In recent years, it has been widely accepted that transcription factor 7-like 2 (TCF7L2) is associated with type2diabetes mellitus (T2DM) in multiple ethnic groups, especially its single nucleotide polymorphisms of rs7903146C/T, rs12255372G/T and rs290487T/C. However, the results previously obtained inChineseHanpopulation are often inconsistent. For clearing this issue, herein we performed meta-analysis based on the reports that can be found to assess theassociation. Inthemeta- analysis, Odds ratio (OR) and 95% confidence interval (95% CI) were calculated with random-effect model or fixed-effect model based on the heterogeneity analysis. The quality of included studies was evaluated by using the Newcastle-Ottawa Scale. The sensitivity analysis was used to confirm the reliability and stability ofthemeta-analysis. In total, 20 case-control studies with 9122 cases of T2DM and 8017 controls were included. Among these case-control studies, we selected 13 ones on rs7903146 C/T, 5 ones on rs12255372 G/T, 8 ones on rs290487 T/C. The results indicated that rs7903146C/T polymorphism was significantly associated with T2DM (T vs. C, OR = 1.73, 95% CI = 1.39–2.16). There was no evidence that rs12255372G/T and rs290487T/C polymorphisms increased T2DM risk (T vs. G, OR = 1.77, 95% CI = 0.88–3.56; C vs. T, OR = 1.08, 95% CI = 0.93–1.25). Subgroup analysisof different regions proved the relationship between rs7903146C/T polymorphismand T2DM risk in both the northern andthe southern China. Theassociationof rs290487 with T2DM was affected by body mass index, whereas theassociationof rs7903146 and rs290487 with T2DM was influenced neither by age nor by sex. In conclusion, this study indicated that the rs7903146C/T polymorphismoftheTCF7L2gene had a significant effect on T2DM risk inChineseHanpopulation, with rs12255372G/T and rs290487T/C polymorphisms showing no significant effect.
analysis indicated that TT genotype of rs878081 poly- morphism signiﬁcantly decreased the AIRE expression, many researchers focused on theassociationbetween AIRE rs878081 polymorphismand RA risk. Garcia et al. (11) showed that the minor allele of rs878081 was signiﬁcantly more frequent in RA patients than in controls from Spain, which was in line with our ﬁndings. However, two studies (12,13) from West and North China, showed no evidence ofassociationbetween rs878081 and RA risk. Such discrepancies could be attributed to four reasons. First, genetic heterogeneity may exist among populations and living environments, but RA results from the intricate interactions between various susceptibility genes and Table 6. Comparison of studied data according to autoimmune regulator (AIRE) genotypes in all rheumatoid
The Hardy-Weinberg equilibrium (HWE) of each SNP was tested by the goodness-of-fit x 2 test to compare the expected frequencies of genotypes in controls, SNPs with P>0.05 were consid- ered to be in HWE . The Independent-Samples T test was used to determine differences ac- cording to age, andthe chisquare or Fisher's exact test was performed to calculate the clinical parametric distributions. Unconditional logistic regression analysis models were used to evalu- ate the relationships between different genotypes and disease risk [Odds ratios (OR), 95% con- fidence intervals (95% CI)] adjusted by age and gender [23,24].To account for multiple testing, Bonferroni correction was applied. Significant associations were defined at p value<0.05/27 = 0.0018. . Haplotypes and haplotype frequencies were calculated using Haploview software (version 4.2). Haplotypes with frequency less than 1% were combined. Statistical analysis was carried out using SPSS 17.0 for Windows. The haplotype with p value<0.05 was considered statistically significant.
Obesity andtype2diabetes are highly prevalent worldwide [1,4,7]. Obesity-associated insulin resistance is a major risk factor leading to type2diabetes [4,6,8]. Evidence has shown that genetic loci related to obesity could contribute to the risk for type2diabetes [10,11,13–16,18,20–26]. For example, allele A of SNP rs9939609 inthe FTO gene was reported to be associated with both increased BMI in various populations and elevated risk for type2diabetes [31–33]. During recent decades, genetic studies have identified multiple susceptible genetic loci related to obesity [2,9]. Although many studies have attempted to investigate the relationship between some obesity-related genetic loci andtype2diabetesin different ethnicities, their associations are still far from fully understood [11–27,34]. Notably, previous studies conducted inChinese populations have shown inconsistent results [11– 14,29,30]. Thus, it is worthwhile to examine the associations between obesity-related SNPs andtype2diabetesin a large sample of a HanChinesepopulation.
molecular marker for evaluating susceptibility to EC. Our findings are consistent with several similar studies that demonstrated the potential associationbetween other XRCC1 genetic variants andthe risk of EC (for example, Arg194Trp, Arg280His, and Arg399Gln). Cai et al. (16) indicated that the Arg194Trp genetic polymorphism may be associated with an increased risk of developing esophageal squamous cell carcinoma (ESCC). Xing et al. (7) found that individuals with the Trp/Trp genotype at the XRCC1 Arg194Trp site had a 2-fold increased risk of ESCC compared with the Arg/Arg genotype (adjusted OR=1.98, 95%CI=1.26-3.12). Zhai et al. (18) showed that, regarding the XRCC1 codon 280 His allele, there was no significant difference between ESCC patients and normal controls (P.0.05). Sobti et al. (17) suggested that the XRCC1 codon 399 Gln/Gln genotype was significantly associated with reduced risk of ESCC (OR=0.31, 95%CI=0.12-0.78, P,0.01). Yu et al. (8) reported that the XRCC1 399 Gln/Gln genotype was associated with an increased risk of ESCC (OR=5.15, 95%CI=2.42-0.93), andthe risk for smokers increased 4.2-fold compared with
Haplotype analysis revealed that the haplotype GGCG conferred a reduced risk of SLE, whereas GGTG was associated with susceptibility to SLE. By analyzing the results presented in Table 2and Table 3, it is possible that the haplotype GGCG, which provides protection to SLE, results from the rs907091 C allele. As with other studies regarding theassociationofgene polymorphisms in SLE, our study still has limitations. This study only investigated SLE patients from a ChineseHanpopulation. In addition, SLE is a heterogenetic disease andthe environment is very important for the disease; gene-geneandgene-environment interactions are needed to clarify the impact ofthegene on SLE.  Therefore, further research should be carried out in a larger number of samples and include analysisofthe combined effect of multiple loci other than one single SNP or a single gene. Function analysisofthegeneandthe SNPs is also required to clarify the pathogenesis of SLE.
c.335T.C was investigated using the created restric- tion site-PCR (CRS-PCR) method with one ofthe primers containing a nucleotide mismatch, which enables the use of restriction enzymes for discriminating sequence variations (33-35). c.3073A.C was detected by the PCR-restriction fragment length polymorphism (PCR-RFLP) method. Following the supplier’s manual, 5-mL aliquots of PCR- amplified products were digested with 2 U restriction enzyme at 37 6 C for 10 h. The digested products were separated by 2.5% agarose gel electrophoresis and observed directly under UV light in order to determine the genotype of MDR1 polymorphisms. To confirm the geno- type results obtained by CRS-PCR and PCR-RFLP, about 20% of PCR-amplified products were randomly selected for DNA sequencing (TaKaRa Biotechnology Co., Ltd., China).
Genomic DNA was extracted by Phenol/Chloroform. Two ml blood sample was collected from the patients and controls, and stored at 280uC. The frozen samples were thawn and centrifuged at 50006g for 15 min, andthe upper layer was removed and discarded. An appropriate amount of lysis buffer (10 mM Tris- HCl, pH 8.0; 0.1 M EDTA; 20 m g/ml RNase A, 0.5% SDS) was added into the tube and mixed with the cell pellet thoroughly. The mixture was incubated at 37 uC for 1 hour. Proteinase K solution (100 m g/ml) was added and mixed thoroughly, and incubated at 37uC overnight. An equal volume of Tris-HCl buffer-saturated phenol solution (pH 7.4) was then added into the mixture, mixed thoroughly and centrifuged at 80006g for 15 min. The upper aqueous layer was carefully removed to a new tube and an equal volume of phenol:chloroform (1:1) was added to the solution, mixed thoroughly and centrifuged at 80006g for 15 min. The upper aqueous layer was removed to a new tube, added with 10% ammonium acetate solution (10 M), mixed thoroughly, added with 2 volumes of ethanol, mixed well and stored at 220uC. The DNA precipitation was washed twice by 75% ethanol and then dissolved in TE buffer. The DNA concentration was determined by a spectrophotometer. The extracted DNA sample was placed into a 1.5 ml micro-centrifugal tube and stored at 280uC. The requirements for Sequenom analysis are: DNA concentration $10 ng/ m l, and OD260/280 = 1.8–2.0.
Hepatocyte nuclear factor 1b (HNF1b), a transcription factor encoded by the transcription factor 2gene (TCF2), plays a critical role in pancreatic cell formation and glucose homeostasis. It has been suggested that single nucleotide polymorphisms (SNPs) of TCF2 are associated with susceptibility to type2diabetes (T2D). However, published results are inconsistent and inclusive. To further investigate the role of these common variants, we examined theassociationof TCF2 polymorphisms with the risk of T2D in a Hanpopulationin northeastern China. We genotyped five SNPs in 624 T2D patients and 630 healthy controls by using a SNaPshot method, and evaluated the T2D risk conferred by individual SNPs and haplotypes. Inthe single-locus analysis, we found that rs752010, rs4430796 and rs7501939 showed allelic differences between T2D patients and healthy controls, with an OR of 1.26 (95% CI 1.08–1.51, P = 0.003), an OR of 1.23 (95% CI 1.06– 1.55, P = 0.001) and an OR of 1.28 (95% CI 1.10–1.61, P = 0.001), respectively. Genotype associationanalysisof each locus also revealed that the homozygous carriers ofthe at-risk allele had a significant increased T2D risk compared to homozygous carriers ofthe other allele (OR 1.78, 95% CI 1.20–2.64 for rs752010; OR 1.82, 95% CI 1.24–2.67 for rs4430796; OR 1.95, 95% CI 1.31–2.90 for rs7501939), even after Bonferroni correction for multiple comparisons. Besides, the haplotype-based analysis demonstrated that AGT in block rs752010-rs4430796-rs7501939 was associated with about 30% increase in T2D risk (OR 1.31, 95% CI 1.09–1.57, P = 0.01). Our findings suggested that TCF2 variants may be involved in T2D risk in a Hanpopulationof northeastern China. Larger studies with ethnically diverse populations are warranted to confirm the results reported in this investigation.
Recent animal studies have indicated that overexpression ofthe elongation of long-chain fatty acids family member 6 (Elovl6) gene can cause insulin resistance and b-cell dysfunction. These are the major factors involved inthe development oftype2diabetes mellitus (T2DM). To identify the relationship between single nucleotide polymorphisms (SNP) of ELOVL6 and T2DM pathogenesis, we conducted a case-control study of 610 HanChinese individuals (328 newly diagnosed T2DM and 282 healthy subjects). Insulin resistance and islet first-phase secretion function were evaluated by assessment of insulin resistance in a homeostasis model (HOMA-IR) and an arginine stimulation test. Three SNPs ofthe ELOVL6 gene were genotyped with polymerase chain reaction- restriction fragment length polymorphism, with DNA sequencing used to confirm the results. Only genotypes TT and CT ofthe ELOVL6 SNP rs12504538 were detected inthe samples. Genotype CC was not observed. The T2DM group had a higher frequency ofthe C allele andthe CT genotype than the control group. Subjects with the CT genotype had higher HOMA-IR values than those with the TT genotype. In addition, no statistical significance was observed betweenthe genotype and allele frequencies ofthe control and T2DM groups for SNPs rs17041272 and rs6824447. The study indicated that the ELOVL6 genepolymorphism rs12504538 is associated with an increased risk of T2DM, because it causes an increase in insulin resistance.
Despite the clear strengths of our study including relatively large sample sizes and robustness of statistical analyses, interpretation of our current study, however, should be viewed in light of several technical limitations. First, all included studies were cross-sectional in design, which precludes us to make inference on causality. Second, because only published studies were retrieved and articles in languages other than English or Chinese were not included, publication bias might be possible, even though our funnel plots and statistical tests indicated no observable bias. Third, our results were based on unadjusted estimates. It seems likely that the CD14 gene C-260T polymorphism individually make a moderate contribution to risk prediction in UC patients, but whether thepolymorphism integrated with other risk factors will enhance the prediction requires additional research. Thus, a more precise analysis should be conducted with individual data, which would Table 2. Subgroup analysisof CD14 C-260T gene polymorphisms and IBD (CD and UC).
It would be hard to interpret results, if significant heterogeneity were present. However, in this meta-analysis, we did not find any obvious heterogeneity and publish bias across studies. Neverthe- less, some limitations should be addressed. Firstly, although funnel plot and Egger’s test show no publication bias, selection bias could have occurred because only studies published in English andChinese were included. Secondly, because the reference groups were not uniformly defined, some selected population-based controls and some used hospital-based cancer-free controls, non- differential misclassification bias is possible; in addition, some control groups may not be representative ofthe general Figure 3. Correlation between Asp1104His and ERCC5 mRNA expression for different populations. A: CEU, 90 Utah residents from northern and western Europe; B: Asians, 45 unrelated HanChinesein Beijing (CHB) and 45 unrelated Japanese in Tokyo (JPT); C: YRI, 90 Yoruba in Ibadan, Nigeria.
Publication search was performed for the potential eligible articles in English andChineseinthe following database: (1) Medline in PubMed searching engine; (2) Embase database; (3) Chi- nese National Knowledge Infrastructure (CNKI); (4) Wanfang Chinese database; (5) VIP Chi- nese database. The latest data for searching articles was November 1 st , 2015. The key words for article searching were: [“vascular endothelial growth factors receptor” or “vasculotropin recep- tor” or “VEGFR”] and [“stroke” or “cerebral infarction” or “cerebrovascular disorders”] and [“single nucleotide polymorphism” or “SNP” or “polymorphism” or “mutation” or “genetics” or “variant”]. Publication language was restricted to English andChinese, andthe subjects were not limited in our search. We also performed a manual search ofthe reference lists of retrieved articles for additional potential studies.
Currently available data suggest a worldwide continuous increase in obesity prevalence, which is recently also being observed in developing countries. This prompts some authors to predict an “obesity epidemic” with an increased prevalence of hypertension, stroke, coronary artery disease, andtype2diabetes mellitus, for which obesity is a major risk factor. Several studies also have investigated whether the 825T allele increases the risk for obesity (Hegele et al. 1999; Siffert et al. 1999a; Siffert et al. 1999b, Stefan et al. 2004), these studies have demonstrated that this allele is associated with obesity or increased BMI. Other similar studies, however, have failed to demonstrate this association (Benjafield et al. 2001; Hinney et al. 2001; Ohshiro et al. 2001; Snapir et al. 2001; Poston et al. 2002; Suwazono et al. 2004; Hayakawa et al. 2007). Furthermore, it has been evaluated prediction of successful weight reduction under sibutramine therapy and C825T polymorphism but no association was found with no- pharmacologic weight loss strategies (Hauner et al. 2003; Potoczna et al. 2004). Because of these varying findings, we considered that the apparent associationbetween GNB3 gene variant and obesity or raised BMI had not been demonstrated conclusively. From an epidemiological point of view, we believe that in order to determine the influence of genetic polymorphisms inthe occurrence of a specific disease, it is necessary to undertake large-scale studies inthe general population. To elucidate better this question we performed this meta-analysis reaching a more significant number of antipsychotic- induced weight gain and BMI related to GNB3 C825T variant.
In various populations worldwide, common variants oftheTCF7L2 (Transcription factor 7-like 2) gene are associated with the risk oftype2diabetes mellitus (T2DM). The aim was to investigate theassociationbetween rs12255372 (G/T) polymorphismintheTCF7L2geneand T2DM in an Iranian population. 236 unrelated patients with T2DM, and 255 normoglycemic controls without diabetes were studied. The PCR-RFLP method was used for genotyping rs12255372 (G/T) polymorphism, andthe SPSS version 18.0 for Windows for statistical analysis. The minor T allele ofTCF7L2 rs12255372 was found to significantly increase the risk of T2DM, with an allelic odds ratio (OR) of 1.458 (95% CI 1.108-1.918, p = 0.007). A significant difference in TT genotype was observed between T2DM patients and normoglycemic controls (OR 2.038, 95% CI 1.147-3.623; p = 0.014). On assuming dominant and recessive models, ORs of 1.52 [95% CI (1.05-2.21) p = 0.026)] and 1.74 [95% CI (1.01-3.00) p = 0.043] were obtained, respectively, thereby implying that the co-dominant model would best fit the susceptible gene effect. This study further confirms theTCF7L2gene as enhancing susceptibility to the development of T2DM.
Pickering and colleagues have initially suggested that hyperten- sion and blood pressure are complex traits , and previous epidemiologic studies have found dozens of risk factors, such as obesity, high-fat diets, smoking, alcohol abuse, excessive salt intake, mental stress, and others to associate with high blood pressure [34–36]. There is growing evidence that interactions among multiple genes and environmental factors may play an important role in determining the susceptibility to various common diseases including hypertension . Our previous study indicated that interaction analysis might give a little more information than the single genetic study . Inthe present study, high BMI and serum TG level were confirmed as risk factors for hypertension by logistic regression analysis. The MDR analysis further demonstrated that the interaction between BMI and rs4305 was associated with hypertension. Since BMI represents the internal metabolic and physiological environment that plays a key role in development of high blood pressure , and ACE is one ofthe most important target for design of anti- hypertensive drugs, it’s not surprising that the interaction of them may play an important role inthe susceptibility to hypertension. Previous genetic epidemiologic study also found the interactions between MMP3 genepolymorphism rs679620 and BMI in predicting blood pressure in African-American women with hypertension . The recent important genetic studies are mainly carried out in well-organized cohorts like Global BPgen, CHARGE, and GenSalt Study, which means the epidemiologic data are readily available [19,41–43]. With the development of statistic methods for evaluation ofgene-environment interaction, we can expect more missing inheritability to be found [44,45].
with high mRNA and soluble expression in knee OA patients. However, the TNF-a rs1800629 genotypes did not show statistical difference between cases and con- trols. In addition, the sample size ofthe study by Munoz- Valle et al. (12) was very small. Thus, we could not exclude the possibility that their ﬁndings might be false- positive. We hypothesized that rs1800629 polymorphism may be in linkage disequilibrium with other potentially functional variants in TNF-a gene or closely linked sus- ceptibility genes, which may contribute to the contradictory ﬁndings. In this study, our data showed that AA genotype was associated with the risk of OA. We do not know whether AA genotype is associated with higher produc- tion of TNF-a expression in this study, which warrants further study to validate the results. Small sample size, low statistical power, and/or clinical heterogeneity may account for the disparities ofthe above studies. In order to overcome the limitations of individual studies and resolve inconsistencies, Kou and Wu (28) reviewed 7 studies with 983 cases and 1355 controls and conducted a meta- analysis to derive a more precise estimation ofthe effect of TNF-a rs1800629 polymorphism on OA risk in 2014. Their results revealed that this polymorphism increased the risk of OA inthe allelic and recessive models (28). Ethnic subgroup analysis indicated that rs1800629 poly- morphism was associated with the risk of OA among Asian populations (28). To date, there are 4 studies (3 Caucasian studies and this study) with moderate sample sizes (12,15,16).
Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting 5–7% of women of childbearing age [1–3]. It is characterized by hirsutism, anovulation, clinical and/or biochem- ical hyperandrogenism, and polycystic ovarian morphology on ultrasound . A large number of women with PCOS also exhibit insulin resistance, b-cell dysfunction, impaired glucose tolerance and/or type2diabetes . It has been reported that about half of PCOS women are overweight or obese  and obesity plays an important role inthe etiology of PCOS [7–9]. Given the high prevalence of obesity in PCOS, both diseases may share similar genetic background . PCOS is a highly complex and heterogeneous disorder. So far, the pathogenesis of PCOS is still incompletely understood, it may be affected by the environmental or genetic factors, or their interactions.
Some limitations of this meta-analysis should be acknowledged. Because ofthe absence of detailed information about BMI, age, and gender in some studies, we did our research based on single-factor estimates without adjustment for the other risk factors mentioned above. On the other hand, our study also showed some strengths. First, the sample sizes ofthe studies included were relatively large, possibly reducing the influence ofthe low allele frequency. Second, our meta-analysis showed much better homogeneity, suggesting the uniform composition or character of our studies. Third, no publication bias was found in our meta-analysis by the funnel plot andthe Egger test.