| Background: Cardiovascular disease(CVD)is a leading cause of disability and death worldwide.Hyperlipidemia is the main cause of CVD,and despite the use of statins and other lipid-lowering drugs,many people fail to meet their lipidlowering goals.Studies have shown that hyperlipidemia is a complex disease caused by multiple factors,including genetic inheritance,environment and their interactions.Early detection of the causes of dyslipidemia and intervention is helpful to improve hyperlipidemia and the occurrence and development of CVD can be reduced.Genome-wide association study(GWAS)have found several novel loci on chromosome 19p13 that are associated with lipid metabolism,including Neurocan(NCAN,MIM[600826]),transmembrane 6 superfamily member 2(TM6SF2,MIM[606563]),cartilage mesolayer protein 2(CILP2,MIM[612419]),PBX homobox 4(PBX4,OMIM[608127]),SURP and G domains contain the protein 1 gene(SUGP1,MIM[607992])and the MAU2 sister chromosome aggregation factor gene(MAU2,MIM[614560]),and these gene lociare associated with coronary artery disease(CAD).Studies have shown that these loci are associated with total cholesterol(TC),low-density lipoprotein cholesterol(LDL-C),high-density low lipoprotein cholesterol(HDL-C),and triglyceride(TG).Although NCAN,TM6SF2,CILP2 PBX4,SUGP1 and MAU2 single nucleotide polymorphisms(SNPs)and the link between the serum lipid has been found in some ethnic group in Europe.However,different race maybe shows different gene heredity and environmental exposure.This study is to investigate the interaction between NCAN-TM6SF2-CILP2-PBX4 SUGP1-MAU2 SNPs and genetic genes and gene-environment and lipid level in the southwest population of China.Objectives: To explore the distribution and differences of blood lipid levels in the population in Guangxi China,and analyze the association between the SNPs and haplotype of the NCAN-TM6SF2-CILP2-PBX4-SUGP1-MAU2 gene cluster and serum lipid levels in the hyperlipidemia and normal groups,as well as the influence of gene-gene and gene-environment interactions on serum lipid levels.Methods: The subjects were divided into two groups,1248 adults(≥18 years old)(55.98±12.78 years)were randomly selected from the sample in the previous period,and 1248 healthy adults(56.87±12.12 years)were randomly selected as the control group.The two groups were matched in age,gender and race.Human genetic methods(studies of Y chromosome and mitochondrial diversity)were used to confirm the inclusion population.Both groups completed a questionnaire and a physical examination.The serum levels of TC,LDL-C,HDL-C,TG,Apo A1,and Apo B values of both groups were detected by venous blood samples,and the whole blood DNA was extracted and tested with a method of sequencing to detect 12 SNPs(rs2238675,rs2228603,rs58542926,rs735273,rs16996148,rs968525,rs17216525,rs12610185,rs10401969,rs8102280,rs73001065 and rs150268548).The distribution of genotypes and alleles of NCAN-TM6SF2-CILP2-PBX4-SUGP1-MAU2 was analyzed in two groups,and the association of serum lipid levels and genotypes,haplotypes and environmental factors was investigated.Results: The levels of systolic blood pressure,diastolic blood pressure,pulse pressure,TC,TG,HDL-C and LDL-C in the hyperlipidemia group were significantly higher than those in the normal group(P < 0.05-0.001),while the body weight,waist circumference and blood glucose levels in the hyperlipidemia group were significantly lower than the normal group(P < 0.001).There were no significant differences in age,gender,height,BMI,smoking status,alcohol consumption,Apo A1,Apo A1/Apo B ratio between the two groups(P > 0.05).The genotypes and allele frequencies of 12 SNPs of NCAN,TM6SF2,CILP2,PBX4,SUGP1 and MAU2 were significantly different between two groups.The allele frequencies of rs2238675 C,rs2228603T,rs58542926 T,rs735273G,rs16996148 T,rs17216525T,rs12610185 A,rs10401969T,rs73001065 G,rs8102280G,rs150268548 A and rs968525 T in hyperlipidemia group were higher than the normal group(P < 0.05).When analyzing the association between genotype and lipid levels in two groups,Serum TC levels and serum TG levels(TM6SF2 rs58542926,TM6SF2 rs735273,CILP2 rs735273,CILP2 rs16996148,CILP2 rs17216525,PBX4)of the minimum allele carriers(NCAN rs2238675,NCAN rs2228603,TM6SF2 rs58542926,TM6SF2 rs735273,CILP2 rs7996148,CILP2 rs17216525,PBX4)Rs12610185,SUGP1 rs10401969 and MAU2 rs8102280),and LDL-C levels(CILP2 rs16996148,MAU2 rs73001065 and MAU2 rs150268548)were higher than those of non-minimum alleles carrier(P < 0.004).Multiple locus linkage disequilibrium(LD)analysis with each point in the study population was not statistically independent.To analyze the association between haplotype and hyperlipidemia,the most common haplotypes were NCANC-T,TM6SF2 T-A,PBX4-SUGP1 G-T and MAU2 C-G-A-T(≥ 30% all the samples).The haplotype of NCAN C-C,TM6SF2 T-A,TM6SF2 C-A,CILP2 GT,PBX4-SUGP1 G-C,MAU2 G-G-G-C,MAU2 G-A-G-C,MAU2 C-G-A-T and MAU2 C-A-G-T were significantly different between the two groups(P < 0.05).Haplotype carriers of NCAN C-C,CILP2 G-T,PBX4-SUGP1 G-C and MAU2 CA-G-T decreased the risk of hyperlipidemia,while haplotype carriers of TM6SF2 T-A,TM6SF2 C-A,MAU2 G-G-C and MAU2 C-G-A-T increased the risk of hyperlipidemia(P < 0.05-0.001).The association between gene-gene interaction and blood lipid level was further analyzed,the serum level of TC in haplotypes carriers of rs58542926C-rs735273 A,rs73001065C-rs8102280G-rs150268548Ars968525 T carriers,and the serum level of LDL-C in haplotype rs73001065Grs8102280G-rs150268548G-rs968525 C and rs73001065C-rs8102280Grs150268548A-rs968525 T.The serum level of TG in haplotype carrier of rs58542926T-rs735273 A were higher than those in haplotype non-carriers(P < 0.006-0.0001).Further analysis of gene-gene haplotype,it showed that the most common haplotype of gene-gene interaction was C-C-C-C-A-G-C-A-T-C-G-A-T(> 15% all the samples).Gene–Gene interaction of haplotype C-C-C-A-G-C-AT-C-G-A-T,T-C-C-A-G-C-A-T-C-G-A-T,T-T-C-A-G-C-A-T-C-G-A-T,C-CC-A-G-C-A-T-C-A-G-C,C-C-C-A-G-C-G-C-G-A-G-C and T-T-T-A-G-C-G-CC-G-A-T,T-T-T-A-G-C-G-C-C-A-G-C and T-T-T-A-G-C-A-T-C-A-G-C was significantly different between hyperlipidemia group and normal group(P < 0.05).The haplotype carries of C-C-C-A-G-C-A-T-C-G-A-T,T-C-C-A-G-C-A-T-CG-A-T,C-C-C-A-G-C-G-C-G-A-G-C and T-T-T-A-G-C-G-C-C-A-G-C and TT-T-A-G-C-A-T-C-A-G-C reduced the risk of hyperlipidemia,And T-T-C-A-GC-A-T-C-G-A-T,C-C-C-A-G-C-A-T-C-A-G-C and T-T-T-A-G-C-G-C-C-G-AT haplotype carries increased the risk of hyperlipidemia.In the normal group andhyperlipidemia,T-C-C-A-G-C-A-T-C-G-A-T,C-C-C-A-G-C-G-C-G-A-G-C and T-T-T-A-G-C-G-C-C-A-G-C and T-T-T-A-G-C-A-T-C-A-G-C haplotype carriers had a low level of TC than the non-carriers,while C-C-C-A-G-C-A-T-CA-G-C and T-T-T-A-G-C-G-C-C-G-A-T haplotype carriers showed a higher level of TC than non-carriers;The TG level of C-C-C-A-G-C-A-T haplotype carriers was lower than that of non-carriers,while the TG level of T-T-C-A-G-C-T haplotype carriers was higher than non-carriers.LDL-C levels in the haplotype carriers were higher than non-carriers,and LDL-C levels were lower in the haplotype carriers than those in the non-carriers.In the normal group and hyperlipidemia group,the Apo A1 level of C-C-C-A-G-C-A-T-C-A-G-C haplotype carriers was lower than that of non-carriers(P < 0.006).GMDR analysis showed that the interaction of rs735273-rs16996148 and MAU2 G-A-GC-CILP2 G-T increased the risk of hyperlipidemia,while similar effects on interactions of rs16996148-Diabetes,CILP2 G-T-Diabetes,T-T-C-A-G-C-A-TC-G-A-T-C-C-C-A-G-C-G-C-G-A-G-C,C-C-C-A-G-C-G-C-G-A-G-C-Diabetes were observed.The Proportional Hazard Model analysis showed that carrying both genotypes of rs735273 AA and rs16996148 GT/GG showed an increased risk of hyperlipidemia,while carrying both genotypes of rs735273 AG/GG and rs16996148 TT decreased the risk of hyperlipidemia.The interaction between carrying rs16996148 TT and diabetes increased the risk of hyperlipidemia.Carrier with both of MAU2 G-A-G-C and CILP2 G-T reduced the risk of hyperlipidemia.The interaction between haplotype of T-T-C-A-G-C-A-T-C-G-A-T and C-C-CA-G-C-G-C-G-A-G-C reduced the risk of hyperglycemia.Interaction of CILP2 G-T carriers and Diabetes,as well as the interaction of C-C-C-A-G-C-G-C-G-AG-C carriers and Diabetes,increased the risk of hyperlipidemia(P < 0.05-0.0001).Conclusions: There were differences in serum lipid levels between the hyperlipidemia group and the normal group,and blood lipid levels were closely related to weight,waist circumference and blood pressure.Different genotypes and allelic frequencies of SNPs in the NCAN-TM6SF2-CILP2-PBX4-SUGP1-MAU2 gene cluster were correlated with lipid levels.The haploid status was different between the hyperlipidemia group and the normal group,and the interaction of SNPs,haplotype and environmental factors also influenced the risk of the disease.Background: Atherosclerotic cardiovascular disease(ASCVD)is a major cause of high morbidity and mortality worldwide,and it was placing a severe burden on global economic development.Dislipidemia has been proven to be an independent risk factor for ASCVD.Treatment of dyslipidemia and other predisposing factors can prevent the occurrence of ASCVD.At present,the population of cardiovascular disease in China is about 270 million.In 2012,the prevalence of dyslipidemia in people over 18 years old in China was 40.40% respectively.Numerous trials and studies have shown that elevated levels of lowdensity lipoprotein(LDL)cholesterol or total cholesterol(TC)can increase the risk of atherosclerotic plaque and subsequent vascular disease;Triglyceride-rich(TG-rich)lipoproteins of hypertriglyceridemia are also involved in the progression of atherosclerotic disease and it is closely associated with a residual risk of cardiovascular disease(CVD).So it is very vital to find out the causes of hyperlipidemia early and to intervene actively.Genome-wide association study(GWAS)studies have confirmed that dyslipidemia is caused by genetic factors,environmental factors,and complex diseases of the interaction of many factors,such as some individual gene loci(SNP)mutations,gender,age,hypertension,smoking,drinking,and body mass index and other factors.Both the MLX interacting protein(MLXIPL)and the Kruppel like factor 14(KLF14)are located on the long arm of chromosome 7.It has been shown that it is significantly associated with coronary heart disease(CHD).It regulates glycolysis and lipogenesis in liver cells and accelerates the process of atherosclerosis.Thepolymorphism of KLF14 is closely related to the cause of type 2 diabetes and metabolic disorders.Objectives: This study aims to investigate differences in lipid level and its distribution among the Hypercholesterolemia(HCH),Hypertriglycemia(HTG)and Normal group(Normal)with Han population in Guangxi.And analysis the relationship of MLXIPL-KLF14 gene polymorphism,haplotypes,gene-gene,and gene-environment that interacted with lipid levels,and identify the main affect factors of lipid levels,and this will be given some reference for future health decision on taking some prevention of strategy with region dyslipidemia on Han population and reduce the risk of cardiovascular disease.Methods: The adult Han people were randomly selected and divided into three groups: 543(64.15±12.12 years)in the HCH group and 521(63.92±13.42 years)in the HTG group.Patients with a family history of hyperlipidemia were excluded from both groups.A total of 678 healthy Han adults(63.78±13.21 years)were selected as the control group.All of them had a regular physical examination,and their age and gender were matched with those of the previous two groups.Human genetic methods(studies of Y chromosome and mitochondrial diversity)were used to confirm the inclusion population.Both groups completed a questionnaire and a physical examination.The serum TC,LDL-C,HDL-C,TG,Apo A1 and Apo B values were detected by venous blood samples in both groups.Whole blood DNA was extracted and sent to the Next Generation Sequencing for genotyping of all 8 SNPs(rs17145750,rs13247874,rs13226650,rs3812316,rs4731702,rs13241538,rs13241165 and rs972283).The distribution of genotypes and alleles of MLXIPL-KLF14 SNPs in the two groups was analyzed,and the association between genotype,haplotype and environmental factors and blood lipid levels was discussed.Results: The BMI,TC,TG,(Apo A1/Apo B),the proportion of type 2 diabetes mellitus and hypertension in the HCH group and were higher than the normal group(P < 0.05-0.001),while HDL-C and Apo A1 were lower than the normal group(P < 0.05-0.001).Compared with the normal group,the BMI,alcohol consumption,TC,TG,Apo A1,proportion of type 2 diabetes and hypertension were higher in the HTG group than the normal group(P < 0.05-0.001),and the HDL-C and Apo A1/Apo B in the hypertriglyceridemia group were lower than those in the control group(P < 0.05-0.001).There were significant differences in genotype and allele frequency between the HCH and normal group,the HTG group and the normal group(P < 0.05-0.001).The genotype and minimum allele frequency(MAF)of all mutation sites complied with the HardiWeinberg equilibrium(PHWE > 0.05).Carrier of rs4731702 and rs13241165 genotypes deceased the risk of HCH,while carrier of rs13226650 and rs3812316 genotypes increased the risk of hypertriglyceridemia(P < 0.05-0.001).In the HCH group,TC level was associated with rs13247874,rs4731702 and rs13241165,LDL-C was associated with rs13247874,TC and HDL was associated with rs4731702 and rs13241165,APOA1/Apo B was associated with rs17145470.In the hypertriglyceridemia group,TC was associated with rs13247874,rs4731702 and rs13241165.LDL-C was associated with rs13247874,HDL-C rs4731702 and rs13241165.TG was associated with rs13226650,rs3812316,rs13241538 and rs972283.APOA1/Apo B was associated with rs17145470.In the normal group,serum level of TC was associated with rs13247874,rs4731702 and rs13241165,and TG level was associated with rs3812316.Further analysis showed that the interaction between rs13226650 and alcohol consumption affected TG level,which was related to HTG.The interaction between rs13226650 and BMI affected the levels of TG and HDL-C.The interaction of rs13241165 with smoking affected the levels of TC and HDLC,which were related to HCH.The interaction of rs13241165 with alcohol consumption affected the level of HDL-C.The interaction between rs17145750 and BMI affected the level of Apo B(P < 0.0001).The interaction of SNPs and environmental exposure factors on HCH and HTG was analyzed.The interaction of rs13241165 with males,smoking and diabetes increased the risk of HCH respectively,while the interaction with alcohol consumption decreased the risk of HCH.The interaction of rs4731702 with males and smoking increased the risk of HCH,and the interaction with alcohol consumption decreased the risk of HCH.The interaction of rs13226650 and rs3812316 with BMI ≥ 24kg/m2,alcohol consumption and diabetes increased the risk of HTG(P < 0.001).In the linkage disequilibrium analysis of gene loci,there was statistical non-independence among the SNP detection sites.The most common haplotypes are MLXIPL C-TG-G,KLF14 T-G-T-G(> 30% of all samples),Haplotype carrier of KLF14 C-GA-A(T2),KLF14 C-C-T-A(T3)and KLF14 T-G-A-G(T6)showed significant differences between the HCH group and the normal group(P < 0.05),in which carriers of T2 and T3 increased the risk of HCH,respectively,while carriers of T6 had the opposite effect.The haplotypes MLXIPL C-C-A-C(B1)and MLXIPL C-T-G-G(B3)showed a significant difference between HTG and the normal group,in which the B1 carrier decreased the risk of HTG,while the B3 carrier had the opposite effect(P < 0.05).When gene-gene interactions were reanalyzed,the most common haplotype interaction frequency was C-T-G-G-T-C-T-A(>15% of all samples).Comparing the HCH group with normal group,There was a significant difference between the haplotypes of C-T-A-C-C-C-A-G,C-T-G-CT-C-T-A,C-T-G-G-T-C-T-A,T-C-A-G-C-C-T-A,T-C-G-G-C-C-A-G and T-CA-T-T-C-T-G(P < 0.001).Haplotypes of C-T-A-C-C-C-A-G and C-T-G-G-T-C-T-A decreased the risk of HCH,while carrying haplotypes of C-T-G-C-T-C-T-A and T-C-G-G-C-C-A-G increased the risk of HCH.The haplotype carrier of C-TA-C-C-G-A-A,C-T-G-C-T-C-T-A,T-C-G-G-C-C-A-G,T-C-A-G-T-G-A-A was a significant difference between the HTG and normal group(P < 0.05),In addition,haplotype carrier of C-T-G-C-C-T-A and T-C-G-G-C-C-A-G increased the risk of HTG,while carrying haplotype T-C-G-G-C-C-A-G and T-C-A-T-T-C-T-G decreased the risk of HTG.In the analysis of the haplotype and environmental exposure interactions of SNP-SNP,the interaction of MLXIPL C-T-G-G with BMI ≥ 24 kg/m2,alcohol consumption and BMI ≥ 24 kg/m2,it can increase the risk of HTG,respectively.Interaction of KLF14 C-C-T-A with males,smoking and diabetes increased the risk of HCH,respectively(P < 0.05-0.001).Among the interactions of haplotypes of gene-gene and environmental exposure factors,the interaction between haplotype C-T-G-C-T-C-T-A and age ≥ 60 years,smoking and diabetes mellitus increased the risk of HCH.The interaction of haplotype TC-G-G-C-C-A-G with BMI ≥ 24 kg/m2 and diabetes increased the risk of HTG.Conclusions: There were significant differences in BMI,TC,TG,(Apo A1/Apo B),HDL-C,Apo A1,type 2 diabetes and hypertension between the HCH and normal group.And there were also significant differences in BMI,alcohol consumption,TC,TG,Apo A1,type 2 diabetes and hypertension between the HTG and normal group.MLXIPL-KLF14 SNPs,different genotypes and allele frequencies were associated with the risk of HCH and HTG.The interactions among MLXIPL-KLF14 SNPs,haplotype,gene and environmental factors also influence the risk of HCH and HTG.In addition to genetic influences,environmental factors also play an important role in the HCH and HTG.And the interaction of SNPs,haplotypes and environmental factors also had an important effect on the risk of dyslipidemia.Background: Although many observational studies have shown an association between plasma homocysteine levels and cardiovascular diseases,controversy remains.Experimental studies can’t be conducted in humans due to medical ethics and other factors.Objectives: In this study,we estimated the role of increased plasma homocysteine levels on the etiology of coronary heart disease and acute myocardial infarction.Methods: A two-sample Mendelian randomization study on the disease was conducted,i.e.“coronary heart disease”(n=184,305)and “acute myocardial infarction”(n=181,875).Nine single nucleotide polymorphisms,which were genome-wide significantly associated with plasma homocysteine levels in 57,644 subjects from the Coronary Artery Disease Genome-wide Replication and Metaanalysis(CARDIo GRAM)plus The Coronary Artery Disease(C4D)Genetics(CARDIo GRAMplus C4D)consortium genome-wide association study and were known to be associated at P < 5×10–8,were used as an instrumental variable.Results: None of the nine single nucleotide polymorphisms were associated with coronary heart disease or acute myocardial infarction(P > 0.05 for all).Mendelian randomization analysis revealed no causal effects of plasma homocysteine levels,either on coronary heart disease(inverse variance weighted;Odds Ratio = 1.015,95% Confidence Interval = 0.923-1.106,P = 0.752)or on acute myocardial infarction(inverse variance weighted;Odds Ratio = 1.037,95%Confidence Interval = 0.932-1.142,P = 0.499).The results were consistent in sensitivity analyses using the Weighted median and Mendelian randomizationEgger methods,and no directional pleiotropy(P = 0.213 for coronary heart disease and P = 0.343 for acute myocardial infarction)was observed.Sensitivity analyses confirmed that plasma homocysteine levels were not significantly associated with coronary heart disease or acute myocardial infarction.Conclusions: The findings from this Mendelian randomization study indicate no causal relationship between plasma homocysteine levels and coronary heart disease or acute myocardial infarction.Conflicting findings from observational studies might have resulted from residual confounding or reverse causation. |
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