Dataset Information

ANGPTL4 variants and their haplotypes are associated with serum lipid levels, the risk of coronary artery disease and ischemic stroke and atorvastatin cholesterol-lowering responses.

ABSTRACT: Background:This study aimed to assess the association between the angiopoietin-like protein 4 gene (ANGPTL4) single nucleotide polymorphisms (SNPs) and serum lipid levels, the risk of coronary artery disease (CAD) and ischemic stroke (IS), and response to atorvastatin therapy in a Southern Chinese Han population. Methods:Genotypes of the ANGPTL4 rs4076317, rs7255436, rs1044250 and rs2967605 SNPs in 1,654 unrelated subjects (CAD, 568; IS, 537; and controls, 549) were determined by the Snapshot technology. Another group of 724 hyperlipidemic patients was selected and treated with atorvastatin calcium tablet 20 mg/day for 8 weeks. Results:The rs2967605 CT/TT genotypes were associated with a decreased risk of CAD (adjusted OR = 0.68, 95% CI = 0.47-0.99, P = 0.043 for CT/TT vs. CC) and IS (adjusted OR = 0.55, 95% CI = 0.38-0.80, P = 0.020 for CT/TT vs. CC). There was no significant association between the four SNPs and angiographic severity of CAD. The subjects with the rs4076317 CG/CC genotypes in controls had higher total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels than the subjects with the GG genotype (P < 0.001; a P < 0.0018 was regarded statistically significant by the Bonferroni correction). The subjects with rs4076317CG/GG genotypes had lower TC and LDL-C levels than the subjects with CC genotype after atorvastatin treatment (P < 0.001). Conclusions:The observed associations suggest that the ANGPTL4 variants have a potential role on serum lipid levels and atherosclerosis-related diseases in the Chinese Han population, especially the ANGPTL4 rs4076317 and rs2967605 SNPs.

SUBMITTER: Yang Q

PROVIDER: S-EPMC6173870 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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<i>ANGPTL4</i> variants and their haplotypes are associated with serum lipid levels, the risk of coronary artery disease and ischemic stroke and atorvastatin cholesterol-lowering responses.

Yang Qian Q Yin Rui-Xing RX Cao Xiao-Li XL Huang Feng F Zhou Yi-Jiang YJ Chen Wu-Xian WX

Nutrition & metabolism 20181005

<h4>Background</h4>This study aimed to assess the association between the angiopoietin-like protein 4 gene (<i>ANGPTL4</i>) single nucleotide polymorphisms (SNPs) and serum lipid levels, the risk of coronary artery disease (CAD) and ischemic stroke (IS), and response to atorvastatin therapy in a Southern Chinese Han population.<h4>Methods</h4>Genotypes of the <i>ANGPTL4</i> rs4076317, rs7255436, rs1044250 and rs2967605 SNPs in 1,654 unrelated subjects (CAD, 568; IS, 537; and controls, 549) were ...[more]

PMID: 30323852

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Project description:Previous genome-wide association studies have showed that the rs12670798 variant in the dynein axonemal heavy chain 11 gene (DNAH11) is associated with some serum lipid phenotypes. The present study was undertaken to detect the DNAH11 rs12670798 variant and G × E interactions on serum lipid levels, coronary heart disease (CHD), ischemic stroke (IS), and the lipid-lowering efficacy of atorvastatin in the Chinese Han population. This study included 1,108 unrelated patients (CHD, 568 and IS, 540) and 541 healthy controls. Genotypes of the DNAH11 rs12670798 were determined by the Snapshot technology. A total of 724 hyperlipidemic patients were treated with atorvastatin calcium tablet 20 mg per day for 8 weeks after genotyping. Serum total cholesterol (TC) levels in controls were different among the three genotypes of the rs12670798 (P = 0.019), the C allele carriers had higher TC levels than the C allele non-carriers. The C allele carriers were associated with an increased risk of CHD (CT genotype: OR = 1.345, 95% CI = 0.975-1.855, P = 0.071; CC genotype: OR = 1.590, 95% CI = 1.109-2.278, P = 0.012). The C allele carriers were also associated with an increased risk of IS (CT genotype: OR = 1.597, 95% CI = 1.153-2.213, P = 0.005; CC genotype: OR = 1.722, 95% CI = 1.192-2.488, P = 0.004). The C allele carriers had lower TC, low-density lipoprotein cholesterol, apolipoprotein (Apo) A1 and ApoB levels than the C allele non-carriers after atorvastatin treatment. Stratified analysis showed that the DNAH11 rs12670798 may interact with the gender, age, body mass index, cigarette smoking, and alcohol consumption to affect the risk of CHD and IS. The DNAH11 rs12670798 variant was associated with elevated serum TC levels, and increased risk of CHD and IS in the Chinese Han population. The C allele carriers had higher serum TC levels and the risk of CHD and IS than the C allele non-carriers, but they had lower TC, LDL-C, ApoA1 and ApoB levels than the C allele non-carriers after atorvastatin treatment.

Project description:BackgroundLittle is known about the association of the dedicator of cytokinesis 7 (DOCK7 rs1748195) and angiopoietin like 3 (ANGPTL3 rs12563308) single nucleotide polymorphisms (SNPs) and their haplotypes with serum lipid levels and the risk of coronary artery disease (CAD) and ischemic stroke (IS) in the Chinese populations. This study aimed to detect such association in a Southern Chinese Han population.MethodsThis study included 1728 subjects (CAD, 568; IS, 539; and controls, 621). Genotypes of the two SNPs were determined by the Snapshot technology.ResultsThe genotypic and allelic frequencies of the rs1748195 SNP were different between CAD patients and controls (P < 0.05 for each), the rs1748195G allele frequency was higher in CAD patients than in controls (27.6% vs. 23.6%, P = 0.024). The genotypic frequencies of the rs12563308 SNP were also different between CAD patients and controls (P = 0.021). The rs1748195 SNP was associated with an increased risk of CAD after controlling for potential confounders and Bonferroni correction (P < 0.025 considered statistically significant; Recessive: OR = 1.79, 95% CI = 1.04-3.06, P = 0.017; Log-additive: OR = 1.27, 95% CI = 1.02-1.57, P = 0.014), whereas the rs12563308 SNP was associated with a decreased risk of CAD (Dominant: OR = 0.69, 95% CI = 0.45-0.94, P = 0.011; Log-additive: OR = 0.73, 95% CI = 0.49-0.89, P = 0.009). The rs1748195 SNP was also associated with an increased risk of severity to coronary artery atherosclerosis (Dominant: OR = 1.45, 95% CI = 1.07-2.11, P = 0.017; Log-additive: OR = 1.35, 95% CI = 1.09-1.82, P = 0.013). The interactions of SNP-environment on serum lipid levels and the risk of severity to coronary artery atherosclerosis, CAD and IS were noted. The rs1748195G-rs12563308T haplotype was associated with an increased angiographic severity to coronary artery atherosclerosis (OR = 1.46, 95% CI = 1.05-2.03), and the risk of CAD (OR = 1.37, 95% CI = 1.08-1.74). The interactions of haplotype-hypertension on the risk of CAD and haplotype-drinking on the risk of CAD/IS were observed.ConclusionsThese results suggest that the DOCK-ANGPTL3 SNPs and their haplotypes were associated with the angiographic severity to coronary artery atherosclerosis and the risk of CAD and IS in the Southern Chinese Han population.

Project description:BackgroundZhibitai, a natural lipid-lowering Chinese medicine, is well tolerated in patients and has low incidence of adverse events. In this study, we evaluated the efficacy, safety, and side effects of Zhibitai in combination with low dose Atorvastatin compared to high dose Atorvastatin in patients with coronary heart disease or at high risk of coronary heart disease.MethodsThis was a randomized, double-blind, multi-center clinical trial on 720 patients with coronary heart disease or at high risk of coronary heart disease. The patients were randomly assigned to a Zhibitai-Atorvastatin group (480 mg Zhibitai twice daily plus 10 mg atorvastatin once daily) or Monotherapy group (40 mg Atorvastatin once daily). Blood samples were obtained at baseline, week 4, and week 8 after a minimum 8-hour fast. Efficacy was evaluated in terms of the changes in the following parameters: lipoprotein profiles [total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C)]. Safety was assessed throughout the study by clinical laboratory tests including liver function [alanine transaminase, aspartate transaminase] and renal function [blood urea nitrogen], and creatine kinase; physical examination; and adverse events monitoring.ResultsTC, TG, LDL-C levels were significantly decreased andHDL-C levels were significantly increased at week 4 and week 8 (all P < 0.05) in both groups but had no significant differences between the two groups (P > 0.05). In subgroup analyses, Zhibitai-Atorvastatin Group produced significantly greater reduction in TG compared with Monotherapy Group at week 8 in patients with TG > 203.72mg/dL (P < 0.01). Among patients with LDL-C levels > 131.48 mg/dL, Zhibitai-Atorvastatin Group produced a greater reduction of LDL-C levels compared with the Monotherapy Group at week 4 (P < 0.05). The incidence of liver dysfunction, headache, or gastrointestinal intolerance was significantly lower in the Zhibitai-Atorvastatin Group compared with Monotherapy Group during the 8-week study peroid (P < 0.001). There were no significant differences in renal function, myopathy, and other adverse events between the groups.ConclusionOverall the two groups have similar lipid regulation efficacy. Zhibitai plus low dose Atorvastatin is more efficacious in lowering TG in patients with TG > 203.72 mg/dL at week 8. There are fewer side effects in Zhibitai plus low dose Atorvastatin group. Long term follow up is required to evaluate cardiovascular outcomes.

Project description:Higher-than-normal levels of circulating triglycerides are a risk factor for ischemic cardiovascular disease. Activation of lipoprotein lipase, an enzyme that is inhibited by angiopoietin-like 4 (ANGPTL4), has been shown to reduce levels of circulating triglycerides.We sequenced the exons of ANGPTL4 in samples obtain from 42,930 participants of predominantly European ancestry in the DiscovEHR human genetics study. We performed tests of association between lipid levels and the missense E40K variant (which has been associated with reduced plasma triglyceride levels) and other inactivating mutations. We then tested for associations between coronary artery disease and the E40K variant and other inactivating mutations in 10,552 participants with coronary artery disease and 29,223 controls. We also tested the effect of a human monoclonal antibody against ANGPTL4 on lipid levels in mice and monkeys.We identified 1661 heterozygotes and 17 homozygotes for the E40K variant and 75 participants who had 13 other monoallelic inactivating mutations in ANGPTL4. The levels of triglycerides were 13% lower and the levels of high-density lipoprotein (HDL) cholesterol were 7% higher among carriers of the E40K variant than among noncarriers. Carriers of the E40K variant were also significantly less likely than noncarriers to have coronary artery disease (odds ratio, 0.81; 95% confidence interval, 0.70 to 0.92; P=0.002). K40 homozygotes had markedly lower levels of triglycerides and higher levels of HDL cholesterol than did heterozygotes. Carriers of other inactivating mutations also had lower triglyceride levels and higher HDL cholesterol levels and were less likely to have coronary artery disease than were noncarriers. Monoclonal antibody inhibition of Angptl4 in mice and monkeys reduced triglyceride levels.Carriers of E40K and other inactivating mutations in ANGPTL4 had lower levels of triglycerides and a lower risk of coronary artery disease than did noncarriers. The inhibition of Angptl4 in mice and monkeys also resulted in corresponding reductions in these values. (Funded by Regeneron Pharmaceuticals.).

Dataset Information

ANGPTL4 variants and their haplotypes are associated with serum lipid levels, the risk of coronary artery disease and ischemic stroke and atorvastatin cholesterol-lowering responses.

Publications

<i>ANGPTL4</i> variants and their haplotypes are associated with serum lipid levels, the risk of coronary artery disease and ischemic stroke and atorvastatin cholesterol-lowering responses.

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