Hereditary heart disease
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The primary cause of death worldwide is Coronary Artery Disease (CAD). Its development is influenced by lifestyle choices, age, sex, and inherited genetic variations. A research group comprising the CARDioGRAM and the Coronary Artery Disease Genetics Consortia has verified ten previously recognized indicators linked to heart disease and discovered 13 new genetic markers that raise the risk of heart disease.
The initial gene linked to myocardial infarction was the LDL receptor gene (LDL-R). Mutations in this gene completely prevent receptor synthesis in hepatocytes (known as "null mutations") or alter it in a way that prevents binding to circulating LDL for elimination in bile. In the Mediterranean region of Spain, 55% of the mutations found in heterozygous patients were null mutations, while the remaining mutations were simple nucleotide mutations, with the most common being 1146 G/A, 1301 C/G, and 829 G/A.
The Pvu II polymorphism in intron 15 is a frequently observed variation that creates RFLP polymorphism (restriction fragment length polymorphism) by enabling the Pvu II enzyme to establish a cutoff and generate fragments of varying lengths during electrophoretic analysis. Although not extensively studied, this variant is believed to impact LDL concentration and coronary risk.
Familial hypercholesterolemia can also be caused by the Arg3500Gln mutation (and, in rare cases, Arg3531Cys) of apolipoprotein B (apo-B100), which serves as a ligand for LDL receptors (known as familial defect of apo-B or FDB). This mutation hinders the recognition of the LDL receptor and makes it challenging to eliminate from the plasma, although it is a less severe cause. Its occurrence is estimated to be one case per 250-1000 individuals.4,6,7
Although certain polymorphisms of the apo-B gene are frequently linked to hypercholesterolemia and coronary artery disease, their association remains uncertain due to conflicting study findings.
Apo-E is a protein that performs the same function as apo-B by binding to lipoproteins that are high in triglycerides, such as very-low-density (VLDL) and intermediate-density lipoproteins (IDL). There are three primary variations of apo-E: the most prevalent is the natural isoform, apo-E3, while the other two are mutant forms. Apo-E2 has a cysteine substitution for arginine at position 158, and apo-E4 has an arginine substitution for cysteine at position 112.
The apo-E4 polymorphic allele exhibits lower affinity towards apo-B/E receptors compared to apo-E3 and is linked to a minor elevation in cholesterol and plasma triglycerides. Its correlation with coronary artery disease is firmly established.
Lipoproteins known as Lp(a) are a minor subset of LDL particles. They differ from regular LDL particles by containing a molecule of apo(a) in addition to apo-B100. Apo(a) is very similar to plasminogen, but it does not play a role in fibrinolysis. The kringle IV ring of apo(a) contains multiple repeated sequences, up to a maximum of 37. This is the same sequence that is repeated five times in plasminogen and is named after a Danish cookie, known as a "kringle."
HDL-PON1, also known as Paraoxonase/aryl esterase, is an enzyme that is found specifically in HDL (associated with apo-A1). Its function is to hydrolyze lipid peroxides and eliminate proinflammatory molecules that result from LDL oxidation. This enzyme is believed to play a significant role in the development of atherosclerosis. It is typically present in the arterial wall and its concentration increases significantly in atheroma, potentially due to heightened oxidative stress.
The ABC1 transporter protein plays a crucial role in facilitating the removal of cholesterol from cells by creating a channel through which it can exit the membrane and be transferred to HDL particles after undergoing LCAT sterification. The discovery that Tangier's disease, a rare genetic disorder characterized by low HDL levels and premature coronary disease, is caused by a mutation in the ABCA1 transporter gene has prompted research into identifying common gene polymorphisms that may impact coronary risk.
Although the impact may be weak, there is a more distinct correlation between the Polymorphism M235T of the angiotensinogen (AGT) gene and hypertension. However, its connection to coronary artery disease is uncertain. While some studies have shown that the 235 TT genotype doubles the risk of coronary heart disease and myocardial infarction, the Copenhagen City Heart Study, which included over 2800 patients, did not find any significant association.
Chymase is an enzyme found in the vascular wall and heart that can convert Ang I to Ang II and big ET-1 to ET-1. The presence of this enzyme clarifies why tissular Ang II production can remain unaffected despite complete ACE inhibition. However, confirming the link between CMA A-1905G polymorphism and myocardial infarction has not been achievable thus far.
The study also examines various polymorphisms, including those found in the gene for the β2 adrenergic receptor (ADRB2-Arg16Gly and Gln27Glu), α-adducin (Gly460Trp), a protein located in the inner layer of the plasma membrane that may contribute to salt-sensitive hypertension, and the endothelin (EDN1) and its A and B receptors (EDNRA and EDNRB). However, it is premature to classify them as risk genes.
The primary objectives are to create treatments that can impede the advancement or avert the onset of CHD. The integration of genome editing, cardiac bioengineering, and cardiac organoid models, facilitated by the latest developments in sequencing technologies and functional genomic models of CHD, will enable the maturation of these technologies. This, in turn, will pave the way for novel regenerative and preventive therapeutic methods to address the fundamental disease mechanisms in CHD patients in the future.