The relationship between dyslipidemia and atherosclerosis continues to be an area of active research, since the prevalence of atherosclerosis and associated cardiovascular complications continue to increase in the industrialized world ¹ . Cardiovascular disease (CVD) constitutes the greatest cause of morbidity and mortality globally with a high incidence in countries of all economic categories ² . Evidence supporting a causal relationship between lipid profile abnormalities and the risk of coronary artery disease (CAD) is overwhelming, confirming that hypercholesterolemia is an independent risk factor for CVD ^{3– 5} . In addition, hypertriglyceridemia and mixed dyslipidemias have been associated with the aggregation of metabolic risk factors, like hypertension (HTN) ⁶ and obesity ⁷ .

Dyslipidemias are a group of metabolic derangements characterized by any or a combination of the following: elevated low density lipoprotein (LDL-c) (>130md/dL), elevated total cholesterol (>200 mg/dL), elevated TG (>150mg/dL), or low high density lipoprotein (HDL-c) (<40mg/dL in men and <50mg/dL in women) ⁸ .

The worldwide prevalence of dyslipidemia varies between different individuals, depending on race, age, socio-economic and cultural factors, lifestyle and genetics. This prevalence has increased significantly in growing cities with economic growth ⁹ . The factors are undoubtedly related to high calorie intake described by other Western nations ¹⁰ ; while lower prevalence has been reported for these pathologies in Canada and South Korea where 45% and 44.1% of their respective populations present evidence of dyslipidemia ^{11, 12} . The difference of prevalence in these nations is indisputably tied to lifestyle with various publications highlighting diets rich in fiber and low in fats and refined sugars ^{13, 14} .

In Brazil, de Souza et al. 2003. ¹⁵ reported the most frequent dyslipidemias in their 1039 sample population were isolated low HDL-C (18.3%), hypertriglyceridemia (17.1%), and isolated hypercholesterolemia (4.2%). These results differ from those reported in the CARMELA study from Mexico between 2003 and 2005 ¹⁶ , where the incidence of dyslipidemia in 1722 person sample size reported 16.4% with hypercholesterolemia and 32.5% with hypertriglyceridemia - slightly higher than those reported in Brazil. The differences could be related to the food preferences within Mexico, which include greater amounts of fat, simple sugars, and processed ingredients ¹⁷ . It must also be noted that these studies are over 10 years old as no more recent publications in Latin America were found. With the continued rise in dyslipidemias and obesity, these numbers do not necessarily reflect the current reality of these pathologies in the studied populations.

In Venezuela, the CARMELA study evaluated the prevalence of these lipid metabolism disorders in the city of Barquisimeto. The researchers found 59.6% of the 1824 subjects to suffer from dyslipidemia in 2003 ¹⁸ . A decade later, Linares et al. ¹⁹ published a study of 1892 sample size from the city of Maracaibo, Venezuela showing a prevalence of 84.8% - the highest figure reported to date. The difference of prevalence is related to both the ten year gap between the studies as well as the regional differences between the sample populations. Even though these two studies occurred in Venezuela, the two sites have different cultures, climate, and completely different nutritional food preferences. The diet of the latter is traditionally high in calories, protein, and carbohydrates with an elevated alcohol intake ²⁰ while only 40% of the former ever ate fast food or other foods outside the home ²¹ .

In the majority of the studies of prevalences there is a clear tendency to evaluate younger populations, (22–24 years of age) as in the study by Barja et al. between 2009–2011 ²³ where 2900 school-age children were evaluated with the average age of 11.42±0.97 years old. Of this sample, 9.4% had isolated hypertrigliceridemia, 7.6% with low HDL-C, 4.9% with isolated hypercholesterolemia, 6.24% with atherogenic dyslipidemia, and 3.9% with mixed dyslipidemia. The existence of hyperlipidemia increases the potential for deposits on the tunica intima and the formation of arterial plaques. A correct early diagnosis of dyslipidemia allows for timely preventive intervention resulting in a reduction cardiovascular disease and facilitates the patient’s clinical treatment ²⁵ .

The association between family history of dyslipidemia and the risk of CVD is supported by a large body of evidence ^{18– 22} . Additionally, the great advancement in DNA analysis techniques has aided research surrounding CVD and related genetics and epigenetics. Understanding gene mutations or polymorphisms involved in the synthesis, transport, and metabolism of lipoproteins allows recognition of potential therapeutic targets and alternative treatments through identification of new molecules ^{1, 3, 20} .

Dyslipidemia is one of the most well characterized cardiovascular risk factors ^{19, 20} . This not only depends on diet, but also on the synthesis and metabolism of lipoproteins conditioned by gene expression. Given the importance and the great diversity of proteins that participate in lipid metabolism, one might expect that a single defect in any step of gene expression would affect the quantity or quality of the product and potentially predispose to dyslipidemias and CVD ¹⁹ .

One genetic abnormalities associated with low HDL-c and increased CVD risk is the Taq IB polymorphism located in chromosome 16q21. This gene alters cholesteryl ester protein transferase (CEPT), which decreases HDL-c concentration ²³ . Some deletions, inversions, and substitutions of the APO AI-IV, CII, and CIII genes are also associated with both premature CVD and low HDL-c ^{24, 25} . Total deficiency of lecithin cholesterol acyl transferase (LCAT) can be seen after transition of C→T in codon 147 of exon 4 (W147R), G→A in codon 293 of exon 6 (M293I), as well as partial deficiencies of LCAT due to transition of C→T. Additionally, the substitution of threonine for isoleucine in codon 123 (T123I) causes decreased HDL-c and higher cholesterol in the intima of arterial vessels ^{26, 27} .

Below, some of the genetic alterations associated with low levels of HDL-c and a higher risk of CVD are highlighted:

The following are some genetic alterations associated with hypercholesterolemia and hypertriglyceridemia, including their relationship with increased cardiovascular risk:

This information justifies the use of genetic markers for early diagnosis and cardiovascular risk assessment, especially in children and adolescents, in order to adopt early nutritional or pharmacologic interventions with the aim to mitigate atherosclerotic artery disease.

The LPL gene is located on the short arm of chromosome 8, on the region 21.3 (8p21.3). It is formed of 10 exons and 9 introns ( Figure 1), and the gene codifies a protein of 475 amino acids ^{53, 54} .

LPL is a multifunctional glycoprotein enzyme that plays an important role on lipid metabolism. After being secreted, it adheres to the luminal surface of endothelial cells where it hydrolyzes TG in circulating lipoproteins. This constitutes the limiting step on lipoprotein elimination, such as CMs from exogenous sources, and those endogenous sources, like VLDL, in circulation ^{55, 56} .

In this way, LPL affects serum levels of TG, generating lipoprotein remnants that are processed by hepatic lipase. Recently, it has been demonstrated that LPL serves as a ligand for the protein related to the LDLR and influences hepatic secretion and VLDL and LDL-c capture ⁵⁷ . Additionally, LPL has been linked to the retention of LDL-c by the sub-endothelial matrix and arterial wall, increasing LDL and VLDL conversion into more atherogenic forms ⁵⁸ . Genetic modifications can affect LPL activity, which results in changes in lipid metabolism. Examples are slow hydrolysis of CMs and VLDL-c, longer LDL-c half-life, and decreased production of HDL ^{59, 60} .

Around 100 mutations have been described on the LPL gene. The most frequent are Asp9sn, Gly188Glu and Asn291Ser. The mutations in the homozygous form are associated with hyperlipoproteinemia type I (familial chylomicronemia). Heterozygous mutations have a significant incidence in the general population (3–7%) and leads to up to a 50% decreased activity of LPL, causing an increase in TG and a decrease in HDL-c. All these lipid profile patterns increase the risk of CVD ⁶¹ .

Genetic studies have revealed around 100 mutations and polymorphisms in simple nucleotides on the LPL gene, some are protective, which others are deleterious:

HindIII is a transition of intronic bases of thymine (T) to guanine (G) on position 495 of intron 8 of the LPL gene, which eliminates the restriction site for the HindIII enzyme ( Figure 2 and Figure 3). Sequential analysis has determined that this HINDIII recognition site corresponds with the binding consensus sequence for the transcription factors Sp1, GATA, C/EBP, and TBP. The first three are implicated in the regulation of the gene transcription involved in lipid metabolism ^{65– 67} . The transcription factor TBP (the binding protein for the TATA box) initiates the formation of the preinitiation complex that permits gene transcription for part of RNA polymerase II ⁶⁸ . Mobility shift electrophoresis has shown that human vascular smooth muscle cells and COS-1 cell carriers of the G/G allelele demonstrated reduced TBP binding affinity ⁶⁹ . THis indicates less LPL expression in polymorphism carriers, conferring functionality of said SNP.

HindIII is one the most frequent polymorphisms found in various studies, which show that the homozygous genotype T/T (H ⁺/H ⁺) represents from 45.1 to 56.4% of Iranian and south Indian populations, respectively most frequent, followed by the heterozygous T/G with 35.8–36.6% and homozygous G/G (H ^-/H ^-), with 6.93–19% ^{64, 65} . Similar results have been reported in Europe ^{66, 67} and Brazil ⁶⁸ .

The allele H+ (presence of thymine “T” or restriction site of HindIII enzyme) results in a cut on the base pair sequence in two bands of 217pb and 139pb. This is associated with a decrease in the activity of LPL in comparison with the allele H- (presence of “G” or absence of the enzymatic restriction site or presence of HindIII polymorphism). With 137pb, in which there is no cut in the LPL gene intron 8 sequence, maintaining a unique sequence of 356pb ( Figure 4) ⁶⁹ , leading to both alterations in lipidic metabolism and cardiovascular risk profile modifications in these populations.

Some studies have demonstrated that the common allele (T or H+) is associated with lower levels of HDL-c in contrast with the uncommon allele (G or H-) ^{70, 71} . In addition, those individuals with H+/H+ genotype had a higher concentration of serum levels of TG when compared with homozygous genotype H-/H- ^{66, 67, 70, 72} . Similarly, there have been reports of high serum levels of LDL-c ⁷¹ and a higher global cardiovascular risk in patients who carry the common allele (T or H+), see Table 1. Some studies had reported a significant drop in the LPL activity among carriers of the uncommon G allele when compared with the more common allele T ⁵⁷ .

LPL expressed by macrophages and other cells contained in the vascular walls is involved in the early atherogenic process and is associated with increased atherosclerosis. Overexpression of LPL is also associated with insulin resistance and HTN by increased sodium retention, inflammation, vascular remodeling, sympathetic nervous system activation, oxidative stress and vasoconstriction ^{73– 75} .

On the other hand, HTN (mostly systolic) has been shown to be associated with the polymorphism HindIII in the Mexican population in studies by Muñoz-Barrios et al. ⁷⁶ . Similarly, the homozygous genotype for the common allele (H+) was associated with a higher risk of myocardial infarction in patients older than 90 years old in contrast with carriers of the uncommon allele (H-), associated with a lower prevalence of cardiovascular complications ⁷⁷ . Clear associations were found between genotypes of LPL HindIII with HTN (H+/H+ with an OR: 2.13; 95% CI: 0.93-4.8) ⁷² and smoking ⁵⁸ . In a more recent study, it was established that the presence of homozygous genotype for the common allele (H+/H+) of the LPL gene is a risk factor for a first episode of myocardial infarction ⁶⁵ . Conversely, studies by Imeni et al. ⁷⁸ in an Iranian population, showed no statistically significant associations between CAD and genotypic distributions of HindIII polymorphism.

Recent studies have shown increased risk of stroke among those with LPL gene variations, particularly in the HindIII gene ⁷⁹ . He et al. reported a lower risk of stroke among patients with HindIII polymorphisms with allele G (G vs T; OR=0.78, CI95%=0.70-0.87, p<0.001). This pattern was observed in patients with ischemic stroke (G vs T. OR=0.84, CI95%=074-0.95, p=0.005) and hemorrhagic stroke (G vs. T; OR=0.60, CI95%=0.48-0.74, p<0.001) ⁸⁰ .

In other studies, Imeni et al. ⁸⁶ evaluated the relationship between CAD risk and the distribution of HindIII polymorphism genotypes and found no statistical significant differences between healthy Irani individuals and those with CAD history. Ahmadi et al. ⁸⁷ also showed no significant association between the gene and CAD in the 115 Swiss subjects evaluated. These findings are in contrary to the expected improved cardio-cerebral function expected and leave this line of research open for future investigations.

This polymorphism has not only been associated with HA, rather also with insulin resistance. This is best demonstrated with a study of 110 Asian females with gestational diabetes who were found to have a reduced resistance to insulin than carriers of this rare allele ⁸⁸.

From a neurologic point of view, there is scant data associating homozygous common genotype (H+/H+) with the development of Alzheimer’s disease of late appearance. This is founded on the LPL function in regulation cognitive function, mediated by cholesterol and Vitamin E transport to neuronal cells on the hippocampus and other brain areas ⁶⁴ .

These investigations suggest that the presence of the HindIII polymorphism exerts a positive influence in lipid metabolism in patients with normal BMI. Future studies should focus in more detail on the protective function of this genetic factor in the general population.

Dyslipidemias are independent risk factors for atherosclerotic artery disease. High TC, TAG and LDL-C, as well as decreased serum HDL-C, are frequently associated with low physical activity and poor eating habits, but there is a large number of mutations and single nucleotide polymorphism related to a specific protein dysfunction within major lipoprotein metabolism pathways like CETP, ApoA, LCAT, LDL receptor, Apo B-100 and LPL.

In this regard, the LPL gene HindIII polymorphism (rare allele H-) poses a protective function through its role in producing an improved lipid profile (low TG and LDL-c and high HDL-c). On the other hand, the presence of common allele (T or H+) is associated with pro-atherogenic dyslipidemias and raised cardiovascular risk. The uncommon allele (G or H-) with an absence of restriction HindIII enzyme exhibits a lower prevalence of at least 20% according to the current available literature.

There are no studies in Venezuela that allows us to know the true prevalence of the HindIII polymorphism, nor to corroborate the association with changes in the lipid profile or an increased risk for cardiovascular diseases, so we suggest performing a national populational genetic study in search for this lipidic disorders with the aim to has a better understanding of the cardiovascular risk factors in Latin America.

All data underlying the results are available as part of the article and no additional source data are required.