| Hypertension is independent risk factors of cardiovascular disease,kidney disease,and stroke.There are 9.4 million people dying each year from the complications of hypertension in the world.The nutrition and health status survey of Chinese residents 2002 indicated that the hypertension prevalence rate was as high as 18.8% in Chinese population(?18 years old),which estimated that the number of cases in China was more than 270 million.The study population were recruited from 135 Cohort of Preventive Therapy on Chronic Disease in Suzhou Industrial Park.In Part 1,we aimed to explore the association between PPARG gene polymorphisms and Essential Hypertension(EH)and detect the possible gene-gene,gene-environment interaction among the PPARG gene polymorphisms on the EH.In Part 2,we aimed to explore the association between AGTR1 gene polymorphisms and EH and detect the possible gene-gene,gene-environment interaction among the AGTR1 gene polymorphisms on the EH.In Part 3,we aimed to discuss the association between the interaction of the two genes and EH.Part 1ObjectiveThrough the the molecular epidemiological study of PPARG genetic variation with EH,to explore the association between PPARG gene polymorphisms and EH and detect the possible gene-gene,gene-environment interaction among the PPARG gene polymorphisms on the EH.Subjects and MethodsSubjects of this case-control study were recruited from a community population by the epidemiological cluster sampling approach in Suzhou,Jiangsu province,China.The study population consisted of 618 hypertensive cases and 973 age-(5 years)and sex-matched normotensives with systolic blood pressure(SBP)<140 mm Hg and diastolic blood pressure(DBP)<90 mm Hg as controls.Hypertensive cases were selected according to SBP?140 mm Hg,and/or DBP ?90 mm Hg,or currently administering antihypertensive medication.The present study did't include:(1)the Secondary hypertension patients(3 times of the BP measurement,the people who had SBP<140 mm Hg and DBP<90 mm Hg or the Secondary hypertension patients);(2)individuals who had serious heart,lung,brain,kidney and tumor diseases history.MB-MDR was used to detect the potential gene-gene interactions among the polymorphisms involved,Haplo.score was used to test the association between PPARG gene haplotypes and the EH.Haplo.glm was available to explore the interaction between PPARG gene haplotypes and smoking/drinking/ BMI/common obesity/ waistline/central obesity/ Uric Acid level/ hyperuricemia on the EH.ResultsWe compared the distribution of genotypes frequencies of all the tag SNPs of PPARG after adjustment for sex,age,BMI,TC,TG,HDL-C,LDL-C,FBG,drinking and smoking.The additive model of rs3856806 showed statistical significance,the ORs(95%CI)was 0.83(0.70-0.99)and the P value was 0.033.The dominant model of rs3856806 showed statistical significance with EH,the ORs(95%CI)C/C : C/T-T/T was 1 : 0.79(0.63-0.98)and the P value was 0.029.The additive model of rs13433696 showed statistical significance with EH,the ORs(95%CI)was 0.83(0.71-0.97)and the P value was 0.020.The dominant model of rs13433696 showed statistical significance with EH,the ORs(95%CI)G/G : G/A-G/G was 1 : 0.78(0.63-0.97)and the P value was 0.027.The additive model of rs9817428 showed statistical significance with EH,the ORs(95%CI)was 1.17(1-1.36)and the P value was 0.047.The dominant model of rs9817428 showed statistical significance with EH,the ORs(95%CI)A/A : A/C-C/C was 1 : 1.28(1.01-1.62)and the P value was 0.037.Furthermore,we compared the distribution of genotypes frequencies of all the tag SNPs after stratification by age,sex,drinking and smoking.There were significant differences of genotypes of rs13433696 in ?55 years groups,male group and female group,the gene variation may play a protective role.There were significant differences of genotypes of rs9817428 in ?55 years groups,non-drinking group,female group and non-smoking group,the gene variation may play a dangerous role.Significant gene-gene interactions among the tag SNPs of PPARG gene was detected.We performed permutation test on the Wmax based on 1000 permutations and found that the 2 and 7-locus models were significant with EH(P=0.007,0.049).The G-C haplotype of PPARG gene was positively associated with EH(Score=2.10,P=0.04).We used EH as the phenotype to fit the model,after adjustment of sex,age,BMI,TC,TG,HDL-C,LDL-C,FBG,drinking and smoking,the G-A haplotypes have significant interactive effect with smoking on EH(P=0.009).ConclusionPPARG gene polymorphisms(rs3856806,rs13433696 and rs9817428)were significantly associated with EH.There was a significant gene-gene interaction among the tag SNPs of PPARG gene.Stratified analysis results suggestted there may be a broader gene-environment interaction.Further gene-environment interaction results showed that PPARG haplotypes G-A had an interactive effect with smoking on EH.Part 2ObjectiveThrough the the molecular epidemiological study of AGTR1 genetic variation with EH,to explore the association between AGTR1 gene polymorphisms and EH and detect the possible gene-gene,gene-environment interaction among the AGTR1 gene polymorphisms on the EH.Subjects and MethodsSubjects of this case-control study were recruited from a community population by the epidemiological cluster sampling approach in Suzhou,Jiangsu province,China.The study population consisted of 618 hypertensive cases and 973 age-(5 years)and sex-matched normotensives with systolic blood pressure(SBP)<140 mm Hg and diastolic blood pressure(DBP)<90 mm Hg as controls.Hypertensive cases were selected according to SBP?140 mm Hg,and/or DBP ?90 mm Hg,or currently administering antihypertensive medication.The present study did't include:(1)the Secondary hypertension patients(3 times of the BP measurement,the people who had SBP < 140 mm Hg and DBP < 90 mm Hg or the Secondary hypertension patients);(2)individuals who had serious heart,lung,brain,kidney and tumor diseases history.MB-MDR was used to detect the potential gene-gene interactions among the polymorphisms involved,Haplo.score was used to test the association between AGTR1 gene haplotypes and the EH.Haplo.glm was available to explore the interaction between AGTR1 gene haplotypes and smoking/drinking/BMI/ common obesity/waistline/central obesity/ Uric Acid level/ hyperuricemia on the EH.ResultsWe compared the distribution of genotypes frequencies of all the tag SNPs of AGTR1 after adjustment for sex,age,BMI,TC,TG,HDL-C,LDL-C,FBG,drinking and smoking.The codominant model of rs2933249 showed statistical significance with EH,the ORs(95%CI)C/C : C/T : T/T was 1 : 0.82(0.63-1.07): 3.24(1.43-7.31)and the P value was 0.003.The recessive model of rs2933249 showed statistical significance with EH,the ORs(95%CI)C/C-C/T : T/T was 1 : 3.38(1.5-7.62)and the P value was 0.002.Furthermore,we compared the distribution of genotypes frequencies of all the tag SNPs after stratification by age,sex,drinking and smoking.There were no significant differences of genotypes with EH.Significant gene-gene interactions among the tag SNPs of AGTR1 gene was detected.We performed permutation test on the Wmax based on 1000 permutations and found that the 2-locus models were significant with EH(P=0.034).There was no haplotype of AGTR1 gene associated with EH.We used EH as the phenotype to fit the model,after adjustment of sex,age,BMI,TC,TG,HDL-C,LDL-C,FBG,drinking and smoking,the C-C haplotypes have significant interactive effect with smoking,drinking,waistline,UA level and hyperuricemia on EH(P=0.047,<0.001,<0.001,<0.001,<0.001).ConclusionThere was no significant association between the AGTR1 gene polymorphism and EH in additive model and dominant model.The variation of rs2933249 showed statistical significance with EH in codominant model and recessive model.There was a broader gene-environment interaction,and the C-C haplotypes have significant interactive effect with smoking,drinking,waistline,UA level and hyperuricemia on EH.Part 3ObjectiveOn the basis of the first part,we further explored the interaction between PPARG gene and AGTR1 gene.We also investigated the interaction of the fore positive correlation tag SNPs of the two genes in the single locus association analysis on EH,and the interaction of the eight negative correlation tag SNPs of the two genes in the single locus association analysison EH.Subjects and MethodsMB-MDR was used to detect the potential gene-gene interactions among the polymorphisms involved.Model 1: To explore the gene-gene interactions of all of the 12 tag SNPs of PPARG and AGTR1 gene,after adjustment for sex,age,BMI,TC,TG,HDL-C,LDL-C,FBG,drinking and smoking.Model 2: To explore the gene-gene interactions of all of the the fore positive correlation tag SNPs of the two genes in the single locus association analysis(rs3856806,rs13433696,rs9817428 and rs2933249),after adjustment for sex,age,BMI,TC,TG,HDL-C,LDL-C,FBG,drinking and smoking.Model 3: To explore the gene-gene interactions of all of the the eight negative correlation tag SNPs of the two genes in the single locus association analysis(rs12631819,rss2920502,rs1175543,s2972164,rs2638360,rs1492100,rs5182 and rs275646),after adjustment for sex,age,BMI,TC,TG,HDL-C,LDL-C,FBG,drinking and smoking.ResultsSignificant gene-gene interactions among the 12 tag SNPs was detected.We performed permutation test on the Wmax based on 1000 permutations and found that the 2 to 10-locus models were significant with EH(P<0.05).Significant gene-gene interactions among the fore positive correlation tag SNPs was detected.We performed permutation test on the Wmax based on 1000 permutations and found that the 2 to 3-locus models were significant with EH(P<0.05).Significant gene-gene interactions among the eight negative correlation tag SNPs was detected.We performed permutation test on the Wmax based on 1000 permutations and found that the 2 and 5-locus models were significant with EH(P<0.05).ConclusionThere was a widespread significant gene-gene interaction among the tag SNPs of PPARG and AGTR1 gene.There were gene-gene interactions of all of the the fore positive correlation tag SNPs of the two genes in the single locus association analysis genes on EH.There were gene-gene interactions of all of the the eight negative correlation tag SNPs of the two genes in the single locus association analysis genes. |
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