The c.*52 A/G and c.*773 A/G Genetic Variants in the UTR′3 of the LDLR Gene Are Associated with the Risk of Acute Coronary Syndrome and Lower Plasma HDL-Cholesterol Concentration

Abstract

Dyslipidemia has a substantial role in the development of acute coronary syndrome (ACS). Low-density lipoprotein receptor (LDLR) plays a critical role in plasma lipoprotein hemostasis, which is involved in the formation of atherosclerotic plaque. This study aimed to evaluate whether LDLR gene polymorphisms are significantly associated with ACS and the plasma lipids profile. Three LDLR gene polymorphisms located in the UTR′3 region (c.*52 A/G, c.*504 A/G, and c.* 773 A/G) were determined using TaqMan genotyping assays in a group of 618 ACS patients and 666 healthy controls. Plasma lipids profile concentrations were determined by enzymatic/colorimetric assays. Under co-dominant and recessive models, the c.*52 A allele of the c.*52 A/G polymorphism was associated with a higher risk of ACS (OR = 2.02, pCCo-dom = 0.033, and OR = 2.00, pCRes = 0.009, respectively). In the same way, under co-dominant and recessive models, the c.*773 G allele of the c.*773 A/G polymorphism was associated with a high risk of ACS (OR = 2.04, pCCo-dom = 0.027, and OR = 2.01, pCRes = 0.007, respectively). The “AAG” haplotype was associated with a high risk of ACS (OR = 1.22, pC = 0.016). The c.*52 AA genotype showed a lower HDL-C concentration than individuals with the GG genotype. In addition, carriers of c.*773 GG genotype carriers had a lower concentration of the high-density lipoprotein-cholesterol (HDL-C) than subjects with the AA genotype. Our data suggest the association of the LDLRc.*773 A/G and LDLR c.*52 A/G polymorphisms with both the risk of developing ACS and with a lower concentration of HDL-C in the study population.

Functional Analysis of 3′UTR Variants at the LDLR and PCSK9 Genes in Patients with Familial Hypercholesterolemia

“…In addition, 5 of the 8 PCSK9-3′ UTR variants were predicted to remove miRNA binding sites and have potentially pathogenic variants. Previous studies have shown that LDLR:c * 504 A>G and c * 773 A>G variants associated with low HDL levels and a higher risk of CVD could downregulate LDLR by illegitimate binding with miR-200a and miR-638, according to in silico predictions [30]. In another study, a bioinformatics analysis of seven 3 ′ UTR variants in PCSK9 carried by Brazilian patients with FH predicted the removal of miRNA binding that could upregulate PCSK9 [19].…”

“…A number of studies have reported an association between common polymorphisms in the LDLR-3 ′ UTR and PCSK9-3 ′ UTR regions with LDL-c levels [19,20,29], low HDL-c levels [30], and the response to lipid-lowering drugs [31,32]. Dysregulation of miRNA binding by 3 ′ UTR polymorphisms has been proposed as the underlying mechanism of lipid abnormalities.…”

Genetic Polymorphisms and Their Interactions with the Risk Factors of Cardiovascular Diseases: Review Chapter

“…After binding to the cell membrane, the molecules are taken into the cell where metabolism and cholesterol synthesis take place (TC, LDL-C, HDL-C). Changes in this gene have been linked to the development of conditions like familial hypercholesterolemia [77][78][79].…”