Selected Genes Associated With CVD-Related Diseases, Pathways, and Nutrigenetics

Abstract

Any dysfunction or obstruction in blood circulation can lead to the development of cardiovascular disease (CVD), which is multifactorial but primarily caused by atherosclerosis. Nutrition is considered as the most significant modifiable environmental factor, with a direct influence on cardiovascular risk mediated by triggering inflammation, oxidative stress, and various physiological, molecular, and biological changes. Despite these well-established mechanisms, targeting nutrition has not led to the expected reduction in CVD mortality rates. This discrepancy is thought to be due to interindividual variability in genetic factors that modulate responses to nutritional interventions. Genetic variants can interact with specific nutrients and dietary components, influencing their effects on cardiovascular health. Advances in nutrigenetics and nutrigenomics which explore nutrient-gene interactions, have led to the development of the concept of personalized nutrition. This approach aims to prevent CVD and other diseases by tailoring dietary treatments to individual genotypes identified through genetic polymorphisms. It is suggested that life expectancy and sustainable healthy living can be enhanced by aligning dietary treatments with specific genetic profiles associated with CVD. Therefore, this review discusses genes linked to CVD and explores how gene-driven differences in dietary responses affect cardiovascular health outcomes.

INTRODUCTION

Blood circulation plays a crucial role in transporting nutrients and oxygen to tissues and organs, while also removing metabolic wastes from the body, through the cardiovascular system.¹ Any dysfunction or obstruction in blood circulation can lead to the development of cardiovascular disease (CVD), which is multifactorial but primarily caused by atherosclerosis.²,³ CVD encompasses a range of circulatory disorders including coronary artery diseases, cerebrovascular accidents, dyslipidemia, hypertension, heart failure, atherosclerosis, congenital heart diseases, and vascular diseases.⁴,⁵,⁶,⁷ According to a report by the World Health Organization (WHO), CVD is the leading cause of death globally. In 2019, approximately 17.9 million people died from CVD, accounting for 32% of all deaths worldwide. Notably, 85% of these deaths were due to stroke and heart attack.⁸

The most significant behavioral risk factors for CVD include lack of physical activity, alcohol and tobacco use, and an inadequate and unbalanced diet. These factors contribute to increased blood sugar, blood pressure, and blood lipids, as well as to overweight and obesity.⁸,⁹ Nutrition, which directly influences cardiovascular risk through the initiation of inflammation, oxidative stress, and various physiological, molecular, and biological changes, is recognized as the most critical modifiable environmental risk factor.¹⁰,¹¹,¹²,¹³ It also indirectly contributes to the development of CVD by affecting the lipid profile, blood pressure, body mass, and the risk of diabetes and atherosclerosis.¹⁰ Therefore, nutritional recommendations have become a global priority for reducing the risk of CVD, leading to the publication of various guidelines.¹⁴,¹⁵,¹⁶,¹⁷,¹⁸ These guidelines are designed for populations rather than for individuals or specific groups.¹⁹ Despite these efforts, the reduction in CVD mortality rates has not reached the expected levels. The differing impacts of genetic factors on responses to nutritional interventions are believed to be a contributing factor to this discrepancy.²⁰ Variations in genetic profiles among individuals and specific ethnic groups affect nutrient requirements, metabolism, and responses to nutritional and dietary interventions. It has been suggested that tailored dietary advice for individuals with specific genotypes may be more effective than general dietary guidelines in preventing chronic diseases.¹⁹

Precision nutrition operates on the principle that a single diet does not suit everyone, recognizing that individuals have unique responses to nutrients. This approach considers how genes react to nutrients, as well as how nutrients interact with epigenetic markers and other regulatory mechanisms that influence genome stability, metabolome, proteome, gut microbiome, and gene expression.²¹ For example, the effects of the apolipoprotein E (APOE) gene and the methylenetetrahydrofolate reductase (MTHFR) gene on cholesterol metabolism and folate metabolism, respectively, are well documented.²²,²³ Consistent cardiovascular effects of interactions between genes such as angiotensin-converting enzyme (ACE), fat mass and obesity-associated (FTO), transcription factor 7-like 2 (TCF7L2), melanocortin 4 receptor (MC4R), brain-derived neurotrophic factor (BDNF), peroxisome proliferator-activated receptor (PPAR), apolipoprotein A (APOA), and fatty acid desaturase (FADS) and macronutrients have been demonstrated in the general population.²⁴ In a study with obese and overweight individuals, a nutrigenetic dietary intervention reduced blood lipid levels and was reported to be a promising intervention for cardiometabolic diseases.²⁵ A systematic review highlighted the critical need to develop nutrigenetic interventions, pointing out the direct effects of macronutrient intake, monounsaturated and polyunsaturated fatty acids, as well as dietary supplements and nutraceuticals on blood lipid levels.²⁶ For example, studies have shown that variations in the APOE gene and interactions with dietary fat, saturated fatty acid, and carbohydrate intake are associated with dyslipidemia.²⁷ Additionally, dietary patterns characterized by frequent consumption of soybeans, mushrooms, dairy products, and nuts, accompanied by low meat intake, have been associated with reduced CVD complications through interactions with the adiponectin (ADIPOQ) and MTHFR genes.²⁸ Furthermore, a diet high in beans and legumes like soybeans and low in fats, junk food, and sweets has shown interactions with the 9p21 polymorphism.²⁹ Other studies have also demonstrated that gene polymorphisms associated with CVD risk can interact with diet.³⁰,³¹,³² A flowchart of the relationship between CVD and personalized nutrition is shown in Fig. 1. These genetic variants may determine individual responses to specific nutrients and dietary components, ultimately affecting cardiovascular health. Therefore, this review explores nutrigenetic effects on CVD.

Fig. 1. Relationship between cardiovascular diseases and personalized nutrition.

CARDIOVASCULAR DISEASES, NUTRIGENETICS, AND NUTRIGENOMICS

The field of nutrition genomics, or molecular nutrition, has developed from research in genetics and nutrition, significantly influenced by the Human Genome Project (HGP).¹²,³³ This discipline explains how food intake interacts with the human genome, aiding in understanding gene expression and metabolic responses that influence individual susceptibility to diseases.³⁴ Nutrition genomics encompasses the areas of nutrigenomics and nutrigenetics, which, despite their relatedness, differ fundamentally.³⁵ Nutrigenomics is defined as a research field that explores the molecular relationships between genes and nutrients in disease prevention or treatment by altering gene expression and metabolic responses through dietary components.³⁴,³⁶,³⁷ It aims to uncover the connections between nutrients, the human genome, and health, incorporating fields such as transcriptomics, epigenomics, metabolomics, and proteomics.³⁶ Conversely, nutrigenetics focuses on how genetic variations, such as single nucleotide polymorphisms (SNPs), affect dietary responses.³³,³⁸,³⁹ The relationship between nutrigenetics, nutrigenomics, and CVD is presented in Fig. 2.

Fig. 2. Relationship between nutrigenetics, nutrigenomics, and cardiovascular disease.

SNP, single nucleotide polymorphism; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.

It has been stated that these genetic variations, which are key to human growth and development, interact with the environment and may affect the risk of CVD through altering the responses to dietary intake.¹²,⁴⁰ Consequently, advancements in nutrigenetics and nutrigenomics, which explore the interactions between food and genes, have led to the development of the concept of personalized nutrition (PN). This approach aims to prevent the onset of diseases such as CVD and to mitigate associated risks.²⁰,³³ It has also been posited that determining genetic polymorphisms related to CVD and applying genotype-based dietary treatments can lengthen life expectancy and promote a sustainable healthy lifestyle.¹² However, a recent systematic review of 266 gene-diet interactions, including variants in cholesterol ester transfer protein (CETP) and alcohol dehydrogenase 1C (ADH1C), found that only 18.8% had a significant association with CVD. The heterogeneity of the studies posed limitations on the analytical measures. Additionally, it has been highlighted that dietary components may also regulate genes or DNA, potentially impacting CVD risks.⁴¹ Meanwhile, another extensive study examining the effects of saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs) on CVDs emphasized the need to integrate microbiomic, epigenomic, genomic, and metabolomic data with dietary responses into personalized nutrition strategies.⁴²

GENETICS OF CARDIOVASCULAR DISEASES

Studies have focused on the analysis of gene-related molecules to understand disease mechanisms. While these molecules may not directly cause diseases, they can serve as markers that improve the understanding of a patient’s prognosis and risk. Alterations in gene expression levels can signal the presence of a disease state, thus potentially serving as biomarkers.⁴³

1. Candidate gene approaches

The candidate gene approach is a basic research method based on the hypothesis that a specific gene plays a role in a certain phenotype or clinical effect. This method is one of the first and simplest approaches to understanding the molecular and cellular functions of genes.⁴⁴ For example, a candidate gene study has shown that the ACE insertion/deletion (I/D) polymorphism is a strong risk factor for coronary heart disease.⁴⁵ In these studies, challenges such as inadequate sample sizes, poor population homogeneity, and uncertainties about whether the proteins encoded by the selected genes are mechanistically related can lead to erroneous results.⁴⁶ Nevertheless, research on genetic biomarkers has successfully pinpointed critical single genes or variants by concentrating on candidate genes in monogenic heart disorders. Notably, the APOE, APOA5, and MC4R genes have been identified as key determinants of plasma cholesterol levels, plasma triglycerides, and body weight.⁴⁷

2. Genome-wide association studies (GWAS)

The completion of the Human Genome Project paved the way for the initiation of GWAS, which continue to be conducted.⁴⁸ The genetic variants most commonly studied in GWAS are SNPs, which account for 80% of genetic variation between individuals, but copy number variations and sequence variations are also studied.⁴⁹,⁵⁰ A polymorphism is defined as genetic variations with a frequency of 1% or higher. It represents a change in a single nucleotide in the DNA sequence.⁵¹ SNPs are known as the most common form of genetic variation,⁵² and It is estimated that there are about 10 million SNPs in the human genome.⁵³

In GWAS, the 9p21.3 SNPs were the first identified loci associated with CVD.⁵⁴ Approximately 75% of the global population carries this risk allele, which has been shown to contribute to coronary atherosclerosis.⁵⁵ The chromosome 9p21 locus is considered highly significant as it represents the genetic variant with the greatest risk.⁵⁶ Subsequently, loci for the long non-coding regulatory RNA ANRIL (antisense noncoding RNA in the INK4 locus) were identified in gene-free regions, and these loci have been linked to an increased risk of myocardial infarction. Another gene identified through GWAS is sortilin, also known as CELSR2/PSRC1/SORT1. While the exact mechanism of variations in this gene remains unclear, it is known to influence cholesterol metabolism. FTO, a gene significantly associated with obesity and diabetes, was later found to also be associated with the risk of myocardial infarction.⁴⁷ Familial hypercholesterolemia is characterized by monogenic mutations in the genes encoding APOB, proprotein convertase subtilisin/kexin type 9 (PCSK9), and low-density lipoprotein receptor (LDLR). Loss-of-function variants in these genes cause increased blood cholesterol levels and a four-fold higher risk of CVD.⁵⁵ More than 200 loci have been reported to be related to CVD and myocardial infarction since 2007.⁵⁷ In addition, the importance of CVD for aging and death has been emphasized in GWAS. For example, the APOE locus, which is associated with both dementia and coronary artery disease, has been strongly associated with longevity.⁵⁸ The identification of genetic risk factors for numerous diseases through GWAS has been pivotal in the field of human genetics.⁵⁹

3. Polygenic risk score

It has been stated that individually defined polymorphisms may be insufficient to predict disease risk. Consequently, polygenic risk scores (PRSs) have been developed through GWAS to predict disease risk by summing the number of risk variant alleles in the human genome.⁵⁵,⁶⁰ A PRS, also known as a genetic risk score, can be calculated in 2 ways: the unweighted genetic risk score, which sums the number of risk alleles regardless of each allele’s effect size, and the weighted genetic risk score, which aggregates alleles taking into account the actual effect of each SNP on the risk factor.⁴⁷ In one study, genetic risk scores constructed from 13 genetic variants associated with myocardial infarction or coronary heart disease were found to be independent predictors of cardiovascular events and elevated coronary artery calcium.⁶¹ Inouye and colleagues⁶² calculated a genomic risk score using lifelong germline DNA to classify individuals in general populations in terms of coronary artery disease (CAD) risk, demonstrating the importance of using genomic information. PRSs have been created to predict the genetic risk of CVDs, type 2 diabetes, and dyslipidemia. It was shown that a healthy lifestyle reduces the incidence of disease in groups with high PRSs.⁶³ It was also emphasized that the development of artificial intelligence-based PRSs could increase the accuracy of risk predictions.⁶⁴

GENES ASSOCIATED WITH CARDIOVASCULAR DISEASES

In total, 321 chromosomal loci have been identified that map to coronary artery disease risk and the pathophysiological pathways of atherosclerosis, including blood pressure, lipid metabolism, immune response and inflammation, nitric oxide (NO) signaling, thrombosis, vascular remodeling, proliferation and transcriptional regulation, pathways associated with ncRNAs, adiposity, and insulin resistance.⁶⁵ Most of the identified loci are in genes associated with lipid metabolism and inflammation.¹³,²⁰

1. APOE gene

APOE, a 34 kDa protein consisting of 299 amino acids, is a key component of triglyceride-rich lipoproteins. It is present on the surface of very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), high-density lipoprotein (HDL), and chylomicrons.⁶⁶ Therefore, its role in lipid metabolism and cholesterol absorption is well known. The APOE gene has three main alleles: ε2, ε3, and ε4.⁶⁷ The ε3 (rs7412-C, rs429358-T) allele is the most common. The ε4 (rs7412-C, rs429358-T) allele is associated with higher plasma APOB and low-density lipoprotein cholesterol (LDL-C) concentrations, with a greater susceptibility to CVD.⁶⁸ In addition, individuals with the APOEε4 allele were reported to be more sensitive to dietary modifications than individuals with the APOE ε3 or ε2 alleles.⁶⁷,⁶⁹

2. APOA1 gene

APOA1, which consists of 243 amino acids,⁷⁰ is synthesized in the liver and intestine and serves as the primary apolipoprotein component of HDL, playing a significant role in reverse cholesterol transport.⁷¹ The APOA1 gene, which encodes APOA1, is located on the long arm of chromosome 11, and a specific SNP has been identified in the promoter region (APOA1−75G→A).⁷² It has been reported that the APOA1-75G/A polymorphism is related to higher high-density lipoprotein cholesterol (HDL-C) levels,⁷³ and a meta-analysis demonstrated the protective role of the APOA1-75G/A polymorphism in CVD.⁶⁵,⁷⁴

3. APOA5 gene

APOA5, which is mainly secreted from the liver, consists of 366 amino acids.⁷⁵ It has been reported that APOA5, which is encoded by the APOA5 gene within the APOA1/C3/A4/A5 gene cluster on chromosome 11q23, modulates lipoprotein lipase activity⁷⁶,⁷⁷ and plays roles in lipid metabolism, especially triglyceride (TG) levels.⁷⁸ Research has shown that individuals with CC homozygotes of the APOA5 gene polymorphism (rs662799) have a 3-fold increased risk of CVD compared to those carrying the T allele. Additionally, the C allele is linked to elevated TG levels.⁷⁹ In a separate study of Caucasian obese individuals, those carrying the rs662799 C-allele of the APOA5 gene exhibited significantly lower HDL-C levels and higher TG levels.⁸⁰ Furthermore, a meta-analysis revealed that the APOA5 rs3135506 gene polymorphism is associated with an increased risk of CVD.⁸¹

4. CETP gene

CETP, which is synthesized in the liver, is a glycoprotein involved in the bidirectional transfer of TG and cholesteryl esters (CEs) between plasma lipoprotein particles.⁸² CETP facilitates HDL-C catabolism and contributes to atherogenicity by regulating the exchange of TG and CE among lipoproteins such as APOB, LDL, VLDL, and HDL-C. It also supports reverse cholesterol transfer by transporting cholesterol esters from HDL3 to HDL2 and from peripheral tissues to the liver.⁸³,⁸⁴ The human CETP gene is located on chromosome 16 in the q21 region (16q21) and contains 16 exons and 15 introns.⁸⁵ A study has shown that increased CETP concentrations in individuals with CETP polymorphisms (rs247616-C, rs12720922-A, rs1968905-G) significantly reduce HDL-C and moderately increase LDL-C levels, influencing the risk of CAD.⁸⁶ The SNP rs5882 (I405V) involves the substitution of isoleucine (I) with valine (V). Consequently, the “G” allele is referred to as the “V” allele, while the “A” allele is known as the “I” allele.⁸⁷ A study exploring the relationship between cardiovascular risk, ischemic stroke formation, and CETP polymorphism found that carriers of the V allele had higher levels of plasma non-HDL, defective HDL, HDL2, HDL3, LDL, VLDL, TG, and total cholesterol (TC). The V allele was identified as a factor contributing to increased dyslipidemia.⁸⁸ Additionally, studies examining the association between CETP gene polymorphisms, LDL, and HDL in the development of atherosclerosis have reported conflicting results.⁸⁹

5. Hepatic lipase (LIPC) gene

LIPC, which is primarily synthesized by hepatocytes and macrophages, is a 65-kD glycoprotein.⁹⁰ It plays a role in various stages of lipoprotein metabolism as a lipolytic enzyme.⁹¹ TG and phospholipids regulate plasma concentrations by hydrolyzing plasma lipoproteins.⁹² This regulatory function is influenced by the composition and quality of HDL particles.⁹³ In a study of male individuals with diabetes, those carrying the T allele (genotypes CT and TT) exhibited higher plasma HDL-C levels compared to those with the C allele. The influence of the LIPC−514C→T polymorphism on HDL-C levels was more pronounced with increased consumption of saturated fats. However, these effects of the T genotype were not observed in obese individuals.⁹⁴ A recent study identified that the LIPC-E97G variant contributes to familial hypercholesterolemia.⁹⁵

6. MTHFR gene

MTHFR, which is a key enzyme in folate metabolism, plays a significant role in the modulation of homocysteine synthesis.⁹⁶ Homocysteine, an amino acid and homolog of cysteine, is derived from methionine. Its role in platelet activation is linked to CVD through atherosclerotic processes.⁹⁷ The MTHFR gene is situated at 1p36.3 on the short arm of chromosome 1.⁹⁸ Researchers have identified nine common and 34 rare mutations in the MTHFR gene, including the prevalent variants C677T (rs1801133), A1298C (rs1801131), and ARG184TER (rs121434294).⁹⁷ The A1298C polymorphism is believed to reduce MTHFR activity by nearly 35%.⁹⁹ The TT genotype of the MTHFR C677T polymorphism is recognized as a risk factor for CVD, characterized by diminished MTHFR enzyme activity and elevated homocysteine levels.⁹⁸,¹⁰⁰ A study indicated that the rs4846049 (G>T) polymorphism in the MTHFR gene is associated with an increased risk of CVD. Additionally, the T allele has been linked to lower levels of HDL-C and APOA. Furthermore, individuals with the T allele and CVD exhibited reduced MTHFR protein levels in their blood mononuclear cells compared to those carrying the G allele.¹⁰¹

7. Arachidonate 5-lipoxygenase (ALOX5 or 5-LO) gene

5-LO, which is encoded by the ALOX5 gene, is involved in the production of leukotrienes (leukotriene-B4, C4, D4, E4) from arachidonic acid.¹⁰²,¹⁰³,¹⁰⁴ The conversion process is facilitated by the auxiliary factor, 5-LO activating protein. Leukotriene C4 increases vascular permeability, while leukotriene B4 is implicated in inflammation.¹⁰⁵ Arterial inflammation plays a role in the pathophysiology of atherosclerosis. Consequently, it has been hypothesized that a polymorphism in the 5-LO gene could be linked to the development of atherosclerosis through increased production of inflammatory leukotrienes.¹⁰⁶,¹⁰⁷ In research conducted within a Chinese population, no significant association was observed between the ALOX5AP rs4073259 polymorphism and ischemic stroke.¹⁰⁸ Subsequent research indicated that ALOX5 polymorphism may contribute to the development of atherothrombosis in middle-aged individuals.¹⁰⁹

8. FTO gene

First identified in individuals with type 2 diabetes in Europe, the FTO gene is associated with body mass index (BMI), obesity, and fat mass¹¹⁰,¹¹¹ and is located at position 16q12.2 on chromosome 16.¹¹² This gene, which also has links to type 2 diabetes, is expressed in numerous tissues, including both peripheral and central areas of the brain. It encodes an alpha-ketoglutarate-dependent dioxygenase that regulates transcription and translation through the methylation of DNA/RNA.¹¹³ Additionally, it encodes a nucleic acid demethylase (2-oxoglutarate dependent) that plays roles in fatty acid metabolism and DNA repair.¹¹² The most commonly studied variants of the FTO gene include rs9939609, rs9930506, rs17817449, and rs12149832.¹¹⁰ The variant rs9939609, which has been extensively investigated in relation to body weight,¹¹⁴ is associated with plasma C-reactive protein (CRP) concentration, thereby contributing to an increased cardiovascular risk.¹¹⁵ According to a meta-analysis, the rs9939609 variant is linked to CVD.¹¹¹ In another clinical study, the AA genotype of rs9939609 was associated with CVD.¹¹⁶ Conversely, recent research has argued that the rs17817449 variant may be associated with a reduced risk of coronary artery disease and arterial hypertension.¹¹⁷

9. ACE gene

ACE, which is involved in the conversion of angiotensin I to angiotensin II within the renin-angiotensin system,¹¹⁸ also inhibits bradykinin.¹¹⁹ The ACE I/D gene polymorphism (rs4340) consists of a 287 bp DNA sequence located in intron 16 of the ACE gene on chromosome 17q23.¹¹⁹ This polymorphism plays a significant role in the pathogenesis of hypertension and CVD and is frequently studied.¹²⁰ ACE is categorized into 3 genotypes: insertion homozygous (II), insertion-deletion heterozygous (ID), and deletion homozygous (DD).¹²¹ Research indicates that the hypertensive effect of the II genotype of the ACE gene, exacerbated by adiposity, is more pronounced,¹²² while the DD genotype is associated with a decreased risk of CVD in the Chinese population.¹²³ Another study found that the ACE I/D polymorphism was linked to acute myocardial infarction by altering ACE activity, which contributes to ulceration, thrombosis, and plaque vulnerability.¹²⁰

10. PPAR genes

The ligand-activated nuclear hormone receptors PPAR family consists of PPARα, PPARβ/δ, and PPARγ.¹²⁴,¹²⁵ These receptors are expressed in adipose tissue and play crucial roles in various metabolic processes, including lipid metabolism, lipogenesis, adipocyte differentiation, glucose metabolism, and insulin sensitivity.¹²⁶ The PPARA gene is located on human chromosome 22 at locus 22q12-q13.1 and comprises eight exons that encode the PPARα protein. Common polymorphisms in PPARA, such as the C/G (rs1800206) and the Leu162Val amino acid substitution, have been identified and are associated with lipid metabolism.¹²⁷,¹²⁸ It has been reported that single nucleotide polymorphisms in PPAR genes are related to obesity and cardiometabolic risk.⁶⁹,¹²⁴ The PPARA rs1800206 C>G (L162V) polymorphism is associated with CVD, and the rs4253778 G>C (intron 7 G/C) polymorphism is related to oxidative stress and inflammation.¹²⁵ In one study, minor allele homozygotes of PPARA rs3856806 and rs12497191 polymorphisms exhibited a lower risk of dyslipidemia, while rs3856806 minor allele homozygotes had a lower risk of higher LDL-C.¹²⁶ In another study, PPARA L162V and PPARG C161T gene polymorphisms were found to be related to the risk of progressive acute coronary syndrome.¹²⁷

GENE REGULATION OF THE LIPID PROFILE RESPONSE TO DIETARY INTERVENTIONS

Guidelines for the prevention of CVD recommend reducing dietary cholesterol and sodium intake, replacing saturated fats with monounsaturated or polyunsaturated fatty acids, and consuming fewer processed carbohydrates and sweetened beverages. The latest nutritional guide from the American Heart Association (AHA) highlights the importance of plant-based nutrition and the consumption of less processed foods. In this context, diets such as plant-based diets, the Mediterranean diet (MedDiet), and the Dietary Approaches to Stop Hypertension (DASH) diet are recommended for CVD prevention.¹²⁹,¹³⁰,¹³¹ However, it has been noted that lipid profiles in response to diet vary among individuals, and genetics may play a significant role in these differences.¹³²,¹³³ For this reason, recent research in nutrition has concentrated on gene expression, exploring how the synthesis of proteins interacts with bioactive components in the diet.¹³⁴ A systematic review reported that personalized diet treatments, which consider lifestyle factors, genotype, phenotype, and dietary information, improve dietary intake more effectively than traditional diet approaches.¹³⁵ Studies on gene-diet interactions of CVD risk factors are briefly summarized in Table 1.

Table 1. Summary of studies on gene-diet interactions of CVD risk factors.

Gene	Polymorphism	Allele	Population	Country	Disease	Dietary intervention	Result/Diet response	Reference
CETP	rs3764261	T	424 adults	Spain	Individuals with MetS at risk of CVD	12 mon	- Carriers of the minor T allele (TT + TG) had higher plasma HDL-C concentrations and lower TG levels	Garcia-Rios et al.84
						- MedDiet (35% fat, 22% MUFA)
						- Low-fat diet (28% fat, 12% MUFA)
APOA1	At the promoter site at −75 bp (−75 base pairs)	A	1,577 adults	America	Healthy individuals	- PUFA consumption (n-3) (M>4%)	- Increased HDL-C concentrations in female carriers of the A allele with PUFA intake (n-3) (energy >8%)	Ordovas et al.92
						- PUFA consumption (n-3) (M>8%)
ALOX5	-	d5	98 adults	African Americans	Healthy individuals	5 capsules (1.0 g/capsule) per day for 6 wk	- A decrease in total TG concentration was found in individuals with the d5 genotype receiving fish oil supplements	Armstrong et al.103
						- Fish oil
						- Corn/soybean oil
APOA5	rs964184	G	734 adults	America	Overweight and obese individuals	2-yr weight loss diet, low fat intake (energy 20%)	- Greater reductions in TC and LDL-C in carriers of the G allele (risk allele)	Zhang et al.136
APOA1	rs670	A	282 adults	Spain	Obese individuals	12 wk	- Increased HDL-C levels in A allele carriers compared to GG allele carriers after low-fat hypocaloric diet intervention	de Luis et al.137
						- High-fat diet (38% carbohydrates, 24% protein, and 38% fat)
						- Low-fat diet (53% carbohydrates, 20% protein, and 27% fat)
LIPC	rs2070895	A	743 adults	America	Overweight and obese individuals	2-yr weight loss diet	- Further reductions in TC and LDL-C with low-fat diet in carriers of the A allele	Xu et al.138
						- 20%, 15% and 65%	- Increase in HDL-C
						- 20%, 25% and 55%
						- 40%, 15% and 45%
						- 40%, 25% and 35%
LIPC	rs1800588	C	42 adults	Spain	Healthy individuals	4 wk	- In carriers of major alleles (CC/CT), increase in HDL-C levels following Western diet compared to Spanish diet	Smith et al.139
						- High-fat Western diet (39% fat)	- No change in minor allele (TT) carriers
						- Low-fat traditional Spanish diet (20% fat)
CETP	rs3764261	C	732 (pounds lost)	America	Overweight and obese individuals	2-yr weight loss diet	- Carriers of the C allele with a high-fat diet showed a greater increase in HDL-C and a greater decrease in TG levels	Qi et al.140
			171 (direct)			- High fat intake (energy 40%)
ACE	rs4343	G	46 adults	United Kingdom	Healthy, non-obese individuals	6-wk high-saturated-fat diet	- 2-fold increase in ACE concentrations and higher systolic blood pressure in individuals with the GG allele	Schüler et al.141
TCF7L2	rs7903146	T	7,018 adults	Spain	Individuals with type 2 diabetes and 3 or more cardiovascular risk factors (hypertension, dyslipidemia, BMI ≥25 kg/m2, smoking, or a family history of CVD; 1 of the 2 criteria)	- MedDiet with 50 mL/day of extra virgin olive oil	- Reduced stroke risk and decreased TC, LDL-C, and TG when adherence to the MedDiet increased in individuals with the TT genotype	Corella et al.142
						- MedDiet with 30 g/day mixed nuts
MLXIPL	rs3812316	G	7,166 adults	Spain	Individuals at risk of CVD	MedDiet (median 4.8 yr follow-up)	- Reduced risk of myocardial infarction in carriers of the G allele compared to carriers of the C allele	Ortega-Azorín et al.143
LPL	rs13702	C	7,187 adults	Spain	Individuals at risk of CVD	MedDiet (median 4.8 yr follow-up)	- Further reductions in TG and reduced risk of stroke in carriers of the C allele after MedDiet intervention	Corella et al.144
APOA1	rs670	A	82 adults	Spain	Obese individuals	Mediterranean type hypocaloric diet (500 kcal per day for 12 wk)	- Decreases in TC and LDL-C levels in carriers of the A allele	de Luis et al.145
TNF-α	rs1800629, rs1799964	A	507 adults	Spain	Individuals with MetS	12 mon	- Decrease in TG and hsCRP in individuals with the G/G allele after 12 mon of MedDiet intervention	Gomez-Delgado et al.146
						- MedDiet (35% fat, 22% MUFA)
						- Low-fat diet (28% fat, 12% MUFA)
APOE	rs429358 and rs7412	ε4	1466 adults	Europe	Healthy individuals	Gene-based personalized dietary advice	- Decrease in TC concentrations was significantly greater in ε4+ than in ε4− participants	Fallaize et al.147
APOE	rs1064725	T	120 adults	Caucasia	Individuals with a moderate risk of CVD	16-wk isoenergetic diet	- Significant reduction in TC after consumption of MUFA-rich diets compared to SFA or n-6 PUFA diets in individuals with the TT allele	Shatwan et al.148
						- Total oil (energy 36%)
						- SFAs (17:11:4)
						- MUFAs (9:19:4)
						- n-6 PUFAs (9:13:10)

CVD, cardiovascular disease; CETP, cholesterol ester transfer protein; MetS, metabolic syndrome; MedDiet, Mediterranean diet; MUFA, monounsaturated fatty acid; HDL-C, high-density lipoprotein cholesterol; TG, triglyceride; APOA1, apolipoprotein A1; PUFA, polyunsaturated fatty acid; ALOX5 or 5-LO, arachidonate 5-lipoxygenase; APOA5, apolipoprotein A5; TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; LIPC, hepatic lipase; ACE, angiotensin-converting enzyme; TCF7L2, transcription factor 7-like 2; BMI, body mass index; MLXIPL, max-like protein X interacting protein-like; LPL, lipoprotein lipase; TNF-α, tumor necrosis factor-α; hsCRP, high-sensitivity C-reactive protein; APOE, apolipoprotein E; SFA, saturated fatty acid.

1. High- and low-fat diets

In a study examining overweight and obese individuals with the rs964184 polymorphism in the APOA5 gene, those on a low-fat diet (20% energy from fat) who were also carriers of the risk allele (G allele) exhibited lower LDL and TC concentrations compared to non-carriers after 2 years of dietary intervention. Conversely, carriers of the risk allele who consumed a high-fat diet (40% energy from fat) showed a more pronounced increase in HDL-C response. No significant interactions were observed between protein intake and the APOA5 rs964184 genotype regarding changes in lipid concentrations.¹³⁶ These results highlight that gene-diet interactions affecting blood lipid profiles become apparent after long-term interventions. It has been noted that variations in HDL-C concentrations are linked to the APOA5 genotype, although the underlying mechanisms remain unclear. Another study investigated the impact of 2 different hypocaloric diets on metabolic changes and lipid profiles in individuals with the APOA1 rs670 gene polymorphism. This study included obese participants who were randomly assigned to either a low-fat diet or a high-fat diet for 12 weeks. Measurements taken after the dietary interventions showed reductions in BMI, waist circumference, body weight, leptin levels, fat mass, and systolic blood pressure. Following the low-fat hypocaloric diet, individuals carrying the A allele experienced an increase in HDL-C levels compared to those with the GG allele.¹³⁷

In a study examining the relationship between the −541C/T polymorphism in the LIPC gene and dietary fat, individuals with the T allele who consumed a diet with less than 30% of energy from fat exhibited higher HDL-C levels. However, when total fat intake was 30% or more of energy, no difference was observed in individuals with the C allele, while those with the TT genotype had lower HDL-C concentrations.¹⁴⁹ Another study investigated the effects of a 2-year dietary intervention (high-fat, 40%; low-fat, 20%) on the lipid profiles of overweight and obese individuals with the LIPC rs2070895 polymorphism. This study found that A allele carriers experienced a decrease in plasma LDL and TC levels and an increase in HDL-C concentrations when following a low-fat diet, compared to G allele carriers. Conversely, A allele carriers on a high-fat diet experienced adverse effects on LDL and TC levels, with no significant change in HDL-C levels.¹³⁸ According to that study by Xu et al.,¹³⁸ carriers of the A allele may experience better modulation of lipid profiles with a diet low in fat (20%) and high in carbohydrates (55%–65%). Another study focused on the effects of the rs1800588 polymorphism in the LIPC gene on blood glucose and lipid responses in Hispanic individuals following a low-fat traditional Hispanic diet versus a Western diet. The results indicated that individuals with the C allele (CC+CT) who consumed a Western diet had higher HDL-C levels. In contrast, those with the T allele did not show a significant increase in HDL-C levels, nor a decrease. Additionally, the same polymorphism, TG, HDL-C, and dietary fat quality were reassessed using data from the Boston Puerto Rico Health Study. It was found that saturated fat consumption was negatively associated with TG and HDL-c levels in individuals with the TT genotype.¹³⁹ These studies showed that LIPC polymorphism affects the response to dietary intake.

In a study utilizing data from 2 independent 2-year randomized controlled trials—Dietary Intervention Randomized Controlled Trial (DIRECT) and Preventing Excess Weight Using New Dietary Strategies (POUNDS LOST)— researchers evaluated the impact of the CETP rs3764261 polymorphism on blood lipid responses to dietary interventions. In the POUNDS LOST study, which involved overweight or obese participants, those carrying the C allele of the CETP rs3764261 polymorphism experienced a greater reduction in TG levels and an increase in HDL-C over 6 months when following a high-fat diet (40% of energy from fat) compared to a low-fat diet (20% of energy from fat). Similarly, the DIRECT study showed comparable changes in TG and HDL-C levels.¹⁴⁰ No significant differences were observed between individuals with AA and CA genotypes. The findings indicate that individuals with the CETP rs3764261 CC genotype may see more pronounced improvements in TG and HDL-C levels when following a low-carbohydrate/high-fat weight loss diet. Another study explored the effects of a high-saturated isocaloric diet on ACE levels. Participants initially followed a high-carbohydrate, low-fat diet for 6 weeks, then switched to a high-saturated fat diet for another 6 weeks under isocaloric conditions. Consumption of the high-fat diet led to a 15% increase in circulating ACE concentration due to increased ACE gene expression. Individuals with the GG genotype exhibited higher baseline ACE concentrations, which doubled following the high-fat diet compared to those carrying the A allele. Additionally, higher systolic blood pressure was noted in individuals with the GG genotype than in those with AA or AG genotypes.¹⁴¹ The study concluded that individuals with the ACE rs4343 GG genotype who consume a high-saturated fat diet may face increased CVD risk.

2. MedDiet

The MedDiet has been shown to play a protective role in CVD, with benefits including limiting oxidation, protecting membrane fluidity, enhancing nitric oxide production, balancing meal distribution, modulating microbial activity, and influencing gene expression.¹⁵⁰ One study assessed the impact of consuming a MedDiet (35% fat, 22% MUFA) versus a low-fat diet (28% fat, 12% MUFA) over one year. It focused on how these diets interact with the rs3764261 SNP at the CETP locus to affect lipid metabolism in individuals with metabolic syndrome (MetS) who are at high risk for CVD. After one year, individuals carrying the T allele (TT+TG) exhibited lower plasma TG concentrations and higher HDL-C levels compared to those with the GG genotype.⁸⁴ In individuals with the TCF7L2 rs7903146 (C>T) polymorphism, those with the TT genotype displayed higher fasting glucose levels and an increased risk of stroke compared to those with the C allele. However, as adherence to the diet increased, the risk of stroke diminished, and levels of TC, LDL-C, and TG decreased. No effect on myocardial infarction was observed.¹⁴² Notably, in the control group (which received a low-fat diet without the MedDiet), individuals with the TT allele had a higher incidence of stroke than those with the CC allele, whereas adherence to the MedDiet for 4.8 years was associated with a reduced incidence of stroke. The study also explored the impact of the max-like protein X interacting protein-like (MLXIPL) rs3812316 polymorphism on dietary response and its association with CVD in individuals at risk, as part of the PREDIMED study. The MLXIPL-rs3812316 polymorphism has been linked to lower TG levels and a reduced risk of hypertriglyceridemia. These protective effects increased with greater adherence to the MedDiet and were associated with a lower risk of myocardial infarction in carriers of the G allele than in those with the CC genotype.¹⁴³ Another segment of the PREDIMED study involving 7187 participants evaluated the association of the lipoprotein lipase (LPL) gene variant (rs13702T>C) with CVD incidence and response to the MedDiet intervention. The rs13702T>C polymorphism was associated with lower TG levels in carriers of the C allele, who also experienced greater reductions in TG following the MedDiet intervention, which is rich in monounsaturated and unsaturated fats. Although the polymorphism was linked to a lower risk of stroke, this association became more statistically significant with the MedDiet intervention.¹⁴⁴ In a separate study involving obese individuals, the rs670 APOA1 gene polymorphism was evaluated after a 12-week Mediterranean-type hypocaloric diet (500 kcal per day). It was found that the A allele (GG, GA+AA) was the risk allele. Post-dietary intervention, BMI, fat mass, waist circumference, and body weight decreased in both A and G allele carriers, with more pronounced effects in A allele carriers. Additionally, there was a decrease in insulin resistance, insulin levels, homeostatic model assessment insulin resistance, LDL-C, and TC in individuals with the A allele.¹⁴⁵

Inflammation has been reported to be an independent risk factor for the development and progression of both cardiac and vascular diseases.¹⁵¹,¹⁵² A study investigated the effects of a low-fat diet and a MedDiet on aging-related processes such as inflammation, oxidative stress, and leukocyte telomere length (LTL) in individuals with coronary heart disease (CHD) who had SIRT1 rs7069102 and rs1885472 polymorphisms. Subjects with the GG genotype who were randomized to the low-fat diet experienced a significant reduction in lipid peroxidation products and tumor necrosis factor-α (TNF-α) levels compared to their baseline levels and those in subjects with the CG+CC genotype. Additionally, an increase in the ratio of reduced to oxidized glutathione was observed. Stabilization in LTL was noted in GG carriers compared to C allele carriers. In contrast, individuals assigned to the MedDiet showed a decrease in telomere length across both genotypes, with no significant changes in CRP and TNF-α levels.¹⁵³ This study demonstrated the beneficial effects of the low-fat diet in individuals with CHD and the SIRT1 rs7069102 polymorphism. Another study assessed the associations of polymorphisms (rs1800629, rs1799964) in the TNFA gene with responses to a low-fat diet versus a MedDiet in individuals with MetS. Conducted with 507 participants from the CORDIOPREV clinical study, the initial findings showed that plasma CRP and both fasting and postprandial TG levels were higher in individuals with the GG genotype than in those carrying the A allele. After a 1-year dietary intervention, plasma CRP and TG levels decreased in carriers of the GG genotype compared to those with the A allele.¹⁴⁶ These results suggest that rs1800629 in the TNFA gene modifies TG metabolism and inflammatory response with the MedDiet in individuals with MetS.

3. Other types of diets and dietary supplements

In a study utilizing data from the Food4Me pan-European personalized nutrition study, individuals carrying the APOE ε4 allele exhibited higher TC levels. It was also observed that gene-based personalized dietary advice significantly promoted the reduction of saturated fat consumption compared to non-gene-based personalized diet therapy.¹⁴⁷ Another study assessed the impact of personalized nutrition therapy, identifying the T allele as the risk allele for the MTHFR gene (CT and TT genotypes), and the ε4 allele as the risk allele for the APOE gene (ε3/ε4 and ε4/ε4 genotypes). Participants received guidance on increasing their folate intake and reducing their saturated fat intake (folate >200 µg/day; saturated fat <11% TEI-UK available data). Following the intervention, participants with the genetic risk reduced their saturated fat consumption to recommended levels, whereas the risk-free genotype group also reduced their intake, but their average consumption remained above the recommended level.¹⁵⁴ This study demonstrated that incorporating genotype-based personalized nutritional recommendations into dietary behavior interventions can lead to positive changes in dietary behavior. In a cross-sectional study investigating the influence of CETP TaqB1 polymorphism on CVD risk factors among individuals with diabetes, the CETP Taq1B B1 allele was found to be protective against CVD risk in those with high dietary insulin index and load.¹³² Another cross-sectional study conducted in Iran explored the impact of polymorphisms in the CETP gene (rs5882 and rs3764261) on the serum lipid profile response to diet over a 3.6-year follow-up period. In this study, higher fish intake was associated with reduced TC in carriers of the A allele in the rs3764261 polymorphism compared to those with the CC genotype. Additionally, G allele carriers of rs5882 who consumed a low-fat and high-carbohydrate diet had better TG levels than individuals with the AA homozygous allele. Furthermore, carriers of the A allele of rs3764261 exhibited higher HDL-C and lower TG levels compared to those with the CC genotype.¹³³

In a study evaluating the impact of CVD-related genes such as APOE and cholesterol 7 alpha-hydroxylase (CYP7A1) on LDL-c response to plant sterol (PS) supplementation, participants received either 2 g of PS per day or a placebo for 28 days. The results showed a dose-dependent reduction in LDL-C levels among individuals carrying the G allele, while no change was observed in those with the TT genotype.¹⁵⁵ Another study analyzed three isoenergetic diets rich in SFA, n-6 polyunsaturated fatty acids (PUFA), or MUFA, which were given for 16 weeks to examine the effect of dietary interventions on blood lipid profile in individuals with moderate cardiovascular risk with LPL and APOE single nucleotide polymorphisms. This study found a significant reduction in TC after consumption of MUFA-rich diets compared to those rich in n-6 PUFA or SFA, particularly in individuals with the TT allele of the APOE SNP rs1064725. In carriers of the G allele of the LPL SNP, a decrease in LDL-C levels was observed in the group consuming a diet rich in n-6 PUFA, although this change was not statistically significant.¹⁴⁸ The study noted that TT homozygotes were more sensitive to dietary fat composition. APOA1, a protein encoded by the human APOA1 gene, plays a role in lipid metabolism and the risk of CHD. A study investigating the influence of dietary fat on HDL-C concentrations in individuals with polymorphisms in the APOA1 gene promoter found that female participants with the A allele had lower HDL-C concentrations compared to G/G homozygotes. Regression model results indicated that when PUFA intake was less than 4% of energy, HDL-C concentrations were approximately 14% higher in individuals with the G/G genotype than in those carrying the A allele. Conversely, with a PUFA intake greater than 8%, HDL-C levels were 13% higher in individuals with the A allele than in G/G homozygotes. This suggests that female individuals with the A allele might benefit from a high-PUFA diet in terms of reducing CVD risk.⁹² In a separate study involving Taiwanese individuals with the rs1801133 polymorphism in the MTHFR gene, the effects of a vegetarian diet and exercise levels on HDL-C levels were examined. This study of healthy adults showed that increased exercise time per week was associated with higher HDL-C levels, while a vegetarian diet was linked to lower HDL-C levels. Combining a vegetarian diet with exercise led to a decrease in HDL-C of 6.5552 mg/dL in individuals with the GG genotype and a decrease of 2.8668 mg/dL in those with the GA+AA genotype. These results indicate that a vegetarian diet tends to lower HDL-C levels, regardless of the rs1801133 genotype, and that higher exercise durations correlate with increased HDL-C levels in individuals carrying the A allele (GA+AA).¹⁵⁶

It is known that dietary responses can be influenced by gene polymorphism. A study was conducted to determine if fish oil and corn/soybean oil supplements impact plasma lipoprotein and lipid concentrations, blood pressure, heart rate, and erythrocyte PUFA composition in individuals with different ALOX5 gene variants (genotypes = dd, d5, and 55). Participants were administered 5 g/day of either fish oil or corn/soybean oil for 6 weeks. At the conclusion of the intervention, a significant reduction in total TG concentration was observed in participants who received fish oil supplements compared to those who received corn/soybean oil supplements. Furthermore, this effect was exclusive to individuals with the d5 genotype and was not observed in those with the dd or 55 genotypes. Additionally, HDL particle concentration decreased with fish oil in individuals with d5 and 55 genotypes relative to those given corn/soybean oil, but no change was noted in those with the dd genotype. No differences were observed in heart rate, blood pressure, or LDL particles.¹⁰³ This study demonstrated that responses to fish oil supplements are affected by the ALOX5 genotype.

CONCLUSION

In the field of CVDs, ongoing GWAS continue to uncover and identify new loci, with numerous investigations exploring how these polymorphisms interact with various diets. For instance, the CETP gene polymorphism is linked to responses to the MedDiet, leading to changes in cholesterol and TG levels. Similarly, polymorphisms in the APOA1 gene may affect HDL-C responses to dietary fats. Additionally, polymorphisms in the APOE, LIPC, and APOA5 genes can modify the impact of high-fat or low-fat diets on lipid profiles. These findings underscore the importance of tailoring dietary recommendations to individual genetic profiles. Despite the growing body of gene studies, research on the interactions between diet and genes remains relatively scarce. There is a pressing need for more research to evaluate the benefits and drawbacks of studying single genes versus multiple genes in conjunction. Moreover, considering the potential effects of gene-drug interactions, such as those involving bioactive food components, could enhance the efficacy of gene-diet studies. Furthermore, the impact of genetic information on an individual’s nutritional status is still unclear. It is crucial to recognize that individuals lacking risk alleles might be inclined to consume more unhealthy foods, while those with risk alleles may require psychological evaluation.

In conclusion, understanding the interactions between genetic makeup and diet is essential for developing personalized nutrition strategies that can significantly reduce the risk of CVDs. Future strategies should focus on collecting genetic information to build databases, enhancing public and healthcare professional awareness through education on nutrigenetics, improving access to genetic testing, conducting multidisciplinary research, and prioritizing long-term clinical studies that emphasize collaboration. These initiatives are poised to contribute to more effective and reliable solutions in the field.