Associations Between Three Gene Polpmorphisms And Serum Lipids And Ischemic Heart And Cerebrovascular Diseases

Part ⅠASSOCIATION OF SNPS IN THE GLUCOKINASE REGULATOR GENE AND SERUM LIPID LEVELS AND THE RISK OF CORONARY HEART DISEASE AND ISCHEMIC STROKEBackground: The enzyme glucokinase(GCK) is the major glucose sensor of the pancreatic β-cells, where it adapts insulin secretion to blood glucose levels. GCK also participates in regulating glycogen synthesis and gluconeogenesis in the liver. GCK activity is controlled in hepatocytes by the glucokinase regulatory protein(GCKR). Genome-wide association studies have identified the glucokinase regulator(GCKR) as a potential locus for modulating high-density lipoprotein cholesterol(HDL-C), low-density lipoprotein cholesterol(LDL-C) and triglyceride(TG). However, the associations between the SNPs in GCKR and the risk of CHD and IS were few and inconsistent and still needed to determine in different populations.Objective: the present study was to determine the association of the GCKR polymorphisms and serum lipid levels, and the risk of coronary heart disease(CHD) and ischemic stroke(IS) in Guangxi Han Chinese population.Methods: Take SNP reported in the literature combined with functional SNP selection strategy, selected 2 SNPs including the rs1260326 loci reported in GWAS associated with lipids, as well as rs8179206 in exons in GCKR area. All of the subjects completed epidemiological investigation, blood lipid levels and other biochemical measures. Genotypes of the GCKR rs1260326 and rs8179206 SNPs in 1736 subjects(CHD, 584; IS, 555; and healthy controls; 597) were determined by the Snapshot technology platform. The present research was carried out in two steps: the first step was carried in the 597 normal controls and the case group(CHD, 584; IS, 555;). the difference in lipid levels and genotypic and allelic frequencies between the controls and the case groups were detected. Then estimate the risk of the GCKR rs1260326 and rs8179206 SNPs for the CHD and IS. The second step: the association between genotypes and lipid levels were determined in the case group and normal controls and the combined population(1736 cases), respectively.Results: 1. The CHD patients had higher BMI, pulse pressure and serum TG levels, but lower levels of diastolic blood pressure, serum TC, HDL-C, Apo A1, the ratio of Apo A1 to Apo B, and the percentages of subjects who consumed alcohol(P < 0.05-0.001) than controls. The IS patients had higher BMI, systolic blood pressure, pulse pressure and serum TG levels, and lower levels of serum TC, HDL-C, Apo A1, the ratio of Apo A1 to Apo B, and the percentages of subjects who consumed alcohol(P < 0.05-0.001) than controls. The genotypic and allelic frequencies of rs1260326 and rs8179206 SNPs were not different between controls and CHD or IS patients, or between CHD and IS patients(P > 0.05 for all), but the TT genotype of the rs1260326 SNP was associated with decreased risk of IS in females(OR = 0.37, 95%CI: 0.18-0.76, P = 0.007).2. When the association of the SNPs and serum lipid levels was analyzed in the cases and controls, the subjects with TT genotype of rs1260326 SNP had higher serum LDL-C levels in controls, and higher TG levels in CHD patients, and lower HDL-C levels in the total populations than the subjects with CC and CT genotypes after adjustment for age, sex, body mass index, blood pressure, alcohol consumption, and cigarette smoking(P < 0.05). But no association between the SNPs and serum lipid levels was found in the IS patients.Conclusions: The present study shows that the TT genotype of GCKR rs1260326 SNP is associated with high LDL-C in controls, high TG levels in CHD patients, and decreased IS risk in females. No association is found between rs8179206 SNP and serum lipid levels and the risk of coronary heart disease and ischemic stroke.PartⅡASSOCIATION OF THE VARIANTS IN THE CELSR 2-PSRC1-SORT1 AND THE RISK OF SERUM LIPID TRAITS, CORONARY ARTERY DISEASE AND ISCHEMIC STROKEBackground: Recent GWAS have found CELSR2-PSRC1-SORT1 variants on chromosome 1p13.3 associated with CHD and plasma lipoproteins based on populations of European, eastern Asia, southern Asia, Middle-Eastern Asia, and Africa Americans. Some loci were found to affect the risk of CHD and IS. However, there were no data in the Guangxi Han populations.Objectives: Our study was to assess the association of CELSR2-PSRC1-SORT1 rs599839, rs464218 and rs6698443 SNPs and serum lipid levels and the risk of CHD and IS.Methods: A total of 561 patients with CHD and 527 patients with IS were recruited from hospitalized patients in the First Affiliated Hospital, Guangxi Medical University. The genotypes of 3 SNPs were detected in 561 CHD and 527 IS patients, and in 590 healthy controls using Snapshot technology platform. All of the subjects completed epidemiological investigation, blood lipid levels and other biochemical measures. The study was divided into two steps: the first step was carried in the 590 normal controls and the case group(CHD, 561; IS, 527;). the difference in lipid levels and genotypic and allelic frequencies between the controls and the case groups were detected. the association between genotypes and lipid levels were determined in the case group and normal controls and the combined population(1678 cases), Respectively. The second step: To estimate the risk of the CELSR2-PSRC1-SORT1 rs599839, rs464218 and rs6698443 SNPs for the CHD and IS.Results: The genotype distribution of all 3 SNPs agreed with HardyWeinberg equilibrium(P > 0.05 for all). The genotype and allele frequencies of the rs599839, rs464218 and rs6698843 SNPs were no differences between the controls and CHD patients(P > 0.05). However, the genotype and allele frequencies of the rs599839 SNP were different between the controls and IS patients(P < 0.05). The minor G alleles of rs599839 and rs464218 SNPs were associated with higher high-density lipoprotein cholesterol concentrations in CHD and IS patients(P < 0.05) after adjustment of age, sex, body mass index, blood pressure, alcohol consumption, and cigarette smoking; respectively. No association was found between the SNPs of rs599839, rs464218 and rs6698843 at the CELSR2-PSRC1-SORT1 and the risk of CHD or IS.Conclusions: The present study shows that the minor G allele of rs599839 and rs464218 SNPs is associated with high HDL-C concentrations in CHD and IS patients.Part ⅢASSOCIATION OF HNF1 A POLYMORPHISMS AND SERUM LIPID TRAITS, THE RISK OF CORONARY ARTERY DISEASE AND ISCHEMIC STROKEBackground: The hepatocyte nuclear factor-1α gene(HNF1A) polymorphisms have been associated with serum lipid traits and glycometabolism in GWAS. Previous reports have indicated that maturity-onset diabetes of the young(MODY) caused by HNF1 A mutations. Plasma lipid metabolism abnormality and genetic variants are associated with CHD and IS. However, little is known about such association in the Guangxi Han populations,the results are not consistent in Other ethnic groups.Objective: The primary aim of this study was to determine the association of HNF1 A polymorphisms(rs1169288, rs2259820, rs2464196 and rs2650000) and serum lipid traits, the risk of CHD and IS.Methods: Selected four SNPs including the rs1169288, rs2259820, rs2464196 and rs2650000 SNPs in GWAS associated with lipids in HNF1 A area depending on SNP reported in the literature combined with functional SNP selection strategy. The genotypes of four SNPs were detected in 562 CHD and 527 IS patients, and in 594 healthy controls using Snapshot technology platform. All of the subjects completed epidemiological investigation, blood lipid levels and other biochemical measures. The study was carried out in three steps: the first step was carried in the 594 normal controls and the case group(CHD, 562; IS, 527;). the difference in lipid levels and genotypic and allelic frequencies between the controls and the case groups were detected. the association between genotypes and lipid levels were determined in the case group and normal controls, Respectively. The second step: the risk of the HNF1 A polymorphisms(rs1169288, rs2259820, rs2464196 and rs2650000) for the CHD and IS was estimated. The third step is the use the material of the first and second steps, further analyze if there are influence about interactions between genes and smoking, alcohol consumption and BMI on serum lipid levels, using Snpstats online software to analysis gene-environment interaction to determine whether the interactions influences the risk of the disease.Results: 1. The genotype and allele frequencies of the rs1169288, rs2259820, rs2464196 and rs2650000 SNPs were no differences between the controls and CHD or IS patients(P > 0.05 for all). Significant linkage disequilibrium was noted among the four SNPs(r2 > 0.5, D’ > 0.8). after the Bonferroni correction of P-values, the minor C allele of rs1169288 was associated with high TG concentrations in the controls(P < 0.01); the minor T allele of rs2259820 and the minor of A allele of rs2464196 were associated with high Apo A1 concentrations in the CHD patients(P < 0.01); respectively.2. The associations between the rs2259820 genotype and the risk of CHD remains significant: Codominant model: TT vs. CC(OR=0.64, 95%CI: 0.44-0.91, P=0.015); Recessive model: CT/TT vs. CC(OR=1.47, 95%CI: 1.06-2.03, P=0.020); the associations between the rs2464196 genotype and the risk of CHD remains significant: Codominant model: AA vs. GG(OR = 0.62, 95%CI: 0.43-0.89,P = 0.010); Recessive model:GG/GA vs. AA(OR =1.51, 95%CI: 1.09-2.08, P = 0.014); rs1169288, rs2259820, rs2464196 and rs2650000 SNPs were not found associated with the risk of CHD and IS. The haplotype of A-C-G-A(rs1169288A-rs2259820C-rs2464196G-rs2650000A) was associated with increased risk of CHD(OR: 1.95, 95% CI: 1.13-3.37, P =0.015), the difference in the overall P value was significant(P=0.044).3. Interactions between genotypes of the two SNPs and smoking, alcohol consumption and BMI on blood lipids were detected. rs2259820 SNP interacted with alcohol on serum TG, but the difference after Bonferroni correction was not significant(P=0.042). rs2464196 SNP interacted with alcohol on serum LDL-C, but the difference after Bonferroni correction was not significant(P=0.043).4. The interaction between haplotypes and smoking on CHD was detected(P=0.011), no smokers in A-C-G-C had been as reference, no smokers in A-CG-A were associated with decreased risk of CHD [OR 0.51(0.26- 0.98)]. The interaction between haplotypes and alcohol, sex on IS were detected(P=0.033, P=0.011; respectively). Male in A-C-G-A was associated with decreased risk of IS [OR 0.26(0.08- 0.80)]; no drinkers in A-C-G-C had been as reference, drinkers in A-T-A-C were associated with decreased risk of IS [OR 0.43(0.20-0.93)], no drinkers in A-T-A-C were associated with increased risk of IS [OR 1.61(1.05- 2.47)].Conclusions: rs1169288 SNP is associated with serum TG, rs2259820 and rs2464196 SNPs are associated with Apo A1 levels, also associated with the risk of CHD. These findings suggest that the HNF1 A polymorphisms may be the genetic risk factors for CHD. The impact of gene-environment interaction factors on serum lipid level are not found, but, the interaction factors on risk of CHD/IS are found.