| PARTⅠAssociation between the MCU rs7901016 SNP and Serum Lipid Levels and Ischemic Cardio-cerebrovascular DiseaseBackground: Coronary heart disease(CHD)and ischemic stroke(IS)are two leading global causes of morbidity and disability.Genetic factors are the major risk factors for CHD and IS,studies have shown that parents’ CHD history is a risk factor for stroke and family history of stroke is a risk factor for CHD.These findings show that these two diseases have similar pathological mechanisms and genetic susceptibility.Mitochondrial calcium uniporter gene(MCU)rs7901016 single nucleotide polymorphism(SNP)has been associated with some serum lipid parameters and CHD in previous genome-wide association study(GWAS).However,little is known about such association in the Han population in South China.Furthermore,it is unclear whether this SNP is also associated with the risk of IS.Objective: This study was undertaken to evaluate the association of the MCU rs7901016 SNP and serum lipid levels,the susceptibility to CHD and IS in the Han population in South China.The gene-environment interactions on the risk of CHD and IS were also further analyzed.Methods: Based on the case-control study of the Guangxi Han Chinese population,1,668 subjects were collected in this study,including 573 normal healthy controls(control group),563 CHD patients(CHD group),and 532 IS cases(IS group).The general information and clinical data of the subjects were collected in the form of questionnaires,and the deoxyribonucleic acid(DNA)of the whole blood genome was extracted.The genotypes of the MCU rs7901016 SNP were determined by the Snapshot technology.The differences in the general situation,serum lipid levels,the genotypic and allelic frequencies between the case and control groups were compared.The differences in serum lipid levels among different genotypes were analyzed in the normal control group.The relationship between the MCU rs7901016 SNP and the risk of CHD and IS was determined by the SNPStats online software,and the influence of gene-environment interactions on the susceptibility to the risk of CHD and IS was also evaluated.Results1.The genotypic and allelic frequencies of the MCU rs7901016 SNP were significantly different between the case and control groups.After the related risk factors were adjusted,the genotypes of the MCU rs7901016 SNP were associated with decreased risk of CHD in different genetic models: co-dominant model(CC vs.TT,OR = 0.41,95% CI = 0.17-0.98,P = 0.037);dominant model(CT+CC vs.TT,OR = 0.63,95% CI = 0.42-0.93,P = 0.02);log-additive model(C vs.T,OR = 0.65,95% CI = 0.47-0.90,P = 0.01).The genotypes of the MCU rs7901016 SNP were also associated with decreased risk of IS in different genetic models: co-dominant model(CC vs.TT,OR = 0.52,95% CI = 0.29-0.92,P = 0.032);dominant model(CT+CC vs.TT,OR = 0.76,95% CI = 0.59-0.97,P= 0.03);log-additive model(C vs.T,OR = 0.76,95% CI = 0.62-0.94,P =0.011).2.Serum low-density lipoprotein cholesterol(LDL-C)levels among different genotypes of the MCU rs7901016 SNP in the control group were significantly different.The subjects with CT/CC genotypes in the control group had lower serum LDL-C levels than those with TT genotype(P < 0.05).3.The interactions of gene-environment on the risk of CHD and IS were observed.The MCU rs7901016 CC genotype interacted with alcohol consumption to reduce the risk of IS(OR = 0.55,95%CI = 0.33-0.92,P =0.021).Conclusions: The MCU rs7901016 SNP was involved in the risk of CHD and IS and serum lipid levels.Compared with non-C allelic carriers,C allelic carriers decreased susceptibility to CHD and IS and had lower serum LDL-C levels in the Han population in South China.The interactions between alcohol consumption and MCU rs7901016 SNP decreased the risk of IS.PARTⅡAssociation between the CYP7A1 rs9297994 SNP and Serum Lipid Levels and Ischemic Cardio-cerebrovascular DiseaseBackground: Cytochrome P450 family 7 subfamily A member 1 gene(CYP7A1)encodes cholesterol 7α-hydroxylase,which catalyzes the initial steps of converting cholesterol to bile acids in the classical pathway.Bile acid synthesis is the predominant metabolic pathway for catabolism of cholesterol in humans.Abnormally elevated levels of plasma cholesterol are a well-known causal risk factor for atherosclerosis,and atherosclerosis is the main pathological basis for CHD and IS.Therefore,promoting the increase of cholesterol excretion in the form of bile acid is an attractive target for the treatment of hypercholesterolemia and atherosclerosis progression.Some studies have found that CYP7A1 SNPs were associated with serum lipid levels and cardiovascular disease(CVD)risk,but the results were inconsistent.Moreover,most of the GWASes were conducted in European and American populations,and the validation of GWASes results across populations could provide more compelling epidemiological evidence for exploring its susceptibility and pathogenesis.Objective: The purpose of this study was to investigate the effect of the CYP7A1 rs9297994 SNP on serum lipid levels and its relationship with the risk of CHD and IS in Han population in South China,and to further analyze the influence of gene-environment interactions on the risk of CHD and IS.Methods: This study was a case-control study based on the Han population in Guangxi,a total of 1,674 participants were collected,including 587 normal controls,548 patients with CHD,and 539 cases of IS.General information and clinical data were collected by means of questionnaires,the whole blood genomic DNA was isolated.The Snpshot technique was used to genotyping of the SNP.Serum lipid levels in the normal group were compared among the three genotypes.The differences in the general situation,serum lipid levels,and the genotypic and allelic frequencies between the case and control groups were assessed.SNPStats was used to analyze the association between the CYP7A1 rs9297994 SNP and the risk of CHD and IS,and the gene-environment interactions on the risk of CHD and IS was futher explored.Results1.There were significant differences in the genotypic and allelic frequencies of the CYP7A1 rs9297994 SNP between the case(CHD or IS)and normal control groups.Adjusting for the related risk factors,the genotypes of the CYP7A1 rs9297994 SNP were associated with increased risk of CHD in different genetic models: co-dominant model(AG vs.AA,OR = 1.36,95% CI = 1.05-1.76;GG vs.AA,OR = 1.86,95% CI = 1.13-3.07,P = 0.011);dominant model(AG+GG vs.AA,OR = 1.41,95% CI = 1.10-1.84,P = 0.0064);log-additive model(G vs.A,OR = 1.36,95% CI = 1.11-1.75,P = 0.0027).The genotypes of the CYP7A1 rs9297994 SNP were also associated with increased risk of IS in different genetic models: co-dominant model(AG vs.AA,OR = 1.34,95% CI = 1.04-1.73;GG vs.AA,OR = 1.79,95% CI = 1.10-2.92,P = 0.015);dominant model(AG+GG vs.AA,OR = 1.40,95% CI = 1.09-1.78,P = 0.0077);log-additive model(G vs.A,OR = 1.34,95% CI = 1.10-1.63,P = 0.0037).2.The CYP7A1 rs9297994 SNP was associated with serum LDL-C and apolipoprotein(Apo)B levels in normal controls.Compared with the subjects with AA genotype,the subjects with AG/GG genotypes had higher serum LDL-C and Apo B levels(P < 0.05).3.The hierarchical analysis of gene-environment interactions showed that the interactions between CYP7A1 rs9297994 GG genotype and smoking(OR = 2.43,95%CI = 1.46-4.07,P = 0.001)or drinking(OR = 3.33,95%CI = 1.96-5.65,P = 0.000)increased the risk of CHD,and the interactions between CYP7A1 rs9297994 GG genotype and drinking increased the risk of IS(OR = 1.69,95%CI = 1.01-2.82,P = 0.045).Conclusions: CYP7A1 rs9297994 G allelic carriers increased the risk of CHD and IS,and G allelic carriers had higher serum LDL-C and Apo B levels.The interactions of the CYP7A1 rs9297994 SNP and environmental factors increased the risk of CHD and IS.PART ⅢAssociation between the MGAT2-DGAT2 Polymorphisms and Serum Lipid Levels and Ischemic Cardio-cerebrovascular DiseaseBackground: Over the past 30 years,with the rapid economic development and unhealthy lifestyles(such as inactivity,westernized diets),and the effects of demographic ageing and urbanization,the blood lipid levels of the Chinese population have increased than before.Epidemiological survey shows that the prevalence of dyslipidemia in the general population aged > 18 years old has reached up to 34.0%.Dyslipidemia is a major risk factor for CVD.As a complex genetic phenotype,an individual’s risk of developing dyslipidemia or CVD is the result of a combination of genetic and environmental factors.The monoacylglycerol acyltransferase 2 gene(MGAT2)-diglyceride acyltransferase 2 gene(DGAT2)cluster,located on chromosome 11,is involved in tryglyceride(TG)synthesis and is related to factors such as obesity and insulin sensitivity.Recently,GWASes have found that several SNPs in the MGAT2-DGAT2 cluster were related to serum lipid levels.However,thus association has not been verified in the Han population in South China,and the correlation has not been reported previously between the MGAT2-DGAT2 custer and the risk of CHD and IS.Objective: The purpose of this study was to explore the relationship between several SNPs in the MGAT2-DGAT2 cluster and serum lipid levels,and to determine the correlation between these SNPs and the risk of CHD and IS.The gene-environment interactions on serum lipid levels and on the risk of CHD and IS were also explored.Methods: This study was based on the case-control study of the Guangxi Han Chinese population.A total of 1666 participants were enrolled,including a normal control group of 561 adults,and two case groups of 1,095 patients(CHD,551;IS,544).The general information and clinical data of the subjects were collected by questionnaires.The whole blood genomic DNA was extracted and the serum lipid levels were detected.rs11236530,rs3060,rs600626,rs609379,and rs10899104 SNPs in the MGAT2-DGAT2 cluster were selected as research sites by the strategy of combining literature reports with tag SNP.Snpshot genotyping technique was used to determine the genotypes of the SNPs.The differences in serum lipid levels among the three genotypes of five loci were compared in the normal group.The differences in the general situation,serum lipid levels,the genotypic and allelic frequencies between the case and control groups were detected.SNPStats online software was used to analyze the relationship between the genotypes and the risk of CHD and IS,and the gene-environment interactions on serum lipid levels and on the risk of CHD and IS were further observed.Results1.The genotypic and allelic frequencies of the DGAT2 rs11236530 locus were significantly different between the control and CHD groups,as well as between the control and IS groups.After the related risk factors were adjusted,the genotypes of the DGAT2 rs11236530 SNP were associated with the risk of CHD in different genetic model after Bonferroni correction: dominant model(CA+AA vs.CC,OR = 1.39,95% CI = 1.09-1.77,P = 0.0086);log-additive model(A vs.C,OR = 1.34,95% CI = 1.09-1.64,P = 0.0051).The genotypes of the DGAT2 rs11236530 SNP were associated with the risk of IS in different genetic model after Bonferroni correction: co-dominant model(CA vs.CC,OR = 1.38,95% CI = 1.05-1.80;AA vs.CC,OR = 2.10,95% CI = 1.18-3.74,P =0.0063);dominant model(CA+AA vs.CC,OR = 1.45,95% CI = 1.12-1.88,P = 0.0044);log-additive model(A vs.C,OR = 1.41,95% CI = 1.14-1.74,P = 0.0015).The other loci were not significantly correlated with the risk of CHD or IS after Bonferroni correction.There was linkage disequilibrium(D’ > 0.5)among the rs600626,rs609379 and rs10899104 SNPs.Haplotype analysis showed that the most common haplotype was A-C-T.As compared with the A-C-T haplotype,the G-A-G(OR = 0.62,95% CI = 0.45-0.86,P = 0.0046)and A-C-G haplotypes(OR = 0.51,95% CI = 0.33-0.78,P = 0.0021)were associated with decreased risk of CHD,and the G-A-G haplotype was associated with decreased risk of IS(OR = 0.67,95% CI = 0.48-0.93,P = 0.0018).2.The subjects with the rs11236530 CA genotype in normal control group had higher serum total cholesterol(TC)levels than the subjects with CC/AA genotypes;the subjects with CA/AA genotypes had lower high-density lipoprotein cholesterol(HDL-C)levels than the subjects with CC genotype.The subjects with the rs3060 CT genotype had higher serum TC levels than the subjects with TT/CC genotypes.The subjects with rs609379CA/AA genotypes had lower serum HDL-C levels than the subjects with CC genotype;the subjects with CA genotype had higher LDL-C levels than the subjects with CC/AA genotypes.No correlation was found between rs600626 and rs10899104 loci and serum lipid levels.However,after Bonferroni correction,only serum HDL-C levels were significantly different among the genotypes of the rs11236530 SNP.3.Gene-environment interaction analysis showed that the interactions of MGAT2-DGAT2 SNPs with smoking and drinking affected serum lipid levels in normal control group.After Bonferroni correction,the differences were still statistically significant.The interactions of rs11236530,rs3060,and rs10899104 SNPs with smoking affected serum Apo B levels,and the interactions of rs11236530 and rs3060 SNPs with alcohol consumption affected serum HDL-C levels.4.The SNP-environment interactions that had a significant effect on blood lipid levels in the normal control group had no significant effect on the risk of CHD or IS.However,when the haplotype-environment interactions on the risk of CHD and IS was analyzed,we found that the G-C-T haplotype-smoking interactions(OR = 2.24,95% CI = 1.13-4.45)increased the risk of CHD,while A-C-G haplotype-smoking interactions(OR = 0.44,95% CI = 0.25-0.79)reduced the risk of CHD(P = 0.00029);the haplotype-smoking interactions had no significant effect on the risk of IS(P = 0.067).The A-C-T haplotype-drinking(OR = 0.45,95% CI = 0.30-0.69),G-A-G haplotype-drinking(OR = 0.23,95% CI = 0.12-0.44),G-C-T haplotype-drinking(OR = 0.26,95% CI = 0.16-0.42)and A-C-G haplotype-drinking(OR = 0.07,95% CI = 0.02-0.29)interactions reduced the risk of CHD(P <0.0001);and the G-A-G haplotype-drinking(OR = 0.41,95% CI = 0.22-0.76)and G-C-T haplotype-drinking(OR = 0.12,95% CI = 0.04-0.36)interactions decreased the risk of IS(P <0.0001).Conclusions: The DGAT2 rs11236530 SNP increased the risk of CHD and IS.Haplotype analysis showed that haplotypes in the MGAT2-DGAT2 cluster were associated with the risk of CHD and IS.The DGAT2 rs11236530 A allelic carriers had lower serum HDL-C levels in normal control group after Bonferroni correction.The interactions of the SNPs in the MGAT2-DGAT2 cluster with environmental factors influenced serum lipid levels,and the interactions of haplotypes with environmental factors affected the risk of CHD and IS. |
PDF Full Text Request