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Gene & Protein in Disease rs670 SNP in APOA1 gene

The frequency of the minor allele varied across SR-B1 receptors also contribute to HDL’s antiatherogenic
continents. In Asia, the frequency ranged from 14% to 47% effects through Apo A-I as binding to these receptors results
with an average of 26%. In America, it ranged from 15% to in cholesterol efflux from macrophages and reduction
31% with an average of 22.125%, while in Europe, it ranged of LDL transcytosis by endothelial cells – key processes
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from 15% to 37% with an average of 22.75%. In Africa, in atherosclerosis pathophysiology. However, SR-B1
only one study reported a frequency of 22.5%. Although receptor overexpression in malignant cells correlates with
minor allele frequencies are influenced by sample size, increased tumor size and reduced survival. In vitro and
it is evident that the rs670 SNP is prevalent in the global in vivo studies suggest that the levels of HDL and its cancer
population, with an average frequency exceeding 20%. cell uptake through SR-B1 receptors are associated with
tumor progression. 28,29 This uptake is hypothesized to serve
4. Discussion as an escape mechanism from oxidative stress-mediated
HDL is involved in reverse cholesterol transport and plays a immune responses, as it increases antioxidant and anti-
critical role in removing excess cholesterol from peripheral inflammatory agents in the tumor microenvironment.
tissues, redirecting it to the liver for excretion or recycling. Based on this mechanism, alternative antitumor therapies
The antiatherogenic role of HDL is achieved by refluxing involve HDL-functionalized nanoparticles delivering
cholesterol from macrophages through SR-B1 receptors in small interfering RNA targeting SR-B1 receptors. 30
the subendothelial layer, preventing their differentiation into Environmental factors, such as diet and drugs, influence
foam cells initiating atherosclerotic plaque formation. In Apo A-I synthesis and secretion primarily by modulating
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addition, HDL exhibits antioxidant and anti-inflammatory peroxisome proliferator-activated receptor alpha (PPARα).
activities mediated by paraoxonase-1 and Apo A-I. These PPARα activates the transcription of genes involved in lipid
mechanisms enable HDL to reduce cholesterol oxidation and carbohydrate metabolism, including APOA1. PPARα
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and regulate macrophage activity, thereby mitigating agonists have emerged as a therapeutic option for managing
oxidative stress and vascular inflammation. 16 metabolic disorders such as dyslipidemia and diabetes,
Apo A-I and its mimetic peptides exert anti- improving reverse cholesterol transport, reducing TG, and
inflammatory and antiatherogenic effects by lowering exerting antidiabetic effects. 32,33 In vivo studies suggest that
adhesion molecule expression, suppressing macrophage PPARα activation enhances mitochondrial activity and
proptosis, and inhibiting monocyte chemotaxis. 17,18 The provides protection against diabetic keratopathy and non-
mechanisms of Apo A-I include cholesterol efflux through alcoholic fatty liver disease (NAFLD). 34,35
SR-B1 receptors and ATP-binding cassette subfamily A Apo A-I, through hepatic PPARα activation, is
member 1 (ABCA1), which inhibit macrophage activation protective against high-fat diet-induced NAFLD. Dietary
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and reduce proinflammatory cytokine expression factors also regulate nuclear signaling via PPARα for Apo
through Janus kinase 2/signal transducer and activator of A-I synthesis. For instance, a low-choline diet is linked to
transcription 3 signaling. 19,20 Furthermore, Apo A-I disrupts methylation of CpG sites in the promoter region of PPARA,
membrane lipid rafts expressing Toll-like 4 receptors, reducing PPARA and APOA1 expression in pregnant
thereby decreasing the activation of the phosphatidyl mice. Other dietary components, such as ellagic acid, n-3
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inositol 3-kinase/PI3K-activated serine-threonine kinase polyunsaturated fatty acids, short-chain fatty acids, and
(PI3K/Akt) signaling pathway in macrophages. 17,21 tryptophan, activate PPARα and increase hepatic Apo A-I
Structural changes in Apo A-I are notably linked to a levels. 38-41 Gene-diet interactions have identified two SNPs
loss of anti-inflammatory activity, ranging from altered in the 3’ untranslated region of PPARA (rs6008259 G > A
affinities for phospholipid structures to conformational and rs3892755 C > T) that interact with n-3 and n-6 long-
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changes induced by the non-enzymatic glycation of lysine chain fatty acid-rich diets, reducing TC and LDL-c levels.
residues. 22,23 Increased modified Apo A-I levels promote Over 150 genetic variations have been identified in
cardiovascular events, dyslipidemia, and diabetes. In APOA1. The first reported variation, Apo A-I Milano,
17
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vivo studies show that Apo A-I and its mimetic peptides involves an Arg173Cys substitution (rs28931573 G>A) that
influence glycemic control by enhancing insulin secretion changes the codon CGC to UGC. 44,45 Another SNP, rs670,
and sensitivity, facilitating insulin-independent glucose located in the promoter region of APOA1, alters a CpG site
uptake, and suppressing gluconeogenesis. Its mechanisms and may affect gene expression rates, thereby influencing
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appear reliant on SR-B1 and ABCA1 receptors to activate Apo A-I synthesis. The rs670 polymorphism is associated
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the PI3K/Akt and AMPK (AMP protein kinase) pathways with increased Apo A-I and HDL-c levels, potentially
in skeletal muscle cells, leading to greater GLUT4 producing HDL particles with higher protein content and
transporter translocation. 25,26 enhanced reverse cholesterol transport, antioxidant, and

Volume 4 Issue 1 (2025) 6 doi: 10.36922/gpd.4354