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

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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.

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Most cited references 38

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Effect of body mass index on all-cause mortality and incidence of cardiovascular diseases--report for meta-analysis of prospective studies open optimal cut-off points of body mass index in Chinese adults.

Bei-Fan Zhou (2002)

To verify the optimal cut-off points for overweight and obesity in Chinese adults based on the relationship of baseline body mass index (BMI) to all-cause mortality, and incidence of cardiovascular diseases from pooled data of Chinese cohorts. The prospective study data of existing cohort studies in China were collected, and the age-adjusted all-cause mortality stratified by BMI were estimated. The similar analysis was repeated after excluding deaths within the first three years of follow-up and after excluding smokers. The incidence of age-adjusted coronary heart disease (CHD) and stroke stratified by BMI were also analyzed. Multiple Cox regression coefficients of BMI for the incidence of CHD and stroke after controlling other risk factors were pooled utilizing the methods of weighting by inverse of variance to reveal whether BMI had independent effect and its strength on the incidence of CHD and stroke. The data of 4 cohorts including 76,227 persons, with 745,346 person-years of follow-up were collected and analyzed. The age-adjusted all-cause mortality stratified by BMI showed a U-shaped curve, even after excluding deaths within the first three years of follow-up and excluding smokers. Age-adjusted all-cause mortality increased when BMI was lower than 18.5 and higher than 28. The incidence of CHD and stroke, especially ishemic stroke increased with increasing BMI, this was consistent with parallel increasing of risk factors. Cox regression analysis showed that BMI was an independent risk factor for both CHD and stroke. Each amount of 2 kg/m2 increase in baseline BMI might cause 15.4%, 6.1% and 18.8% increase in relative risk of CHD, total stroke and ischemic stroke. Reduction of BMI to under 24 might prevent the incidence of CHD by 11% and that of stroke by 15% for men, and 22% of both diseases for women. BMI or = 28 (kg/m2) is the appropriate cut-off points for underweight, overweight and obesity in Chinese adults.

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Scavenger receptors in atherosclerosis: beyond lipid uptake.

James Freeman, Jill J Ranger (2006)

Atherosclerotic vascular disease arises as a consequence of the deposition and retention of serum lipoproteins in the artery wall. Macrophages in lesions have been shown to express > or = 6 structurally different scavenger receptors for uptake of modified forms of low-density lipoproteins (LDLs) that promote the cellular accumulation of cholesterol. Because cholesterol-laden macrophage foam cells are the primary component of the fatty streak, the earliest atherosclerotic lesion, lipid uptake by these pathways has long been considered a requisite and initiating event in the pathogenesis of atherosclerosis. Although the removal of proinflammatory modified LDLs from the artery wall via scavenger receptors would seem beneficial, the pathways distal to scavenger receptor uptake that metabolize the modified lipoproteins appear to become overwhelmed, leading to the accumulation of cholesterol-laden macrophages and establishment of a chronic inflammatory setting. These observations have led to the current dogma concerning scavenger receptors, which is that they are proatherogenic molecules. However, recent studies suggest that the effects of scavenger receptors on atherogenesis may be more complex. In addition to modified lipoprotein uptake, these proteins are now known to regulate apoptotic cell clearance, initiate signal transduction, and serve as pattern recognition receptors for pathogens, activities that may contribute both to proinflammatory and anti-inflammatory forces regulating atherogenesis. In this review, we focus on recent advances in our knowledge of scavenger receptor regulation and signal transduction, their roles in sterile inflammation and infection, and the potential impact of these pathways in regulating the balance of lipid accumulation and inflammation in the artery wall.

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Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia.

Christopher Johansen, Jian Wang, Matthew Lanktree … (2010)

Genome-wide association studies (GWAS) have identified multiple loci associated with plasma lipid concentrations. Common variants at these loci together explain <10% of variation in each lipid trait. Rare variants with large individual effects may also contribute to the heritability of lipid traits; however, the extent to which rare variants affect lipid phenotypes remains to be determined. Here we show an accumulation of rare variants, or a mutation skew, in GWAS-identified genes in individuals with hypertriglyceridemia (HTG). Through GWAS, we identified common variants in APOA5, GCKR, LPL and APOB associated with HTG. Resequencing of these genes revealed a significant burden of 154 rare missense or nonsense variants in 438 individuals with HTG, compared to 53 variants in 327 controls (P = 6.2 x 10(-8)), corresponding to a carrier frequency of 28.1% of affected individuals and 15.3% of controls (P = 2.6 x 10(-5)). Considering rare variants in these genes incrementally increased the proportion of genetic variation contributing to HTG.

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Author and article information

Contributors

Qian Yang: yangqer@163.com

Rui-Xing Yin:

ORCID: http://orcid.org/0000-0001-7883-4310

yinruixing@163.com

Xiao-Li Cao: maten1996@gmail.com

Feng Huang: huangfeng3000@126.com

Yi-Jiang Zhou: today781118@163.com

Wu-Xian Chen: nncwx@163.com

Journal

Journal ID (nlm-ta): Nutr Metab (Lond)

Journal ID (iso-abbrev): Nutr Metab (Lond)

Title: Nutrition & Metabolism

Publisher: BioMed Central (London )

ISSN (Electronic): 1743-7075

Publication date (Electronic): 5 October 2018

Publication date PMC-release: 5 October 2018

Publication date Collection: 2018

Volume: 15

Electronic Location Identifier: 70

Affiliations

[1 ]GRID grid.412594.f, Department of Cardiology, Institute of Cardiovascular Diseases, , the First Affiliated Hospital, Guangxi Medical University, ; Nanning, 530021 Guangxi People’s Republic of China

[2 ]GRID grid.412594.f, Department of Neurology, , the First Affiliated Hospital, Guangxi Medical University, ; Nanning, 530021 Guangxi People’s Republic of China

Author information

Rui-Xing Yin http://orcid.org/0000-0001-7883-4310

Article

Publisher ID: 308

DOI: 10.1186/s12986-018-0308-5

PMC ID: 6173870

SO-VID: f29612d6-b3c5-497a-a9c8-d3de04efd7c8

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 1 May 2018

Date accepted : 26 September 2018

Funding

Funded by: the Science Foundation of Guangxi Returned Oversea Scholars

Award ID: 0991004

Award Recipient : Rui-Xing Yin

Funded by: the National Natural Science Foundation of China

Award ID: 81460169

Award Recipient : Rui-Xing Yin

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ScienceOpen disciplines: Nutrition & Dietetics

Keywords: angiopoietin-like protein 4 gene,single nucleotide polymorphism,coronary artery disease,ischemic stroke,lipids,atorvastatin

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ScienceOpen disciplines: Nutrition & Dietetics

Keywords: angiopoietin-like protein 4 gene, single nucleotide polymorphism, coronary artery disease, ischemic stroke, lipids, atorvastatin

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

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Most cited references 38

Effect of body mass index on all-cause mortality and incidence of cardiovascular diseases--report for meta-analysis of prospective studies open optimal cut-off points of body mass index in Chinese adults.

Scavenger receptors in atherosclerosis: beyond lipid uptake.

Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia.

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