expressed between the offspring of the LLI and their spouses (Passtoors et al. It is likely that the effects of epigenetic changes manifest in part by effects on gene expression. Longevity-selected lines of Drosophila show gene expression profiles that are similar to younger control flies (Sarup et al. To date, studies of longevity and healthy aging have shown few consistent and many inconsistent results. This is probably due in part to the nature of the variants we seek to find, which may be rare or even private, may act in concert or as a ‘signature’, and which may buffer against the presence of other variants. It is also due to inter-ethnic differences, population stratification, differences in phenotype definition and study design, effects of and confounding by known and unrecognized non-genetic factors in part due to cohort effects, and exacerbation by insufficient sample size. Nevertheless, the results of longevity studies to date establish their importance for our understanding of health and disease.APOE, though another, FOXO3A, was replicated in multiple candidate gene studies. Additional candidate genes are associated in more than one but not all studies. Many of these correspond to signals that hover below GWS in GWAS studies, and when analyzed together for commonalities of pathways or other processes by means such as gene set analysis, as a group are significantly associated with these phenotypes. Epigenetics is quickly emerging as a critical aspect of aging and longevity. Centenarians delay age-related methylation changes, and they can pass this methylation preservation ability on to their offspring, probably via genetic variants that affect methylation QTLs.Only one gene has emerged as consistently found in studies of LLI, Importantly and perhaps surprisingly, centenarians appear to have the same numbers of GWAS-identified common disease variants as ordinary people, and yet they have lived long and, to a great extent, free of disease. Specific examples support the idea that centenarians may have advantageous alleles of ‘buffering’ genes that allow them to remain healthy despite the presence of ‘buffered’ deleterious alleles in other genes. It will be important to determine how generalizeable this is—does it apply only to a few genes, or is it a general mechanism for suppression of disadvantageous alleles of many genes? As others have pointed out (Bergman et al.


IL1B and IL8. We performed a genetic association study between IL8-251 (rs4073) and IL1B-511 (rs16944) polymorphisms in AERD, aspirin-tolerant asthma (ATA), and healthy control subjects. Using allelic discrimination by real-time PCR, we found statistically nonsignificant associations between AERD, ATA, and healthy control subjects for the GG and GA genotypes of IL1B (rs16944). Interestingly, the AA genotype showed an increased frequency in the AERD patients versus the ATA group . This is the first observation that IL1B polymorphisms are involved in AERD. Thus, future studies must investigate whether interleukin-1β is released in the airways of AERD patients and whether it relates to genetic polymorphisms in the IL1B gene.Aspirin exacerbated respiratory disease (AERD) is characterized by chronic hyperplastic rhinosinusitis, nasal polyposis, asthma, and aspirin sensitivity. The mechanisms which produce these manifestations of intolerance are not fully defined, current research focuses on cyclooxygenase 1 (COX-1) inhibition, metabolism of arachidonic acid, and the COX pathway to the lipoxygenase (LO) route, inducing increased synthesis of leukotrienes (LT). The biological plausibility of this model has led to the search for polymorphisms in genes responsible for proinflammatory cytokines synthesis, such as  The mecTNF, IL1B, IL6, and IL8 are involved in chronic inflammatory and autoimmune diseases. Interleukin 1 (IL-1) is a cytokine associated with inflammatory responses and found in two forms, IL-1α (produced by the IL1A gene) and IL-1β (IL1B), with both genes located on chromosome 2. IL-1 is expressed in nasal polyps, nasal epithelium, macrophages, activated T lymphocytes, and monocytes; its expression is regulated by adhesion molecules, and others inflammatory cytokines [IL1B polymorphisms have been associated with inflammatory bowel disease and gastric cancer among other diseases [β have been recognized as key players in the pathogenesis of asthma [Other factors such as polymorphisms in the genes for proinflammatory cytokines including ytokines . IL1B podiseases . Recentlf asthma . In the n = 78) and aspirin-tolerant asthma (ATA) (n = 135) were recruited from the allergy and otolaryngology departments at the Instituto Nacional de Enfermedades Respiratorias (INER). Healthy control subjects (HCS) (n = 134) were invited to participate through AERD-screening campaigns. All participants underwent simple spirometry, inhaled methacholine challenge, and nasal challenge with lysine-aspirin (L-ASA) according to international guidelines to determine the degree of bronchial hyperresponsiveness and confirm AERD diagnosis. The AERD group had positive L-ASA and methacholine challenges, the asthmatic group had positive methacholine challenge, but negative L-ASA challenge, and the healthy control subjects were volunteers with negative L-ASA and methacholine challenges. A positive L-ASA challenge was defined as a decrease of at least 40% in total nasal airflow after L-ASA application compared with baseline measures; methacholine challenge was considered positive with a decrease of at least 20% in forced expiratory volume in one second (FEV1) compared with baseline FEV1 after the administration of different concentrations of methacholine ; in case it does not have it, it is considered negative. Blood samples were collected for genotyping studies in the HLA laboratory research. The study was approved by the science and bioethics committees of INER, and all participants gave their informed consent [Patients with aspirin-exacerbated respiratory disease (AERD) n = 7 and aspi consent . Patient consent , 11.Peripheral blood was drawn by venipuncture, and genomic DNA was obtained using the commercial BDtract DNA isolation kit . The DNA was quantified by absorption of ultraviolet light at 260 nm wavelength using an ACTGene spectrophotometer .IL1B and rs4073 in IL8. Genetic data from each of the polymorphisms are described in We selected two polymorphisms in two genes related to chronic inflammation: rs16944 in IL1B) and rs4073 (IL8) was performed by real-time PCR (RT-PCR) on a 7300 Real Time PCR System  using Taqman commercial probes  for each of the polymorphisms mentioned above and followed the cycling program: preread 50°C, 1 minute; absolute quantitation: 50°C, 2 minutes, 1 cycle; 95°C, 10 minutes, 1 cycle; 95°C, 15 seconds, 60°C 1 min, 40 cycles; postread 50°C, 1 minute. The results were assessed taking into account the allelic discrimination and absolute quantitation in all samples; additionally, we included four contamination controls per plate (nontemplate controls). The interpretation was performed with Sequence Detection Software (v. 1.4). The fluorescence signal detectors used were VIC which was assigned to the B allele and FAM assigned to the A allele for both SNPs.Allelic discrimination of SNPs rs16944  software for Windows, to identify the difference between the allele and genotype frequencies of each polymorphism evaluated. A p-value <0.05 was considered significant. In addition, odds ratios and 95% confidence intervals were calculated with Epi-info (v. 6.04) software.Statistical analysis was performed between groups of cases (AERD and ATA) versus the healthy control subjects by IL8 (rs4073) and IL1B (rs16944) gene polymorphisms in the three groups. Genetic data for the SNPs included in this study are shown in IL8 rs4073 SNP was not statistically significant and different between the three studied groups.Clinical data for the three groups were compared and are described in IL1B (rs16944) SNP for AERD and ATA patients versus the healthy control subjects showed nonstatistically significant associations. Interestingly, the AA genotype showed increased frequency in the AERD patients when compared to the ATA group (GF = 0.19 versus 0.07); this association was statistically significant   Tables  and 4 anIL1B-511 polymorphism (rs16944 AA genotype) compared to aspirin-tolerant asthmatics.The airways of aspirin-sensitive patients are characterized by chronic inflammation with cell infiltration even when they are not exposed to aspirin or other NSAIDs . In addiβ has been reported to be involved in the genesis of both asthma [IL1B promoter gene, mainly at positions-511 G/A (rs16944) and -31 C/T. For example, Park et al., in 2004, did not find any association between these polymorphisms and either asthma or atopy in a Korean population [IL1B-511 polymorphism (rs16944) [IL1 gene polymorphisms in asthmatic families (n = 244), but they reported an association with the DNA microsatellite D2S308 in these asthma families (p = 0.00001) [IL1B-511 C/T and nasal polyps [Interleukin-1h asthma , 14 and h asthma . Most st11 G/A rs944 and -rs16944) , but Mfurs16944) . In 20030.00001) . In paral polyps . EvidencIL1B-511 polymorphism (rs16944 AA genotype) is three-fold higher in AERD (19.2%) than in ATA patients (7.4%), suggesting that patients carrying this polymorphism may exhibit genetic susceptibility to develop AERD.In the present study, we have demonstrated that the frequency of the β in bacterial infections [β after stimulation with lipopolysaccharide [IL1B promoter region haplotypes including rs16944 [β. Our report is the first demonstration of the involvement of IL1B polymorphism in AERD. The sample size is relatively small, particularly in the AERD group, which may limit the statistical power, so it would be desirable to replicate our findings in an independent population.Findings on the biological functionality of the rs16944 polymorphism have not been consistent across studies. The AA genotype has been associated with higher gastric mucosal levels of IL-1fections , while mccharide . Recent  rs16944 –26. AlthIL1B gene.Future studies must investigate whether this cytokine is released in the airways of AERD patients and whether its levels relate to genetic polymorphisms in the IL8 alleles (−251T and 781C) have been associated with asthma in a European population [Interleukin-8 has been implicated in asthma and found in high concentrations in bronchoalveolar lavage fluid of patients with acute asthma exacerbations . In factpulation , but notpulation . In the


Rs2910164, a Single nucleotide polymorphism (SNP) located in the precursor microRNA sequence of miR-146a, is the only MicroRNA sequence SNP studied in papillary thyroid cancer (PTC). Association studies had been performed in US and UK-Northern European populations, but results were inconsistence. This study evaluated the association between rs2910164 and the risk of PTC as well as benign thyroid tumor (BN), and examined the clinicopathological characteristics of PTC and BN for different genotypes.This case-control study genotyped rs2910164 in 753 PTCs, 484 BNs and 760 controls in a Chinese Han population. Clinicopathological and genetic data were collected and compared. Multivariate logistic regression was performed to calculate adjusted odds ratios (ORs).P<0.001), lower serum thyrotropin levels , and lower rates of level VI lymph node metastasis  and lateral neck lymph node metastasis  compared with PTC only. Then we supposed a possible progression from BN to PTC which may involve rs2910164 in and performed a multivariate logistic regression analysis of PTC/BN and BN cases to determine risk factors of this progression. Results showed that the rs2910164 GG homozygote  was the only risk factor in this study.There were no differences in rs2910164 genotype distributions between the three groups. PTC cases with three genotypes  had similar clinicopathological characteristics except the existence of “para-cancer” BN . PTC/BN patients were older (P = 0.009), and had smaller cancer lesions (Rs2910164 was not associated with increased risk of PTC and BN in Chinese patients, but may play a latent role in the transformation from BN to PTC. The incidence of thyroid cancer, the fifth leading cancer in females, is increasing MicroRNAs are small noncoding RNA molecules that function as post-transcriptional suppressors of gene expression, and are involved in almost all cellular processes, such as proliferation, differentiation, apoptosis and metabolism The genetic predisposition of a benign thyroid tumor (BN) has been little studied, although more than 70% of females develop a BN in their lifetime. The aim of this study was to evaluate the association between the rs2910164 SNP and the risk of PTC and BN, and to determine the clinicopathological characteristics of PTC and BN in patients with different genotypes.In this case-control study, the case population consisted of 760 PTC cases and 485 BN patients treated at the Department of Head and Neck Surgery, Cancer Hospital, Fudan University, Shanghai, China, from January 2010 to December 2010. All subjects were ethnic Chinese Han and came from Eastern China, including Shanghai, Jiangsu and the surrounding regions. Enrollment criteria including histologically identified diagnosis, no previous surgical or medical treatment of thyroid disease, no history of familial thyroid cancer, and no radiation exposure. The control population consisted of 760 cancer-free healthy subjects recruited from the Taizhou Longitudinal Study in the same period, with the selection criteria including no individual history of cancer or thyroid disease The management of thyroid tumor in the Cancer Hospital, Fudan University was described previously Seven PTC cases and one BN case were excluded from subsequent study because of low quality DNA samples for genotyping.About 3–5 ml venous blood was collected from each subject. The Qiagen Blood Kit  was used to extract genomic DNA. Genotyping was performed with the MassARRAY iPLEX platform  using an allele-specific matrix-assisted laser desorption/ionization time of flight mass spectrometry assay (MALDI-TOF) t test as appropriate. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by univariate and multivariate logistic regression analyses to determine associations between rs2910164 genotypes and alleles and the risk of PTC and BN, and the clinicopathologic characteristics of different population groups defined by histological diagnosis and genotype. In logistic regression analysis, SNP genotypes were categorized by defining dummy variables. A P-value <0.05 was considered statistically significant. All the statistical analyses were performed with the SPSS Software version 12.0 .Differences in selected variables and Hardy-Weinberg equilibrium were evaluated using the Chi-square test and Student As shown in The genotypic and allelic distributions of rs2910164 SNP in PTC, BN and controls are summarized in The PTC patients with different rs2910164 genotypes were compared to determine the clinical characteristics of individual genotype carriers. As shown in CC v.s CG = 0.079; PCC v.s GG = 0.001; PCG v.s GG = 0.075). The correctedαvalue (the probability of making Type I Error) was 0.0125. The PCC v.s GG = 0.001<0.0125 suggested a significant difference of PTC/BN incidence between CC and GG homozygote carriers.Among 753 PTC, 96 cases were reported to have concurrent para-cancer BN  by pathologists, including 77 nodular goiters, and 19 adenomas. Among the 96 PTC/BN cases, 40 cases was incidental PTC, which were diagnosed as BN by US preoperatively. It is interesting that the frequency of finding para-cancer BN in PTC with CC, CG and GG genotypes were statistically different. . To evaluate the differences between any two of these three groups, separate Chi-square tests were performed . A possible explanation was that the malignant lesions might have originated from a susceptible background of long-lasting benign tumors and remained at an early stage of carcinogenesis. The high frequency of rs2910164 GG genotypes in PTC/BN suggested that the Mir-146a SNP rs2910164 G allele may play a potential important role in progression to PTC.The mechanism of the transformation from BN to PTC has not been extensively studied, but a high TSH level and Hashimoto’s thyroiditis were regarded as risk factors for PTC as demonstrated in a series of reports To further evaluate the potential risk factors associated with this possible progression from BN to PTC, the clinicopathologic and genetic features of BN cases and 96 PTC/BN cases were compared. Univariate analysis showed that the GG genotype (P = 0.026) and G allele (P = 0.020) distribution of rs2910164 were associated with carcinogenesis on a background of BN, whereas gender, age, presence of Hashimoto’s thyroiditis, and serum TSH level had no significant effects Table 5.The SNP rs2910164 is located in the stem structure of human pre-mir-146a and causes a C:U mismatch from a G:U pair between the sequence of mature mir-146a and its passenger strand 1. PTC and BN are initiated independently but share the same predisposition risk factor (rs2910164) simultaneously, 2. There is a progression from BN to PTC and rs2910164 is involved in this progression. As summarized in ,  and In some retrospective studies, approximately 10% of subjects with nodular goiter in the thyroid glands were found to have incident PTC It was useful to find out the PTC cases in patients with thyroid nodules by evaluating gender, age, TSH level, HT status and any other clinical parameters while finding PTC in patients with thyroid nodule is different to identify the cases with BN which may progress to PTC. Results from our study were in agreement with the published results that a high TSH level and Hashimoto thyroiditis were both associated with an increased frequency of PTC in patients with thyroid nodule The potential mechanism of rs2910164 contributing to the progression from BN to PTC is possibly associated with an increased expression of the altered target gene of mature miR-146a caused by the G allele. Jazdzewski et al found that the expression of the mature miR-146a was 2-fold lower in C allele carriers than in G allele carriers in vitro and 3.9-fold lower in CC homozygotes than in GG homozygotes in a series of cell lines Some limitations of this study should be acknowledged. Although our study was based on surgical pathology which provided accurate diagnoses of all nodules, we did not include patients who did not have surgery, thus selection bias may exist in patients with BN. Moreover, the mechanism of rs2910164 on thyroid carcinogenesis from BN is based on an association study, and experimental studies to directly confirm the role of rs2910164 are warranted. Although our results should be interpreted with caution, it provided a helpful clue to study the mechanism through what BN progress to a PTC lesion, to elucidate the potential role of rs2910164 in thyroid carcinogenesis and to find out those BNs more predispose to developing a PTC lesion.In summary, genotype distributions of rs2910164 were similar between PTC cases, BN patients and healthy controls. Different genotypes were also not associated with focal types or aggressiveness of PTC in the Chinese patients, but GG homozygote carrier had statistically higher portion of PTC/BN. PTC/BN was a special subgroup with relatively indolent behavior and a higher frequency of the GG genotype compared with PTC alone. Multivariate logistic regression analysis showed that the GG homozygote was the only risk factor associated with a possible malignant transformation from BN to PTC, whereas age, gender, serum TSH level and Hashimoto thyroiditis were not associated with this process. As a simple case-control study, our results should be interpreted with caution and more validation populations and experimental evidence are needed in future studies.


The goal of our study is to investigate the combined contribution of 10 genetic variants to diabetes susceptibility.Bibliographic databases were searched from 1970 to Dec 2012 for studies that reported on genetic association study of diabetes. After a comprehensive filtering procedure, 10 candidate gene variants with informative genotype information were collected for the current meta-anlayses. Using the REVMAN software, odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the combined contribution of the selected genetic variants to diabetes.NLRP1 rs12150220 , IL2RA rs11594656 , and CLEC16A rs725613 . APOA5 −1131T/C polymorphism was shown to be significantly associated with of type 2 diabetes . No association with diabetes was showed in the meta-analyses of other six genetic variants, including SLC2A10 rs2335491, ATF6 rs2070150, KLF11 rs35927125, CASQ1 rs2275703, GNB3 C825T, and IL12B 1188A/C.A total of 37 articles among 37,033 cases and 54,716 controls were involved in the present meta-analyses of 10 genetic variants. Three variants were found to be significantly associated with type 1 diabetes (T1D): IL2RA rs11594656 and CLEC16A rs725613 are protective factors of T1D, while NLRP1 rs12150220 and APOA5 −1131T/C are risky factors of T1D and T2D, respectively.Our results demonstrated that  The prevalence of diabetes is soaring up in the recent decades. The global number of diabetes patients was 173 million in 2002 and will increase to 350 million by 2030. As a group of metabolic diseases characterized with high blood sugar, most diabetes is caused by either a lack of insulin for type 1 diabetes (T1D) or a blockage in the insulin signaling pathway for type 2 diabetes (T2D). The classical symptoms of diabetes consist of polyuria, polydipsia, polyphagia and weight loss. Diabetes also causes damages to blood vessels and capillaries that may eventually lead to coronary heart diseases and blindness, respectively.T1D and T2D are two major types of diabetes IL2RA, NLRP1, IL12B and CLEC16A. IL2RA gene encodes the α-chain of IL-2 receptor (IL-2R) complex which acts as an important modulator to regulate T-cell immune response NLRP1 gene encodes a member of the Ced-4 family of apoptosis proteins that can stimulate innate immunity IL12B gene encodes a subunit of an important immunomodulatory cytokine, IL-12. IL-12 induces production from NK and T cells of interferon γ (IFN-γ) which favors Th1 cell differentiation CLEC16A encodes C-type lectin domain family 16 (CLEC16A) protein highly expressed on B-lymphocytes, natural killer (NK) and dendritic cells T1D is an autoimmune disease. Little or no insulin is produced by pancreatic beta cells that may be mistakenly attacked after an infection or some other triggers. The present meta-analyses of T1D focus on four immunomodulatory genes including SLC2A10 and CASQ1), 2 genes in lipid metabolism (APOA5 and KLF11), and 2 genes in signal transduction (ATF6 and GNB3). SLC2A10 gene encodes a member of the facilitative glucose transporter family with an effect on maintaining glucose homeostasis. CASQ1 gene encodes acidic glycoprotein calsequestrin 1 (CASQ1) that is a calcium storage protein and calcium is considered to regulate the expression of the insulin-responsive glucose transporter GLUT4 APOA5 is located on human chromosome 11q23, in the APOA1/APOC3/APOA4 gene cluster KLF11 encodes Kruppel-like factor 11 with the function of regulating hepatic lipid metabolism ATF6 encodes UPR transducer unfolded protein that is related to the endoplasmic reticulum stress in the β-cell pathogenesis of type 2 diabetes GNB3 encodes the β3 subunit of hetero-trimeric G proteins in insulin signaling The impairment of insulin signaling in T2D is complex. Insulin signaling is involved in both glucose and lipid metabolism. In the present meta-analyses of T2D, we selected 2 genes in glucose metabolism (Associations between single-nucleotide polymorphisms (SNPs) of the above 10 genes and diabetes (including T1D and T2D) have been reported in different ethnic populations NLRP1 rs12150220, IL2RA rs11594656, CLEC16A rs725613,APOA5 −1131T/C, SLC2A10 rs2335491, ATF6 rs2070150, KLF11 rs35927125, CASQ1 rs2275703, GNB3 C825T, and IL12B 1188A/C.An initial search was performed through online databases including PubMed, Embase, SpingerLink, Web of Science, Chinese National Knowledge Infrastructure (CNKI), and Wanfang. The keywords comprise the terms including “diabetes” together with “SNP” or “polymorphism” or “variants” or “mutation”. The selection of studies in our meta-analysis was abided by the criteria as follows: (1) case-control studies; (2) selected studies have sufficient data to calculate ORs with the corresponding 95% CIs; (3) every polymorphism has at least 3 independent datasets from the retrieved articles; (4) selected polymorphisms have not been addressed in previous meta-analysis of diabetes. Finally, the current meta-analysis involved a total of 10 genetic variants comprising 2) statistic 2 value of equal to or greater than 50% indicates a substantial heterogeneity among the studies in the meta-analysis that used a random-effect model for the analysis. For I2 value less than 50%, a fixed-effect model will be applied for the meta-analysis. The combined ORs and the corresponding 95% CIs were calculated using the fixed-effect model or the random-effect model if I2 is less than 50%. P values less than 0.05 were considered to be significant.All the analyses were performed in Review Manager , rs12150220 of NLRP1 gene (I2 = 0%), 1188A/C of IL12B gene (I2 = 0%), −1131T/C of APOA5 gene (I2 = 1%), rs2335491 of SLC2A10 gene (I2 = 0%), rs2070150 of ATF6 (I2 = 0%), and rs35927125 of KLF11 gene (I2 = 7%). No visual bias was showed in the meta-analyses of these 7 SNPs (CLEC16A gene (I2 = 69%), rs2275703 of CASQ1 gene (I2 = 65%), and C825T of GNB3 gene (I2 = 82%). Therefore random-effect tests were applied for the meta-analyses of the above 3 SNPs. Their funnel plots were demonstrated in No evidence of statistical heterogeneity was observed for 7 SNPs , includie 7 SNPs . Our datNLRP1 gene was involved with 3 studies NLRP1 gene was significantly associated with T1D risk in the Caucasian and Brazilian populations . Meta-analysis of rs11594656 of IL2RA gene among 17,523 T1D cases and 19,909 controls IL2RA gene was significantly associated with T1D risk in the Caucasian and Japanese populations . Meta-analysis of −1131T/C of APOA5 gene APOA5 gene was associated with T2D in Chinese and Caucasian populations  and 1 T2D-associated SNP (APOA5 −1131T/C). Our meta-analyses were unable to find significant associations of the rest 6 SNPs with T1D or T2D. Moreover, power analysis showed that there might be a lack of power for the meta- analysis of SLC2A10 rs2335491  under a moderate risk of diabetes (OR = 1.2). These might partly explain our failure to observe significant results for the meta-analyses of some polymorphisms.In the present study, a comprehensive systematic overview of genetic association studies was performed for the susceptibility of T1D and T2D. We scrutinized all the candidate case-control studies to identify the eligible SNPs with at least three independent datasets. Our meta-analyses of 10 polymorphisms showed significant evidence for 3 T1D-associated SNPs , although there are minimal heterogeneity among the involved studies from different ethnic groups (I2 = 0). And KLF11A rs35927125 is monomorphic in Asians, however, its minor allele frequency in Caucasian populations ranges from 8.8–12.2% (Fst = 0.0232). On the contrary, there were little ethnic difference for CLEC16A rs725613 and GNB3 rs5443 (Fst <0.1), although there exist large heterogeneity in the involved studies (I2>60%). For CASQ1 rs2275703, the heterogeneity might come from the discrepancies of the samples in the case-control studies.After Bonferroni correction, only the association of SNP rs11594656 with T2D remains significant. However, false discovery rate (FDR) test, a less conservative correction for multiple hypothesis testing, shows that the q values are 5.11E-5 for NLRP1 is an important mediator of programmed cell death NLRP1 plays a pivotal role in the pathogenesis of some inflammatory diseases NLRP1 rs12150220 polymorphism and T1D susceptibility. Although large ethnic differences of allele frequency were found for NLRP1 rs12150220 , minimal heterogeneity was observed in the meta-analysis of this polymorphism (I2 = 0%). Our results support NLRP1 rs12150220 as a protective genetic factor of T1D and provide hints to clarify the mechanistic role of NLRP1 gene in the pathogenesis of T1D.Pancreatic β-cell inflammation and apoptosis plays a pivotal role in the pathogenesis of T1D +CD25+ regulatory T cells so as to maintain immune homeostasis IL-2RA rs12722495 was shown to contribute to the risk of T1D by lowering IL-2 signaling and diminishing the function of CD4+CD25+ regulatory T cells IL-2RA rs11594656 as a protective factor with the risk of T1D in Polish population +CD25+FOXP3+ regulatory T cells through maternal insulin treatment was shown to reduce the risk of T1D in children +CD25hi regulatory T cell-mediated suppression was showed in T1D patients IL-2RA rs11594656 polymorphism and T1D, although the influence of rs11594656 polymorphism on the regulation of IL-2RA gene remains to be unveiled in the future.Evidence from both genetic and animal model studies has shown a crucial role of IL-2/IL-2RA in the pathogenesis of T1D CLEC16A gene is located in the major histocompatibility complex class II region (16p13), and it encodes a member of the C-type lectin domain containing family. CLEC16A gene variants were associated with multiple autoimmune diseases such as T1D CLEC16A gene variants were shown to be associated with the alternative splicing event in the CLEC16A transcription CLEC16A rs725613 and T1D among 5,074 samples from Caucasian and Chinese populations (P = 0.01). A significant heterogeneity (I2 = 69%) among these ethnic samples warranted a replication in additional populations.APOA5APOA5 could probably play a role in the pathogenesis of T2D by regulating the cholesterol homeostasis APOA5 gene variants were also reported to be associated with the lipid levels APOA5 gene, our significant observation for APOA5 −1131T/C polymorphism may only partly explain the risk of T2D. Minimal heterogeneity among the involved studies in our meta-analysis (I2 = 1%), however, along with previous results APOA5 −1131T/C among the studies in our meta-analysis (68.8–76% in Chinese versus 93.7% in Caucasians).High level of glucose was shown to induce expression of There are some limitations in the present study. Firstly, publishing bias might exist in this meta-analysis. Case-control studies with a lack of significant results were much harder to be published than those with positive findings. In addition, only publications in English and Chinese were included in the current meta-analyses. All these may distort the results in our meta-analyses. Secondly, some of the involved case-control studies NLRP1 rs12150220, IL2RA rs11594656, CLEC16A rs725613 and APOA5 −1131T/C) and diabetes. Meta-analysis among 4,456 samples has confirmed that rs12150220 of NLRP1 gene is a risk factor of T1D in Caucasian and Brazilian populations. Meta-analysis among 37,432 samples has confirmed that rs11594656 of IL2RA gene is a risk factor of T1D in Caucasian and Japanese populations. Meta-analysis among 5,074 samples has confirmed that rs725613 of CLEC16A gene is a risk factor of T1D in Caucasian and Chinese populations. Another meta-analysis among 4,005 samples indicates that −1131T/C of APOA5 gene is a risk factor of T1D/T2D in Chinese and Caucasian populations.In conclusion, we identify significant associations between 4 SNPs (


It has been confirmed that tumor necrosis factor-alpha (TNFα), a macrophage-derived pro-inflammatory cytokine, plays an important role in the pathogenesis of psoriasis vulgaris and psoriatic arthritis (PsV&PsA). In contrast, the reported association of TNFα gene promoter region single nucleotide polymorphisms (SNPs) and PsV&PsA has remained controversial. Accordingly, we performed a meta-analysis to provide new evidence that SNPs in the TNFα gene promoter region alter not only the risk of psoriasis vulgaris (PsV) or psoriatic arthritis (PsA) but also of PsV&PsA.Interrelated literature dated to October 2012 was acquired from the PubMed, ScienceDirect, and SpringerLink databases. The number of the genotypes and/or alleles for the TNFα promoter in the PsV and PsA and control subjects was obtained. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to calculate the risk of PsV and/or PsA with TNFα promoter SNPs.A total of 26 papers of 2159 for PsV  and 2360 for PsA  were included in our meta-analysis. The results showed that the variant genotype and allele of TNFα -308A/G was protective in pooled groups of patients with PsV&PsA . However, the variant genotypes and alleles of TNFα -238A/G and -857T/C had an increased risk of PsV&PsA . Moreover, the meta-analysis revealed a significant association between TNFα -238A/G and -857T/C polymorphism and PsA susceptibility . In contrast, the variant genotypes and alleles of TNFα -308A/G proved to be protective against PsV , whereas TNFα -238A/G was found to have a risk association .SNPs in the TNFα gene promoter region alter the risk of PsV and/or PsA. Psoriasis is a common autoimmune disorder that primarily involves the skin . Severe complications, including generalized involvement of the body (erythroderma), extensive pustular lesions, and an associated arthritis known as psoriatic arthritis (PsA), make psoriasis complex and heterogeneous Tumor necrosis factor-alpha (TNFα), a macrophage-derived pro-inflammatory cytokine, has been proven to play an important role in the pathogenesis and development of PsV & PsA. By inducing and recruiting multiple cytokines, TNFα activates the inflammatory process of PsV & PsA in the skin, joints, and bowel We searched the PubMed, ScienceDirect, and SpringerLink databases for papers published up to October 2012. An electronic search was performed using combinations of the following search terms without any limits: “tumor necrosis factor-alpha”, “TNFα”, “promoter”, “polymorphisms”, “single nucleotide polymorphism”, “genotype”, “psoriatic arthritis”, “PsA”, and “psoriasis”. Reference lists were checked to identify repeated literature.For selection in the analysis, each study met all of the following criteria: (1) clinical subtypes of psoriasis, including PsV and/or PsA, according to the Moll and Wright or CASPAR criteria or diagnosed by clinical specialists; (2) a case-control or cohort study; (3) the inclusion the distributions of genotypes and/or alleles within the TNFα promoter provided for both the patients and controls; and (4) the reporting of the basic characters of the participants, including ethnicity, age and gender. The exclusion criteria were as follows: (1) a case report, review or descriptive study; (2) clinical subtypes of psoriasis, including erythroderma or extensive pustular lesions; (3) a lack of normal population as controls; (4) duplicate data in the studies; and (5) an inability to obtain the necessary data.The quality assessment of the selected studies was performed independently by two authors using the Newcastle-Ottawa Scale (NOS) The following information was extracted from each study: first author, publication year, country of origin, patient ethnicity and demographic characteristics, subtypes of psoriasis , the number of cases and controls, the number of genotypes and/or alleles for the TNFα promoter in the cases and controls, and consistency tests of genotype frequencies with the Hardy-Weinberg equilibrium model (HWE). Two authors analyzed each paper according to the inclusion and exclusion criteria and independently extracted the information. In some studies, only the novel data were extracted because a portion of the data had already been reported. Disagreements were resolved by discussion.2-based Q test and I2 statistic 2>50%, the heterogeneity was considered significant. A fixed-effects model was a better choice to calculate the pooled ORs when the heterogeneity was not significant, otherwise a random-effects model was used because of the heterogeneity among the studies. To explore the source of heterogeneity, a meta-regression analysis was performed when the number of studies was more than ten in a group for which heterogeneity existed The risks of the variant genotypes and alleles compared with the wild-type for six sites of TNFα promoter SNPs were estimated separately. Different subgroups divided by ethnicity or disease subtype were analyzed. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to calculate the risks of PsV and/or PsA with TNFα promoter SNPs. A p value <0.05 was considered statistically significant. In the forest plots, OR>1 represented a risk effect and <1 a protective effect. In our meta-analysis, the heterogeneity among the studies was tested by a χAccording to the inclusion and exclusion criteria, 26 papers regarding the association between TNFα promoter SNPs and the risk of PsV & PsA, including 14 studies for PsA 1. TNFα -308A/G, -238A/G, -857T/C and -1031C/T polymorphism and susceptibility to PsV & PsA2 = 3.9%), which suggested that the variant genotype of TNFα -308A/G (AA+AG) was protective. For the two alleles of TNFα -308A/G (A vs G), the same protective effect  because of the heterogeneity among the 26 studies. To explore the heterogeneity source, a meta-regression analysis was performed, and the result indicated that the concomitant variable, the psoriasis subtype, had statistical significance  while the publication year and ethnicity had no statistical significance (p>0.05). A subgroup analysis was performed.We pooled all the studies involving both PsV and PsA to evaluate the disease risk associated with TNFα -308A/G, -238A/G, -857T/C and -1031C/T polymorphisms. The meta-analysis showed a significant association between the two genotypes of TNFα -308A/G (AA+AG vs GG) and PsV & PsA in a pooled group of 22 studies . The result of the meta-regression analysis showed that the publication year had statistical significance  while ethnicity and psoriasis subtype had no statistical significance (p>0.05).However, the overall meta-analysis involved 19 and 22 studies, which separately indicated that the variant genotype (AA+AG) and allele (A) of TNFα -238A/G exhibited an increased risk of PsV & PsA .Similarly, for the genotypes (TT+TC vs CC) and alleles (T vs C) of TNFα -857T/C, the pooled ORs were found to be 1.536  and 0.867  for the allele with the random-effects model . A meta-regression analysis was not performed for <10 studies involved in the group in which heterogeneity existed.Our meta-analysis did not reveal a significant association between the TNFα -1031C/T polymorphism and susceptibility to PsV & PsA. The pooled ORs were 0.894  for the genotype with the fixed-effects model .The meta-analysis showed a significant association between the two genotype of TNFα -238A/G (AA+AG vs GG) and PsA in eight pooled studies that included one study involving an Asian group from Japan 2 = 36.7%), which indicated that there was a significant association between the genotypes of TNFα -857T/C (TT+TC vs CC) and PsA (2 = 20.5%). Excluding the Asian group, the pooled ORs were not significantly affected .The pooled OR from the eight studies including one Asian group  and PsA  c. Addit and PsA  d using 2 = 47.9%). No pooled OR was performed for the TNFα -488A/G polymorphism, as only one study was involved.Our meta-analysis did not reveal a significant association between TNFα -308A/G, -1031C/T and -863A/C polymorphism and the susceptibility to PsA. Together with the results of heterogeneity and publication bias tests, the values of ORs and 95% CIs for the risk of susceptibility in patients with PsA are shown in 3. TNFα -308A/G, -238A/G, -857T/C and -1031C/T polymorphism and susceptibility to PsV2<50.0%).A meta-analysis was performed on all the PsV patients and subgroups divided by ethnicity and subtype of PsV, revealing a significant association between the two genotypes of TNFα -308A/G (AA+AG vs GG) and PsV in 14 pooled studies . To explore the source of heterogeneity, a meta-regression analysis was performed, and the result showed that the concomitant variable of publication year had a statistical significance  while ethnicity, type of PsV and HWE consistency test had no statistical significance (p>0.05). However, we also calculated the pooled ORs in the subgroups divided by ethnicity and type of PsV, and the same risk of the variant genotypes (AA+AG) and allele (A) of TNFα -238A/G was found in all the subgroups with the existence of heterogeneity using the random-effects model, which was not found using the fixed-effects model in subgroups of type II PsV  and allele (A) of TNFα -238A/G had an associated increase risk of PsV . Similarly, the same publication bias was found in the pooled groups of PsV . The funnel plots for publication bias are shown in It is well known that TNFα plays a crucial role in autoimmune and infectious diseases as a proinflammatory cytokine; however, the mechanism of altered PsV & PsA risk owing to SNPs in the TNFα gene promoter region remains unknown. A possible explanation is the abnormal expression of the TNFα gene mediated by variations in the TNFα promoter. This premise was supported by studies noting that the TNFα -857C allele was associated with positive response to drug treatment in PsV patients treated with etanercept (Recombinant Human Tumor Necrosis Factor-α Receptorα:IgG Fc Fusion Protein)It remains controversial whether PsV and PsA are different clinical manifestations of one disease or two different clinical entities. On the one hand, PsV and PsA exist unseparated in patients because of the complex and heterogeneous nature of PsV & PsA Although a meta-analysis completed by Rahman et al. revealed that PsA risk was associated with TNFα -238A/G polymorphism  and not with TNFα -308A/G polymorphism  Furthermore, similar to a previous meta-analysis performed by Chunying Li et al. Our meta-analysis has several limitations. First, heterogeneity was observed in some groups; although a subgroup analysis was performed, heterogeneity also existed with unclear sources in some subgroups. This finding indicated that the genetic background, combined with linkage disequilibrium patterns, epigenetic modifications, and clinical heterogeneity, made the relationship between the risk of disease susceptibility and TNFα promoter SNPs more complicated. Second, on analyses the risk of psoriasis with TNFα promoter SNPs, patients only with PsV and/or PsA were involved, but not with erythroderma or pustular lesions. Besides, only Caucasian and Asian patients were involved in the subgroup analysis; therefore, the assessment of disease risk is not applicable to other disease subtypes and ethnicities. Third, apart from the limited sample size or quality control of genotyping in some of studies, some subgroup analyses only involved three studies; this small sample size indicated insensitivity with regard to exploring the real association. Finally, as some negative-association studies are often unpublished, it seems unavoidable that publication bias may influence the meta-analysis results. Accordingly, caution should be exercised when interpreting the results of this meta-analysis.This meta-analysis confirms the previous results that TNFα -238A/G and TNFα -308A/G polymorphisms are associated with PsV or PsA susceptibility. Furthermore, this meta-analysis shows that the TNFα -857T/C variant increases the risk of PsA significantly, whereas TNFα -857T/C and TNFα -238A/G polymorphisms are risk effects in the pooled analysis of PsV & PsA. In contrast, the TNFα -308A/G polymorphism is a protective effect for PsV & PsA. No significant association between TNFα-308A/G, -1031C/T, or -863A/C polymorphism and PsA susceptibility was revealed by this meta-analysis. Thus, further studies are needed to elucidate the precise contribution of those SNPs to the pathogenesis of PsV& PsA by using proteome-wide analysis of SNPs (PWAS) Checklist S1PRISMA 2009 Checklist.(DOC)Click here for additional data file.