Apolipoprotein E genotype and the cardiovascular disease risk phenotype: Impact of sex and adiposity (the FINGEN study)

doi:10.1016/j.atherosclerosis.2012.01.042

Atherosclerosis

Volume 221, Issue 2, April 2012, Pages 467-470

https://doi.org/10.1016/j.atherosclerosis.2012.01.042 Get rights and content

Abstract

Here the impact of APOE genotype on CHD risk in UK adults is reported, along with an analysis of APOE genotype × BMI/age/sex interactions.

APOE genotype had a significant impact on fasting total:LDL-cholesterol (TC:LDL-C) ratio, triglycerides, % HDL3, and the Framingham 10-year CVD risk score (P < 0.05), with an overall trend towards lower and higher risk in E2- and E4-carriers, respectively, relative to the wild-type E3/E3 genotype. A greater impact of genotype on TC:HDL-C was observed in females, which explained 16% of the variability in this outcome versus 6% in males. APOE genotype was also associated with plasma C-reactive protein and adhesion molecule concentrations (P < 0.05), with significant genotype × BMI interactions observed.

Our observations indicate that the association between the APOE genotype and CHD risk is unlikely to be homogenous and highlights the risk of inaccurate estimations of genotype–phenotype associations in population subgroups without appropriate stratification for sex and adiposity.

Introduction

The APOE epsilon genotype is a prevalent genetic risk factor for coronary heart disease (CHD). Numerous studies summarised in three meta-analyses [1], [2], [3], indicate an odds ratio (OR) of CHD in the general population of 1.0–1.5 in carriers of the E4 allele (25% of Caucasian populations) relative to the wild type E3/E3 genotype, which is exacerbated (>2 fold higher) in those in a pro-inflammatory state, such as smokers [4].

The aetiological basis of the association is poorly understood but is often attributed to higher concentrations of LDL-cholesterol (LDL-C) in E4 carriers. However, it appears unlikely that the modestly higher LDL-C concentrations (0.10–0.15 mmol/l, equivalent to a 3% higher concentrations amongst UK males), can explain the reported differential in CHD risk. Furthermore the observation that macrophage APOE expression in APOE-null mice inhibits atherosclerosis, but has little effect on plasma lipid concentrations [5], provides evidence of a lipid-independent impact of apoE on CHD pathology.

In addition to its role in lipoprotein metabolism, apoE is immuno-modulatory and anti-inflammatory. Although studies in transgenic animals and macrophages have indicated that APOE genotype modulates inflammation and associated regulatory cell signalling pathways [6], its impact on inflammation in humans is unknown.

Here we report on the impact of APOE genotype on established and novel lipid and inflammatory CHD biomarkers in healthy UK adults (participants in the FINGEN study). Furthermore we examine the impact of physiological variables, including sex, age and adiposity, on APOE genotype × biomarker associations.

Section snippets

Materials and methods

The baseline data from the FINGEN cohort [7] are used in the current analysis. A particular strength of this medium sized cohort is that volunteers were recruited prospectively on the basis of APOE genotype, age and sex which greatly strengthens the power of the study to examine the interaction of genotype with these potential physiological determinants, compared with an analysis of randomly recruited participants. The study was approved by the local research ethics committees (LREC) and all

Data and statistical analysis

The independent effects of genotype, and genotype × sex, genotype × age, and genotype × BMI interactions on the biochemical variables were determined using general linear modelling (SPSS Version 15 Chicago, USA). For variables where sex × genotype interactions emerged, regression analysis was used to estimate the relative contribution of genotype to the dependent variables in males and females separately.

To predict how the effect of genotype would translate into cardiovascular disease (CVD) risk

Results

No genotype × age interactions were evident for any of the outcomes measures. APOE genotype influenced TC (P < 0.001) and LDL-C (P < 0.001), with 8% and 16% lower concentrations in the E2 group relative to the wild-type E3/E3 (Table 1). APOE genotype also affected HDL-C with concentrations of 1.53, 1.42, and 1.38 mmol/L, in the E2, E3 and E4 groups, respectively (P = 0.035). These genotype effects on TC and HDL-C were reflected in the TC:HDL-C and apoB:apoA1 ratios, (P < 0.001). The concentration of

Discussion

The principal findings of the current study are three-fold. Firstly, the data indicate that, in addition to LDL-C, there is an impact of APOE genotype on other lipid fractions (viz. HDL-C, TC:HDL-C and TG), lipoprotein size and apolipoprotein concentrations, particularly in women. Secondly APOE genotype influences the inflammatory profile in humans. Thirdly, the impact of APOE genotype on the CHD risk phenotype is dependent on adiposity.

Based on the Framingham Offspring Cohort data [10], the

Conflict of interest statement

CMW is a consultant to Pepsico UK. PCC is a consultant to Danone Research Centre for Specialized Nutrition, has received speaking fees from Solvay Healthcare, Solvay Pharmaceuticals, Abbot Nutrition, B. Braun Melsungen, Fresenius Kabi and Nestle and has research funded by Vifor Pharma. AMM has a number of ongoing projects with Unilever Plc. All others authors have no specific conflicts of interest to report.

Acknowledgements

The authors thank Dorothy Bedford, Josephine Cooney, Christine Gourlay, Elaine McDonald, Elizabeth Murray, Grace Stewart, May Stewart, Philip Stewart, Elli Vastardi and Jan Luff for technical assistance, and all study participants. This research was supported by an award from the Food Standards Agency, UK (RRD7/N02/A).

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Short communicationApolipoprotein E genotype and the cardiovascular disease risk phenotype: Impact of sex and adiposity (the FINGEN study)

Abstract

Introduction

Section snippets

Materials and methods

Data and statistical analysis

Results

Discussion

Conflict of interest statement

Acknowledgements

Lancet

Biochem Biophys Res Commun

Am J Clin Nutr

Am Heart J

J Am Coll Cardiol

J Lipid Res

Association of apolipoprotein E genotypes with lipid levels and coronary risk

JAMA

Short communication
Apolipoprotein E genotype and the cardiovascular disease risk phenotype: Impact of sex and adiposity (the FINGEN study)