TCF7L2 rs7903146 polymorphism is associated with gastric cancer: a case-control study in the Venezuelan population

AIM: To explore the association between TCF7L2 rs12255372 and rs7903146 single nucleotide polymorphisms(SNPs) and gastric cancer risk in Venezuelan patients.METHODS: We performed a case-control study including 122 paraffin-embedded archived intestinaltype gastric cancer samples and 129 biopsies obtained by superior endoscopy from chronic gastritis patients. Gastric cancer samples were classified according the degree of carcinoma differentiation. Genomic DNA was extracted from tissues, and the two SNPs of TCF7L2 gene(rs12255372 and rs7903146) were genotyped by polymerase chain reaction-restriction fragment length polymorphism reactions. Multiple regression analysis with adjustments for age and gender were performed and best-fitting models of inheritance were determined.RESULTS: After adjusting for age and sex the TCF7L2 rs7903146 TT genotype was associated with gastric cancer risk under the recessive genetic model(OR = 3.11, 95%CI: 1.22-7.92, P = 0.017). We further investigated the distribution of rs12255372 and rs7903146 genotypes according gastric cancer stratified by degree of differentiation, and we observed that carriers of rs7903146 T allele(CT + TT vs CC) had a significantly increased risk of moderate/well differentiated gastric cancer(dominant model, OR = 2.55, 95%CI: 1.35-4.80, P = 0.004), whereas the rs7903146 TT genotype was associated with poorly differentiated gastric cancer in the recessive model(OR = 3.65, 95%CI: 1.25-10.62, P = 0.018). We did not find association between rs12255372 SNP and the susceptibility of developing gastric cancer. CONCLUSION: TCF7L2 rs7903146 polymorphism is associated with gastric cancer risk in the Venezuelan population, and could be related to determine the degree of differentiation of tumor cells.     

TCF7L2基因单核苷酸多态性与汉族2型糖尿病遗传易感性关系的研究

目的探讨TCF7L2基因单核苷酸多态性与汉族人2型糖尿病遗传易感性的关系。方法无血缘关系江苏地区汉族人1535例,分为2型糖尿病组（T2DM）、糖耐量减低组（IGT）和正常糖耐量组（NGT）,LDR法检测TCF7L2基因rs7903146（C／T）及rs12255372（G／T）单核苷酸多态性。结果（1）T2DM、IGT组rs7903146位点T等位基因频率均高于NGT组,但差异无统计学意义;（2）糖代谢异常组rs7903146位点CT基因型频率及T等位基因频率则显著高于NGT组（P均〈0．05）,T等位基因参与糖代谢异常发生的相对风险为1．589,人群归因危险度为2．1％。结论TCF7L2基因单核苷酸多态分布存在明显的种族异质性,rs7903146位点T突变可能是中国汉族人群糖代谢异常发生的遗传因素之一。     

亚甲基四氢叶酸还原酶基因rs4846049 G/T多态性与中国汉族人群缺血性卒中的相关性

目的：探讨亚甲基四氢叶酸还原酶(methylenetetrahydrofolatereductase, MTHFR)基因3'-非翻译区rs4846049 G/T多态性与中国汉族人群缺血性卒中发病风险的相关性。方法采用病例对照研究设计,选取396例缺血性卒中患者和378名健康体检者(对照组),病例组大动脉粥样硬化和小动脉闭塞型分别为268例和128例。采用聚合酶链反应-限制性片段长度多态性和直接测序法检测MTHFR 基因rs4846049 G/T多态性。结果以GG基因型为参照,TT基因型使缺血性卒中发病风险显著增高[优势比(odds ratio, OR)2．87,95%可信区间(confidence interval, CI)1．43~5．76;P=0．003];与G 等位基因比较,T 等位基因使发病风险显著增高( OR 1．62,95% CI 1．28~2．06;P<0．001)。亚组分析显示, rs4846049 G/T 多态性可显著增高 LAA 和 SAO 亚型卒中的发病风险(P均<0．05)。结论 MTHFR基因rs4846049 G/T多态性可能与中国汉族人群缺血性卒中易感性增高有关,T等位基因可能是中国汉族人群缺血性卒中的遗传危险因素。     

代谢综合征患者过氧化物酶体增殖物激活受体δ+294T/C基因多态性与血脂、肥胖和左室肥厚的关系

目的探讨代谢综合征(MS)患者过氧化物酶体增殖物激活受体δ(PPARδ)+294T/C基因多态性与血脂、肥胖和左室肥厚的关系。方法检测300例MS、174例高血压病(EH)和143例2型糖尿病(DM)患者的体重指数(BMI)、腰围、血压、血脂、空腹血糖(FBG)和空腹血浆胰岛素(FINS)。MS诊断根据1999年WHO亚太诊断标准,其中389例患者行超声心动图检测心脏结构改变,应用聚合酶链反应-限制性片段长度多态性方法测定PPARδ+294T/C基因多态性。结果PPARδ+294T/C基因多态性各基因型频率分布组间比较差异无统计学意义。MS组血浆总胆固醇、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)水平和BMI明显高于DM组。MS组和EH组的左室重量(LVM)、左室重量指数(LVMI)和左室肥厚罹患率均明显高于DM组。MS组CC型血浆总胆固醇和LDL-C水平明显高于TT型和TC型[总胆固醇:CC型(6.13±1.86)mmol/L比TC型(5.14±1.10)mmol/L或TT型(4.99±1.42mmol/L),P<0.05或P<0.01;LDL-C:CC型(3.82±1.52)mmol/L比TC型(3.14±0.88)mmol/L或TT型(2.90±0.87)mmol/L,P<0.05或P<0.01]。分析PPARδ各基因型与LVMI和BMI的关系,发现MS组C等位基因携带者(CC+TC)LVMI和BMI明显高于TT型[LVMI:CC+TC(46±10)g/m2.7比TT(44±10)g/m2.7;BMI:CC+TC(26±3)kg/m2比TT(25±3)kg/m2,P<0·05]。结论MS患者PPARδ+294T/C基因多态性与肥胖和脂质紊乱关系密切,C等位基因携带者较TT基因型患者左室重构明显。     

白细胞介素13基因-1112C/T多态性与支气管哮喘患者发病及血浆总IgE水平的相关性

目的探讨白细胞介素13(IL13)基因启动子区-1112C/T多态性与支气管哮喘(简称哮喘)的相关性及对血浆总IgE水平的影响。方法将哮喘患者(100例)和健康人(100名)被分为哮喘组和对照组,用聚合酶链反应限制性片段长度多态性(PCRRFLP)方法检测哮喘组与对照组-1112位点多态性,用酶联免疫吸附法(ELISA)测定血浆总IgE水平。结果-1112位点等位基因C、T频率在两组间分布的差异具有显著性(χ2=901,P<001),等位基因T与哮喘关联[OR(T/C)=203,95%CI=127～323,P<001]。两组基因型(TT、CT、CC)频率的分布比较差异有显著性(χ2=719,P<005),其优势比OR(TT/CC)=299,95%CI=106～841(P<005);OR(CT/CC)=204,95%CI=109～381(P<005);OR(TT/CT)=146,95%CI=049～437(P>005);在哮喘组CC、CT及TT基因型患者的血浆总IgE水平分别为(204±89)kU/L、(320±108)kU/L、(376±147)kU/L,而在对照组CC、CT及TT基因型患者的血浆总IgE水平分别为(96±34)kU/L、(122±42)kU/L、(150±36)kU/L。同组内T等位基因携带者血浆总IgE水平高于非携带者;同一基因型中哮喘组总IgE水平高于对照组。结论IL13基因-1112位点多态性是影响哮喘的重要候选基因,T等位基因与哮喘关联,并可能通过增强IL13基因的表达影响血浆总IgE水平。     

醛固酮合成酶基因多态性与小动脉顺应性的研究

目的探讨醛固酮合成酶（CYP11B2）基因-344C／T多态性与小动脉顺应性（C2）的关系及其临床意义。方法（1）用CVProfilorDO-2020动脉脉搏分析仪测量大小动脉顺应性,共224例,其中C2异常组123例,对照组101例。（2）用多聚酶链反应-限制性片段长度多态性分析方法检测CYP11B2基因-344C／T多态性。结果（1）C2异常组TT基因型、T等位基因频率均高于对照组,但差异无统计学意义（55．3％比41．6％,P〉0．05,75．6％比66．8％,P〉0．05）。（2）CC型与CT型合并分析,显示C2异常组TT型频率显著高于对照组（30．3％比18．8％,P〈0．05）。（3）协方差分析显示,与CT／CC型比较,TT型者C2显著降低。（4）Logistic回归分析表明,TT型是导致C2减退重要的基因型（P=0．043,OR=1．9395％ CI1．02～3．63）。结论CYP11B2基因-344C／T多态性与小动脉顺应性C2密切相关,TT型是C2减退的敏感基因型。     

Association of TCF7L2 rs7903146 Gene Polymorphism with the Risk of NAFLD and CAD in the Chinese Han Population

Background and Aims: Coronary artery disease (CAD) is a major cause of morbidity and mortality in patients with non-alcoholic fatty liver disease (NAFLD). Previous studies have suggested that TCF7L2 rs7903146 was related to the risk of developing NAFLD but the conclusions are not consistent and no related study has been conducted in Chinese populations. The aim of this study was to investigate the association between TCF7L2 rs7903146 and the risk of developing NAFLD and CAD in a Chinese Han population.Methods: TCF7L2 rs7903146 genotypes were measured by the MALDI-TOF-MS from 143 NAFLD patients, 159 CAD patients, 131 NAFLD + CAD patients, and 212 healthy controls. The demographic data and serum lipid profiles of all subjects were collected. The distributions of genotype and allele frequency in each group were also tested. Logistic regression was used to investigate the risk of TCF7L2 rs7903146 with NAFLD and CAD. All statistical analyses were conducted using SPSS 23.0.Results: There were no significant differences in the distributions of TCF7L2 rs7903146 genotype and allele frequency in each of the two groups, and the TCF7L2 rs7903146 CT + TT genotype did not increase the risk of developing NAFLD, CAD, and NAFLD + CAD. Except for body mass index in the control group, the differences of clinical parameters between the TCF7L2 rs7903146 T allele carriers and non-carriers in each group were not significant. In the non-obese group, the TCF7L2 rs7903146 CT + TT genotype was a protective factor for the development of NAFLD in the non-obese subjects (odds ratio=0.359, 95% confidence interval: 0.134-0.961, p = 0.041).Conclusions: TCF7L2 rs7903146 was not associated with the risk of developing NAFLD, CAD, and NAFLD + CAD in the Chinese Han population. In the non-obese population, the TCF7L2 rs7903146 CT + TT genotype was a protective factor against the development of NAFLD.     

Association between plasma levels of proprotein convertase subtilisin/kexin type 9 (PCSK9) and lipids with rs7903146 polymorphisms of the TCF7L2 gene in diabetic patients

The rs7903146 polymorphism of TCF7L2 gene is known as the strongest genetic risk factor for type 2 diabetes mellitus (T2DM). The polymorphism is in association with clinical profile of T2DM patients. PCSK9 is a serine protease that promotes LDLR degradation and regulates circulating levels of lipids. The association of this polymorphism with PCSK9 and metabolic profile of diabetic and healthy subjects was investigated. This cross-sectional study was performed on 132 T2DM patients and the same number of healthy subjects. All the participants were genotyped for the rs7903146 single nucleotide polymorphism by the PCR-RFLP method. Metabolic profile including plasma levels of PCSK9, triglycerides, total cholesterol, non-HDL cholesterol, LDL cholesterol, HDL cholesterol, fasting plasma glucose, and HBA1C was measured. PCSK9, total cholesterol, and LDL-C levels were lower in the diabetic patients as compared to the healthy subjects. There were also direct and significant associations between PCSK9 and TG, TC, LDL-C, and non HDL-C in the subjects. Values of plasma glucose, HbA1c, PCSK9, TC, and LDL-C were higher in patients with TT genotype, but the differences were not statistically significant for all. A positive Spearman correlation was found between PCSK9 levels and the genotypes in all the participants. The results confirm the association of rs7903146 in the TCF7L2 gene with metabolic parameters and PCSK9. The T allele was associated with higher lipid and PCSK9 levels.

     

A functional polymorphism in the promoter region of the microsomal triglyceride transfer protein (MTP -493G/T) influences lipoprotein phenotype in familial hypercholesterolemia

The microsomal triglyceride transfer protein (MTP) has a key function in intracellular apolipoprotein (apo) B lipidation and secretion of very low density lipoprotein (VLDL). A recently discovered functional polymorphism in the promoter of the MTP gene (-493G/T) affects the plasma concentration of low density lipoprotein (LDL) cholesterol and the VLDL distribution between large and small particle species in healthy men. This phenotype is likely to be explained by an effect on VLDL synthesis. Against this background, we studied the effect of the MTP-493G/T polymorphism in a large cohort (217 men and 211 women) with heterozygous familial hypercholesterolemia (FH). A 40% to 50% lower serum triglyceride level was observed in homozygous carriers of the MTP-493 T allele (T/T, 0.93+/-0.34; G/T, 1.54+/-1.40; and G/G, 1.56+/-1.24 mmol/L; T/T vs G/T P=0.04, T/T vs G/G P=0.02). In contrast to the situation in healthy subjects, the MTP promoter polymorphism did not have a significant effect on the LDL cholesterol levels in FH subjects, although the same trend was observed (T/T, 7.31+/-1.87; G/T, 7. 80+/-2.12; and G/G, 7.91+/-2.31 mmol/L, NS). Adjustment for the apo E gene polymorphism by inclusion of subjects homozygous for the apo E3 allele only revealed a reciprocal high density lipoprotein cholesterol-elevating effect (T/T, 1.41+/-0.73; G/T, 1.18+/-0.27; and G/G, 1.16+/-0.29 mmol/L; T/T vs G/T P=0.06, T/T vs G/G P=0.04). This effect seemed to be sex-specific because it was accounted for by the female patients. In conclusion, the LDL cholesterol-lowering effect of the rare MTP gene promoter variant (MTP-493T) present in healthy subjects is shifted to a triglyceride-lowering effect in FH. These data suggest that the MTP gene has a role in modulating the clinical phenotype of FH.