TERT、VEGF基因单核苷酸多态性及其单体型与新疆维吾尔族长寿的关联研究
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摘要
目的：探讨新疆维吾尔族TERT、VEGF基因单核苷酸多态性及其单体型与长寿的关联。方法：共纳入新疆维吾尔族研究对象361例,其中长寿组为112例,对照组为249例,采用病例一对照研究方法,用SNaPshot SNP分型技术对TERT基因8个SNP位点rs2736098(SNP1)、rs2736100(SNP2)、rs2853676(SNP3)、rs10069690(SNP4)、rs4975605(SNP5)、rs2075786(SNP6)、rs2736118(SNP7)、rs2853691(SNP8)进行基因的检测,同时进行单体型与长寿的关联研究。采用同样技术对VEGF基因3个SNP位点rs2146323(SNP1)、rs3024997(SNP2)、rs10434(SNP3)进行基因检测,同时进行单体型与长寿的关联研究。结果：第一部分：新疆维吾尔族长寿组身高、体质量、体质量指数低于对照组,收缩压、外周脉压高于对照组,差异有统计学意义(P<0.05)。长寿组总胆固醇、高密度脂蛋白胆固醇、肌酐及尿酸高于对照组,甘油三酯低于对照组,差异有统计学意义(P<0.05)。长寿组高胆固醇血症、高尿酸血症的患病率高于对照组,超重、肥胖及高甘油三酯血症的患病率明显低于对照组,差异有统计学意义(P<0.05)。两组间舒张压、脉压指数、血糖、高血压患病率及高血糖患病率差异无统计学意义(P>0.05)。第二部分：1)TERT基因SNP2位点分析显示,长寿组中G和T等位基因频率分别为62.1%和37.9%,对照组分别为51.6%和48.4%；长寿组中GG、GT、TT基因型频率分别为36.6%、50.9%、12.5%,对照组分别为24.9%、53.4%、21.7%。TT基因型和T等位基因频率在长寿组低于对照组,差异有统计学意义,P值分别为0.026和0.009。进一步分析表明,以GG基因型作为参照,携带TT基因型与GG基因型相比(P=0.008,OR=0.392,95%CI：0.193～0.796)；携带GT+TT基因型与GG基因型相比(P=0.023,OR=0.574,95%CI：0.355～0.928)；携带T等位基因者与G等位基因者相比(P=0.009,OR=0.652,95%CI：0.473～0.900),差异有统计学意义；2)TERT基因SNP6位点分析显示,长寿组中T和C等位基因频率分别为66.5%和33.5%,对照组分别为56.2%和43.8%；长寿组中TT、TC、CC基因型频率分别为45.5%、42.0%、12.5%,对照组分别为34.9%、42.6%、22.5%。CC基因型和C等位基因频率在长寿组低于对照组,差异有统计学意义,P值分别为0.044和0.009。进一步分析表明,以TT基因型作为参照,携带CC基因型与TT基因型相比(P=0.013,OR=0.426,95%CI：0.216～0.842)；携带C等位基因者与T等位基因者相比(P=0.009,OR=0.647,95%CI:0.465～0.899),差异有统计学意义；3)单体型分析显示无论长寿组、对照组,单体型Hap1-AT出现频率最高,Hap1-AT、Hap3-GC频率在长寿组高于对照组,Hap2-AC频率在长寿组低于对照组,差异均无统计学意义；4)TERT基因SNP2位点不同基因型间脉压、脉压指数比较发现在长寿组中,携带GT+TT基因型者脉压、脉压指数高于GG基因型携带者,差异有统计学意义。SNP6位点分析显示在对照组中,携带TC+CC基因型者脉压指数高于TT基因型携带者,差异有统计学意义。第三部分：1)VEGF基因SNP1位点分析显示,长寿组中C和A等位基因频率分别为70.1%和29.9%,对照组分别为62.3%和37.7%；长寿组中CA, AA基因型频率分别为47.3%、45.5%、7.2%,对照组分别为42.6%、39.3%、18.1%。AA基因型和A等位基因频率在长寿组低于对照组,差异有统计学意义,P值分别为0.025和0.041。进一步分析表明,以CC基因型作为参照,携带AA基因型与CC基因型相比(P=0.011,OR=0.356,95%CI: 0.156～0.808)；携带A等位基因者与C等位基因者相比(P=0.041,OR=0.704,95%CI：0.502～0.987),差异有统计学意义；2)单体型分析显示无论长寿组、对照组,单体型Hap1-CG出现频率最高,Hap1-CG频率在长寿组高于对照组,Hap2-CA、Hap3-AG频率在长寿组低于对照组,差异无统计学意义；3)VEGF基因SNP1位点不同基因型间脉压、脉压指数比较发现对照组中携带CA+AA基因型者脉压高于CC基因型携带者,差异有统计学意义。结论：TERT基因rs2736100和rs2075786位点多态可能与新疆维吾尔族长寿有关,rs2736100位点TT基因型和T等位基因、rs2075786位点CC基因型和C等位基因可能是长寿的不利因素。VEGF基因rs2146323位点多态可能与新疆维吾尔族长寿有关,AA基因型和A等位基因可能是长寿的不利因素,rs2736100、rs2075786和rs2146323位点多态可能通过影响血管功能参与长寿。
Objective:To investigate the correlation of the single nucleotide polymorphisms and haplotypes of TERT and VEGF genes with longevity in XinJiang Uygur population. Methods:A case-control design was applied in this study. In brief, a total of 361 Uygur subjects were selected in the study including 112 individuals≥90 years old and 249 controls. The genomic DNA was extracted from all peripheral blood samples. Based on genotype data from the international HapMap project, the tagging single nucleotide polymorphisms (tSNPs) were selected and linkage disequilibrium values D'and r2 were calculated in the population using the Maximation likelihood method. Haplotype frequencies were estimated using Phase 2.0 software.The locus of TERT gene including rs2736098(SNP1), rs2736100(SNP2), rs2853676(SNP3), rs10069690(SNP4), rs4975605 (SNP5), rs2075786(SNP6), rs2736118(SNP7), rs2853691(SNP8) were genotyped by snapshot method and the haplotype distribution was estimated. The same way was used in testing the locus of VEGF gene including rs2146323 (SNP1), rs3024997 (SNP2), rs10434 (SNP3), while the relationship of single nucleotide polymorphisms and haplotypes with genetic susceptibility to longevity was investigated. Results:Section one. Systolic blood pressure (SBP), pulse pressure (PP) in longevity group were significantly higher than in control group, while height, weight and body mass index (BMI) were significantly lower than in control group (P<0.05). There was a significant difference in the level of total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), creatinine, uic acid and triglyceride (TG) between longevity group and control group (P<0.05). The prevalence of hypercholesterolemia and hyperuricemia was higher and the prevalence of overweight, obesity and hypertriglyceridemia was lower in longevity group than in control group.There were no significant differences in diastolic blood pressure (DBP), pulse pressure index (PPI), fasting blood glucose (FBG) and the prevalence of hypertension and hyperglycemia between the two groups (P>0.05). Section two:1) Eight common SNPs of TERT gene were chosen to be tagging SNPs. All polymorphisms were in Hardy-weinberg equilibrium both in longevity and in control group. The frequencies of G and T allele of TERT SNP2 in longevity group were 62.1%,37.9% and 51.6%,48.4% in the control group. The frequencies of SNP2 genotypes of GG, GT and TT in longevity group were 36.6%,50.9%,12.5%and 24.9%,53.4%,21.7% in control group respectively. The distributions of TT genotype and T allele of SNP2 (SNP rs2736100) in longevity group were lower than in control group and P equals to 0.026,0.009. The SNP rs2736100 was significantly associated with longevity (TT versus GG:P=0.008, OR=0.392,95%CI: 0.193～0.796; GT+TT versus GG:P=0.023, OR=0.574,95%CI:0.355～0.928; T versus G: P=0.009, OR=0.652,95%CI:0.473-0.900); 2) The frequencies of T and C allele of TERT SNP6 in longevity group were 66.5%,33.5% and 56.2%,43.8% in the control group. The frequencies of SNP6 genotypes of TT, TC and CC in longevity group were 45.5%,42.0%, 12.5% and 34.9%,42.6%,22.5% in control group respectively. The distributions of CC genotype and C allele of SNP6 (SNP rs2075786) in longevity group were lower than in control group and P equals to 0.044,0.009. The SNP rs2075786 was significantly associated with longevity (CC versus TT:P=0.013, OR=0.426,95%CI:0.216～0.842; C versus T:P=0.009, OR=0.647,95%CI:0.465～0.899); 3) The haplotype analysis revealed that the frequency of Hap 1-AT was highest in both groups. The frequencies of Hap 1-AT, Hap3-GC were higher in longevity group than in control group while the frequency of Hap2-AC was lower in longevity group. There was no statistically significant difference. 4) PP and PPI in GT+TT genotype combination were markedly higher than in GG genotype of TERT SNP2 in longevity group, while PPI in TC+CC genotype was markedly higher than in TT genotype of TERT SNP6 in control group. Section three:1) Three common SNPs of VEGF gene were chosen to be tagging SNPs. All polymorphisms were in Hardy-weinberg equilibrium both in longevity and in control group. The frequencies of C and A allele of VEGF SNP1 in longevity group were 70.1%,29.9% and 62.3%,37.7% in the control group. The frequencies of SNP1 genotypes of CC, CA and AA in longevity group were 47.3%,45.5%,7.2% and 42.6%,39.3%,18.1% in control group respectively. The distributions of AA genotype and A allele of SNP1 (SNP rs2146323) in longevity group were lower than in control group and P equals to 0.025, 0.041. The SNP rs2146323 was significantly associated with longevity (AA versus CC: P=0.011,OR=0.356,95%CI:0.156～0.808; A versus C:P=0.041, OR=0.704,95%CI: 0.502～0.987); 2) The haplotype analysis revealed that the frequency of Hapl-CG was highest in both groups. The frequency of Hapl-CG was higher in longevity group than in control group, while the frequencies of Hap2-CA, Hap3-AG were lower in longevity group. There was no statistically significant difference.3) The level of PP in CA+AA genotype combination was markedly higher than in CC genotype of VEGF SNP1 in control group. Conclusion:Our study revealed that TERT gene rs2736100 and rs2075786 polymorphisms might be associated with longevity in Xinjiang Uygur population. TT genotype, T allele of rs2736100 and CC genotype, C allele of rs2075786 were the adverse factors of longevity. VEGF gene rs2146323 polymorphism might be associated with longevity. AA genotype and A allele were the adverse factors of longevity in Xinjiang Uygur population. rs2736100, rs2075786 and rs2146323 might be associated with longevity through impacts on vascular function.
Objective:To investigate the correlation of the single nucleotide polymorphisms and haplotypes of TERT and VEGF genes with longevity in XinJiang Uygur population. Methods:A case-control design was applied in this study. In brief, a total of 361 Uygur subjects were selected in the study including 112 individuals≥90 years old and 249 controls. The genomic DNA was extracted from all peripheral blood samples. Based on genotype data from the international HapMap project, the tagging single nucleotide polymorphisms (tSNPs) were selected and linkage disequilibrium values D'and r2 were calculated in the population using the Maximation likelihood method. Haplotype frequencies were estimated using Phase 2.0 software.The locus of TERT gene including rs2736098(SNP1), rs2736100(SNP2), rs2853676(SNP3), rs10069690(SNP4), rs4975605 (SNP5), rs2075786(SNP6), rs2736118(SNP7), rs2853691(SNP8) were genotyped by snapshot method and the haplotype distribution was estimated. The same way was used in testing the locus of VEGF gene including rs2146323 (SNP1), rs3024997 (SNP2), rs10434 (SNP3), while the relationship of single nucleotide polymorphisms and haplotypes with genetic susceptibility to longevity was investigated. Results:Section one. Systolic blood pressure (SBP), pulse pressure (PP) in longevity group were significantly higher than in control group, while height, weight and body mass index (BMI) were significantly lower than in control group (P<0.05). There was a significant difference in the level of total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), creatinine, uic acid and triglyceride (TG) between longevity group and control group (P<0.05). The prevalence of hypercholesterolemia and hyperuricemia was higher and the prevalence of overweight, obesity and hypertriglyceridemia was lower in longevity group than in control group.There were no significant differences in diastolic blood pressure (DBP), pulse pressure index (PPI), fasting blood glucose (FBG) and the prevalence of hypertension and hyperglycemia between the two groups (P>0.05). Section two:1) Eight common SNPs of TERT gene were chosen to be tagging SNPs. All polymorphisms were in Hardy-weinberg equilibrium both in longevity and in control group. The frequencies of G and T allele of TERT SNP2 in longevity group were 62.1%,37.9% and 51.6%,48.4% in the control group. The frequencies of SNP2 genotypes of GG, GT and TT in longevity group were 36.6%,50.9%,12.5%and 24.9%,53.4%,21.7% in control group respectively. The distributions of TT genotype and T allele of SNP2 (SNP rs2736100) in longevity group were lower than in control group and P equals to 0.026,0.009. The SNP rs2736100 was significantly associated with longevity (TT versus GG:P=0.008, OR=0.392,95%CI: 0.193～0.796; GT+TT versus GG:P=0.023, OR=0.574,95%CI:0.355～0.928; T versus G: P=0.009, OR=0.652,95%CI:0.473-0.900); 2) The frequencies of T and C allele of TERT SNP6 in longevity group were 66.5%,33.5% and 56.2%,43.8% in the control group. The frequencies of SNP6 genotypes of TT, TC and CC in longevity group were 45.5%,42.0%, 12.5% and 34.9%,42.6%,22.5% in control group respectively. The distributions of CC genotype and C allele of SNP6 (SNP rs2075786) in longevity group were lower than in control group and P equals to 0.044,0.009. The SNP rs2075786 was significantly associated with longevity (CC versus TT:P=0.013, OR=0.426,95%CI:0.216～0.842; C versus T:P=0.009, OR=0.647,95%CI:0.465～0.899); 3) The haplotype analysis revealed that the frequency of Hap 1-AT was highest in both groups. The frequencies of Hap 1-AT, Hap3-GC were higher in longevity group than in control group while the frequency of Hap2-AC was lower in longevity group. There was no statistically significant difference. 4) PP and PPI in GT+TT genotype combination were markedly higher than in GG genotype of TERT SNP2 in longevity group, while PPI in TC+CC genotype was markedly higher than in TT genotype of TERT SNP6 in control group. Section three:1) Three common SNPs of VEGF gene were chosen to be tagging SNPs. All polymorphisms were in Hardy-weinberg equilibrium both in longevity and in control group. The frequencies of C and A allele of VEGF SNP1 in longevity group were 70.1%,29.9% and 62.3%,37.7% in the control group. The frequencies of SNP1 genotypes of CC, CA and AA in longevity group were 47.3%,45.5%,7.2% and 42.6%,39.3%,18.1% in control group respectively. The distributions of AA genotype and A allele of SNP1 (SNP rs2146323) in longevity group were lower than in control group and P equals to 0.025, 0.041. The SNP rs2146323 was significantly associated with longevity (AA versus CC: P=0.011,OR=0.356,95%CI:0.156～0.808; A versus C:P=0.041, OR=0.704,95%CI: 0.502～0.987); 2) The haplotype analysis revealed that the frequency of Hapl-CG was highest in both groups. The frequency of Hapl-CG was higher in longevity group than in control group, while the frequencies of Hap2-CA, Hap3-AG were lower in longevity group. There was no statistically significant difference.3) The level of PP in CA+AA genotype combination was markedly higher than in CC genotype of VEGF SNP1 in control group. Conclusion:Our study revealed that TERT gene rs2736100 and rs2075786 polymorphisms might be associated with longevity in Xinjiang Uygur population. TT genotype, T allele of rs2736100 and CC genotype, C allele of rs2075786 were the adverse factors of longevity. VEGF gene rs2146323 polymorphism might be associated with longevity. AA genotype and A allele were the adverse factors of longevity in Xinjiang Uygur population. rs2736100, rs2075786 and rs2146323 might be associated with longevity through impacts on vascular function.
引文
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