REVISIÓN

 

Genetic variation of apolipoproteins, diet and other environmental interactions; an updated review

Variaciones genéticas de las apolipoproteínas y su interacción con componentes de la dieta y otros factores ambientales; una revisión actualizada

 

 

Mercedes Sotos-Prieto and José Luis Peñalvo

Area of Epidemiology and Population Genetics. Centro Nacional de Investigaciones Cardiovasculares (CNIC). Madrid. Spain.

Correspondence

 

 

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ABSTRACT

This paper summarizes the recent findings from studies investigating the potential environmental modulation of the genetic variation of apolipoprotein genes on metabolic traits. We reviewed nutrigenetic studies evaluating variations on apolipoproteins-related genes and its associated response to nutrients (mostly dietary fatty acids) or any other dietary or environmental component. Most revised research studied single nucleotide polymorphism (SNP) and specific nutrients through small intervention studies, and only few interactions have been replicated in large and independent populations (as in the case of -265T > C SNP in APOA2 gene). Although current knowledge shows that variations on apolipoprotein genes may contribute to the different response on metabolic traits due to dietary interventions, evidence is still scarce and results are inconsistent. Success in this area will require going beyond the limitations of current experimental designs and explore the hypotheses within large populations. Some of these limitations are being covered by the rapidly advance in high-throughput technologies and large scale-genome wide association studies.

Key words: Apolipoprotein. Gene-diet interaction. Environment. Nutrigenetics. Dietary interventions.

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RESUMEN

Este artículo resume los hallazgos recientes de estudios que investigan la potencial modulación, por parte de factores ambientales, del riesgo metabólico asociado a determinadas variantes genéticas de apolipoproteínas. Se han revisado estudios nutrigenéticos que evalúan variaciones en genes relacionados con apolipoproteínas y su asociación en respuesta a la ingesta de nutrientes (frecuentemente ácidos grasos) o cualquier otro componente de la dieta o del medio ambiente. La mayoría de la bibliografía revisada se centra en polimorfismos de un solo nucléotido (SNP) y nutrientes específicos a través de estudios de intervención de pequeña escala y pocas interacciones han sido replicadas en poblaciones independientes y de gran tamaño (como en el caso del SNP-265T > C en el gen APOA2). Aunque el conocimiento actual indica que ciertas variaciones genéticas de las apolipoproteínas pueden contribuir a la diferente respuesta sobre determinados factores metabólicos debido a las intervenciones dietéticas, la evidencia es todavía escasa y los resultados son inconsistentes. El éxito en esta área requiere superar las limitaciones de los diseños experimentales actuales y explorar estas hipótesis en poblaciones más amplias aprovechando el rápido avance de las tecnologías de alto rendimiento y la disponibilidad de datos del genoma completo.

Palabras clave: Apolipoproteína. Interacción gen-dieta. Ambiente. Intervenciones dietéticas.

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Introduction

Cardiovascular disease (CVD) is the leading cause of death worldwide, and its multifactorial etiology involves both genetic and environmental causes. Among environmental (or modifiable) causes, smoking, sedentary behaviors, and inadequate dietary habits, explain partially the high prevalence of intermediate CVD risk phenotypes (hypercholesterolemia, excess of body weight, hypertension, etc.).¹ Nowadays, however, and ever since the sequencing of the human genome, modern cardiovascular epidemiology also incorporates the genetic component of the disease aiming to integrate CVD genetic and environmental determinants.

As markers of CVD risk, lipoprotein concentrations are directly associated with environmental variables such as diet, and lifestyle in general, but genetics also play a significant role in modulating this association.

Several polymorphisms in genes encoding proteins related to lipid metabolism and etiologic factors of CVD have been found to increase CVD risk.^2,3 Although there are a number of genes associated with CVD, the apolipoprotein (APO) loci (APOA1, APOA2, APOA4, APOC3, APOA5, APOB, APOE) are perhaps one of the best studied genetic variables because of its relevance to CVD in relation to dietary habits.³

The impact of single nucleotide polymorphisms (SNP) on CVD risk and the ability of environmental components to modulate genotype-phenotype associations is being increasingly recognized. Among environmental components, nutrients, and specifically fatty acids have been widely studied given the fact that dietary fat composition (quality and quantity) plays an important role in metabolic factors, including a marked effect on lipoproteins.^4-6 Most current efforts are directed to understand these complex interactions in what have been called nutrigenetic studies. The ultimate goal of this research area is to tailor preventive recommendations, even treatments, based on individual genetic backgrounds. In order to achieve this, sound scientific evidence including replication studies, analyzing gene-environment interactions in large and varied populations is needed.

The number of scientific papers published on this field of research has increased considerably in the last few years. Given the fact that APO has been one of the most studied genes regarding lipid metabolism and dietary interventions, this paper aims to update the current knowledge on this topic by summarizing a selection of the literature that investigates the potential environmental modulation (not only diet but other components as well) of the genetic variation of APO genes on metabolic traits to summarize the scientific evidence available to provide personalized recommendations.

 

Genetic variation of apolipoproteins, cardiovascular risk phenotypes and environmental modulation

From table I to table VII, we present landmark studies as well as a selection of recent investigations on the APO gene-environment interaction on metabolic traits phenotypes, focusing on the genetic variation of APOA1, APOA4, APOCIII, APOA2, APOA5, APOB and APOE genes in relation to dietary interventions.

Apolipoprotein A1 (APOA1)

APOA1 is the major protein of HDL-C, a cofactor of lecithin-cholesterol acyltransferase (LCAT) and has a key role in the reverse cholesterol transport process.⁷ Genetic variation in this gene has been associated with premature coronary atherosclerosis.⁸ The most studied variant in this gene is -75 G > A, reported to be associated with HDL-C concentrations.^2,9,10

Most of the studies analyzed dietary interactions (table I), and only one analyzed training exercise as part of environmental modulation.¹¹ Data support that in dietary intervention studies using polyunsaturated fatty acids (PUFA) supplementation in normolipidaemic subjects, the A allele-carriers of the-75 G > A polymorphism appear to be associated with hyper-response to changes in the amount of fatty acids as well as high carbohydrate intake.^12-14 Interestingly, women carrying the A variant, but no men, seem to be more susceptible to dietary fatty acids changes and high carbohydrate diet.^12,14,15

Apolipoprotein A4 (APOA4)

APOA4 plays an important role in dietary fat absorption and chylomicron synthesis⁸ and can serve as an activator of the LCAT.¹⁶ Several genetic variations in APOA4 have been reported. The most studied (table II) SNPs have been those reporting changes in the amino acids Gln360His and Thre347Ser. Some of them suggesting that 360His allele to be a hypo-responsive isoform^9,17 while others reported it as a hyper-responsive^18,19 or with not effect at all.²⁰ It overall seems that 360Gln and 347Ser individuals, with higher genetic risk to high lipid levels, seem to benefit to changes on dietary fat.^17,21-26

Apolipoprotein CIII (APOCIII)

APOC3 is a component of chylomicrons, VLDL, and HDL, and inhibits the activity of lipoprotein lipase and delays VLDL clearance.¹⁶ Most of the genetic variants studied in APOCIII gene are localized in the promoter region. The C3238G with two alleles S1 and S2 has been associated with higher TG, TC, APOC3 concentrations, and other CVD markers.^22,27 Polymorphisms in this gene are usually analyzed together with APOA1/APOA4 as they form a gene cluster,^9,21 and isolated results are scarce and inconsistent (table III). For example, while Lopez-Miranda and co-workers²⁷ found that subjects carrying the S2 allele changing from low fat diet to a MUFA-rich diet showed a decrease in LDL-C,²⁷ more recently Herron and co-workers found that S2 carriers had smaller LDL peak particle independently of the dietary cholesterol intake,²² although differences in dietary intervention and characteristics of the population evaluated in the two studies have to be considered.

Apolipoprotein A2 (APOA2)

APOA2 is the second most important apolipoprotein of HDL-C. Some studies showed a positive relationship between APOA2 and synthesis of LDL-APOB in humans.²⁸ Although some studies have found an overexpression of APOA2 in hypertriglyceridemic, obese and insulin-resistant subjects,²⁹ its role in humans is still controversial. The -256C > T polymorphism in the APOA2 gene promoter is one of the most studied, and CC genotype has been associated with increased Body Mass Index (BMI) or obesity in different populations and on those following a saturated fatty acid (SFA)-rich diet^30-32 (table IV). This gene-SFA interaction determining BMI on this SNP is the first gen-diet interaction consistently replicated in large and independent populations.^30-32 Based on this, it could be of interest to further explore the possible modulation of this association by specific dietary or physical activity patterns that will lead to wider recommendations, or if this polymorphism also influences other cardiovascular risk factors such as the ratio APOA1/APOA2 or the development of atherosclerosis.³³

Apolipoprotein A5 (APOA5)

APOA5 enhances the activity of lipoprotein lipase and inhibits VLDL-triglyceride (TG) production.^34,35 Multiple studies have shown consistent associations between genetic variants in this gene and fasting TG concentrations^34,36,38 but gene-environment interactions have not been yet fully addressed. Among the few studies that have examined the influence of environmental factors on possible genetic variations, the most important are those that contemplate possible gene-diet interactions.^34,37,39-42 Only the Dietary Intervention and Regular Exercise (DIRE) study contemplates regular exercise as part of the intervention.³⁷ Most of the cross-sectional studies analyzing gene-diet interactions in large populations agreed that those with higher genetic risk (C carriers in -1131T > C SNP) may modulate that risk controlling the content and quality of fat^34,39,40,42 (table V). The evidence however is still poor and each study reports different phenotypes and interactions.

Apolipoprotein B (APOB)

APOB is the primary apolipoprotein of chylomicrons and LDL-C. Through a mechanism that is not yet fully understood, high levels of APOB can lead to atherosclerotic plaques and heart disease.⁴³ A number of SNPs have been studied in this gene (-516C > T, XbaI, EcoRI, Msp1, signal peptide I/D, BsP). Regarding -516C > T SNP nonsignificant gene-diet interactions have been found modulating plasma lipids levels.^44,45 Only one study found that male carriers of the minor allele had higher insulin resistance when followed intervention with SFA-rich diet⁴⁶ (table VI). Evidence for an interaction between the XbaI SNP and diet is inconsistent.^47-49 No other environmental-associated interactions have been studied.

Apolipoprotein E (APOE)

One of the most studied apolipoprotein is the APOE given its key role in lipid metabolism. The most studied genetic variation in APOE gene results from three common alleles in the population: E2/E3/E4.⁵⁰ There is consistent evidence that APOE4 is associated with hypercholesterolemia and 40-50% higher risk of CVD whereas APOE2 prevents from high cholesterol levels.^51-53 However, when analyzing gene-diet interactions some discrepancies are found (table VII). There are more than 40 interventions studies analyzing APOE gene variation, a selection of them are presented in table I. The individual variability of APOE phenotype in response to diet appears to be determined by a genetic variant (E2/E3/E4). Some studies found that APOE4/E4 individuals respond to dietary fat content (especially SFA) with greater responses in the LDL phenotype.^51,52,54,55 However, other studies did not find such interaction or any other gene-diet interaction,^56-58 which suggest that intense research in this area is needed. Similarly, results support that on a low-fat/low-cholesterol diet, the effect of lowering LDL-C is twice as great in men than women, suggesting an APOE-mediated gen-gender interaction.⁵¹

 

Conclusions and future directions

There are a number of studies analyzing the response of metabolic traits via modulation of the APO genetic variability after dietary intervention. Although scientific evidence is accumulating, the area of consensus is still limited. This is mostly due to different study conditions, design, including very different sample sizes, characteristics of the population, duration, nature of the dietary intervention, phenotypes analyzed, postprandial or fasting state of the individuals, as well as to the intervariability in lipid response due to polygenic regulation. Conclusions are therefore difficult to draw, more so when information is often derived from small intervention trials in which the usually small size of the group carrying the allele frequency for the particular SNP of interest, hinders a well-powered analysis of the gene-environment interaction. Either larger, well-standardized intervention trials, or smaller trials with prospective recruitment according to genotype are needed to fully establish the impact of diet on genotype-metabolic traits association to establish personalized dietary recommendations. In the past, genetic studies were carried out with conventional techniques; however, the introduction of high-throughput techniques has boosted the information available on nutritional genomics. In this line, Genome Wide Association studies (GWAs) carried out by large international consortia are delivering fundamental data on genetic variants that contribute to complex diseases. However, the area of nutrigenetics still faces the problem of the lack of standardizing procedures to study the biological complexity of phenotypes, dietary intake, study design, and background of the population genotyped, as mentioned above. To increase the validity of individual nutrigenetic studies, replication of results in different populations is crucial to control for potential information and selection bias. To avoid limitations in the conventional methods for measuring dietary and recognizing the need for standard phenotypic and exposure measures, particularly as related to Genome Wide Association studies, the National Human Genome Research Institute (NHGRI) initiated the PhenX Toolkit in 2006, "High-Priority Phenotype and Exposure Measures for Cross-Study Analysis in Genome-Wide Association Studies. The project, PhenX (https://www.phenx.org/) produces a toolkit that facilitates use of the selected consensus measures in GWAS and other large scale genomic efforts (www.phenxtoolkit.org).

Summarizing the current knowledge, it seems that variations in APOA1, APOA4, APOB, APOA5, and APOE genes may contribute to the different response to dietary interventions on metabolic traits.^{9,11,12,14,19,21,25,34,37,40,47,51,52,59-63} Specifically APOA1 -75A, APOA4 Gln360, APOB -X (XbaI), APOA5 -1131C, APOE4 tend to induce different lipids concentrations depending dietary fat^{9,11,12,14,19,21,25,34,37,40,47,51,52,59-63} despite not all studies being in agreement.^22,24,45,46 To this date, the only SNP that has been replicated in different populations (Framingham Offspring Study (whites),³¹ the Genetics of Lipid Lowering Drugs and Diet Network Study (whites),³¹ Boston-Puerto Rican,³¹ Mediterranean³² and Asian populations)³² following the criteria above mentioned is the APOA2 -265T > C. In conclusion from these studies, CC individuals with a priori higher genetic risk to obesity, seem to modulate their BMI only when they have a low SFA dietary intake.

Derived from the literature reviewed, it seems evident that although advances in gene-nutrient interactions have been made, there is a need of studies that analyze dietary patterns, instead of isolated nutrients to address large population behavioral changes. Furthermore, the study of other environmental components (physical activity, smoking habits, stress, sleep deprivation) should be contemplated in future recommendations based on the individual genetic risk given that there is a lack of studies analyzing this environmental components.

 

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Correspondence:
Mercedes Sotos-Prieto
Area of Epidemiology and Population Genetics.
Centro Nacional de Investigaciones Cardiovasculares (CNIC).
C/ Melchor Fdez. Almagro, 3.
28029 Madrid. Spain.
E-mail: mercedes.sotos@externo.cnic.es

Recibido: 4-II-2013.
Aceptado: 13-VI-2013.