Associations between plasma lipid parameters and APOC3 and APOA4 genotypes in a healthy population are independent of dietary cholesterol intake

doi:10.1016/j.atherosclerosis.2005.03.023

Atherosclerosis

Volume 184, Issue 1, January 2006, Pages 113-120

https://doi.org/10.1016/j.atherosclerosis.2005.03.023 Get rights and content

Abstract

To determine whether APOC3 and APOA4 genotypes influence plasma cholesterol fluctuations following a high cholesterol diet, a healthy population of 40 men and 51 women were studied. The crossover intervention randomly assigned participants to an EGG (640 mg/d cholesterol) or placebo (0 mg/d cholesterol) diet for 30 days, with a 3-week washout between periods. Allele-specific oligonucleotide hybridization was utilized to determine the presence or absence of APOC3 and APOA4 polymorphisms. Differences in plasma cholesterol between hyper- and hypo-responders were not influenced by genotype. However, an interaction (P < 0.0001) did exist between APOA4 allele, diet and gender with regard to triglycerides (TG). While female carriers of the APOA4³⁴⁷ S allele had lower TG concentrations than those with the common T/T allele, males with the S allele had higher concentrations. The APOC3 SstI polymorphism analysis revealed that heterozygous carriers of the S2 allele had higher (P < 0.05) plasma apo C-III and TG concentrations, regardless of gender or dietary period. In addition, carriers of the S2 allele had smaller LDL peak particle diameter than those having the common APOC3 genotype.

The presence of individual alleles in this population was associated with differences in plasma lipids and LDL size. However, these relationships were independent of dietary cholesterol.

Introduction

The approach of the nutrition community has been to provide general dietary guidelines aimed at decreasing the incidence of coronary heart disease (CHD) through normalizing plasma lipoprotein concentrations. One of these recommendations has been to limit intake of high cholesterol foods, such as eggs, in an attempt to reduce plasma total cholesterol (TC) and LDL cholesterol (LDL-C) concentrations. However, extensive research does not support a consistent relationship between egg intake and CHD incidence. In part, this could be due to the fact that individuals do not experience a homogeneous response to cholesterol consumption. Therefore, it is difficult to predict the impact of cholesterol intake on plasma lipoproteins and cardiovascular risk at the individual level.

Inter-individual variation in response to diet can be attributed in part to factors, such as gender, age, ethnicity, hormonal status and obesity. However, this variation also has a significant genetic component, mediated in part by candidate genes involved in lipoprotein metabolism. The presence of a variant allele may influence the metabolism of nutrients in a way that deviates from classical understanding. This alteration in metabolism may further impact the regulation of additional genes that play a role in chronic disease progression.

Polymorphisms at candidate genes for lipoprotein metabolism have been extensively investigated for their potential use as markers for disease risk. Moreover, some of these polymorphisms have been further examined for possible gene–diet interactions [1]. For example APOC3 and APOA4 are two apolipoprotein candidate genes that are commonly studied under these conditions.

The APOC3 gene, located on chromosome 11q23, is highly polymorphic [2]. One single nucleotide polymorphism (SNP) (C → G) at nucleotide 3238 in the 3′ untranslated region of the APOC3 gene has been identified as the SstI polymorphism, which results in a guanine for cytosine substitution and produces two alleles: APOC3*S1 and APOC3*S2 [3]. The S2 allele, which has a frequency of 0.08–0.21 in Caucasians [4], has been previously associated with elevated plasma triglycerides (TG), TC and apo C-III concentrations as well as high blood pressure [5]. Furthermore, the SstI polymorphism has been implicated by several studies as having a role in the plasma lipid response to dietary intake [4], [6], [7] and has been reported to be associated with hypertriglyceridemia in viscerally obese men [8].

The APOA4 gene is also located on chromosome 11q23 and has a SNP (G → T) at residue 360, which results in a glutamine to histidine substitution [9]. The presence of the APOA4³⁶⁰ variant genotype (1/2), which has a frequency of 0.08 in Caucasians, has been shown to attenuate the LDL-C response to dietary cholesterol consumption [10]. In contrast, other studies have suggested that carriers of the APOA4³⁶⁰ 2 allele may be more likely to develop an atherogenic lipoprotein profile in response to elevated saturated fat consumption [11]. Those who are identified as having the common APOA4³⁶⁰ (1/1) genotype may possess an additional APOA4³⁴⁷ polymorphism (A → T), which is characterized by a threonine to serine substitution at residue 347 [12]. Various studies have shown that individuals who are homozygous for the rare APOA4³⁴⁷ S allele (S/S) may have lower concentrations of TC, LDL-C and TG; however, these results are controversial and have been contradicted by other studies [13].

The objective of the present study was to determine whether polymorphisms at the APOC3 or APOA4 genes play a significant role in the variation in plasma lipid response to dietary cholesterol consumption previously seen in a population of healthy men and women [14], [15].

Section snippets

Materials and methods

Liquid pasteurized whole eggs and cholesterol-free/fat-free eggs (placebo) were purchased from Better Brands Inc. (Windsor, CT, USA). Enzymatic TC and TG kits were obtained from Roche-Diagnostics (Indianapolis, IN, USA). Aprotonin, sodium azide and phenyl methyl sulfonyl fluoride (PMSF) were obtained from Sigma Chemical (St. Louis, MO, USA). Malonaldehyde bis (diethyl acetal) was obtained from Aldrich (Arlington Heights, IL, USA).

Results

Characteristics of subjects including body mass index, age, systolic- and diastolic blood pressure are presented in Table 1. Participants maintained their body weight during the entire length of the study. Baseline values for plasma total cholesterol (TC), LDL-C, triglycerides (TG) and HDL-C are also presented in Table 1. For this study population, women had higher plasma TC (P < 0.05) and higher HDL-C concentrations (P < 0.001) than men. In contrast, men had higher plasma TG than women (P < 0.05).

Discussion

The APOA4 protein is synthesized primarily by the intestine and may play a role in chylomicron (CM) production [20]. In the circulation, APOA4 is also associated with other TG-rich lipoproteins and HDL particles. APOA4 functions in the reverse cholesterol transport pathway as an activator of LCAT [21] and might also be a ligand for the HDL receptor [22]. APOA4 also influences TG metabolism by mediating the transfer of APOC2 from HDL to CM [23], enhancing the activation of LPL. Because of its

Acknowledgements

This work was supported by the American Egg Board. KLH is the 2002 recipient of the American Egg Board Egg Nutrition Center Dissertation Fellowship in Nutrition.

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To accomplish, this preliminary study brought the information on the ApoA4 polymorphism in the Asian Indians residing in Delhi and adjacent areas. The minor alleles of the Ser347 and His360 showed significant association with lipid risk factors like high levels of OXLDL, TC, and low HDL levels. However neither of these polymorphisms showed an association with CAD.
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Associations between plasma lipid parameters and APOC3 and APOA4 genotypes in a healthy population are independent of dietary cholesterol intake

Abstract

Introduction

Section snippets

Materials and methods

Results

Discussion

Acknowledgements

Am J Clin Nutr

Atherosclerosis

Am J Clin Nutr

J. Lipid Res

J Nutr

J Biol Chem

J Biol Chem

J Biol Chem

Atherosclerosis

J Biol Chem

J Lipid Res

J Lipid Res

Influence of genetic polymorphisms on responsiveness to dietary fat and cholesterol

Am J Clin Nutr

Apo C-III gene polymorphisms and risk for coronary artery disease

J Lipid Res

An apolipoprotein CIII haplotype protective against hypertriglyceridemia is specified by promoter and 3′ untranslated region polymorphisms

Proc Natl Acad Sci

Apo C-III gene variants modulate post-parandial response to both glucose and fat tolerance tests

Circulation

Genetic polymorphisms of human plasma apolipoprotein A-IV is due to nucleotide substitutions in the apolipoprotein A-IV gene

J Biol Chem