LDLR rs688 TT Genotype and T Allele Are Associated with Increased Susceptibility to Coronary Artery Disease—A Case-Control Study

Abstract

Purpose: The low-density lipoprotein receptor is responsible for the binding and uptake of plasma LDL particles and plays a critical role in maintaining cellular cholesterol homeostasis. LDLR gene SNP rs688 has been reported to be associated with increased plasma total and LDL cholesterol in several populations and can lead to elevated plasma LDL levels, resulting in an increased risk for atherosclerosis and coronary artery disease. This study aimed to explore genetic LDLR variant rs688 for its potential roles in coronary artery disease. Methodology: This study recruited 200 coronary artery disease patients and 200 healthy individuals. Genotyping of LDLR-rs688C > T gene variations was performed using the allele specific PCR method. Correlation of LDLR-rs688C > T gene variants with different clinicopathological features of coronary artery disease patients was performed. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were applied to evaluate the correlation of this microRNA polymorphism with coronary artery disease risk. Results: A significant difference was observed in genotype distribution among the coronary artery disease and matched healthy controls (p = 0.003). The frequencies of all three genotypes CC, CT, TT reported in the patient samples were 14%, 65% and 21% and in the healthy controls samples were 18%, 73% and 9%, respectively. The increased risk of developing CAD in Indian patients was found to be associated with LDLR rs688 TT genotype (OR = 3.0, 95% CI, 1.43 × 6.2; p = 0.003) RR 1.87 (1.20–2.91) p = 0.0037) and also the increased risk of developing CAD was reported to be associated with LDLR rs688 T allele (OR = 0.74, 95% CI, 1.57–0.97; p = 0.03) RR 0.85 (0.73–0.99) p = 0.03) compared to the C allele. Therefore, it was observed that more than a 3.0- and 0.74-fold increase risk of developing CAD was associated with TT genotype and T allele in Indian coronary artery disease patients. Conclusion: The findings indicated that LDLR rs688 TT genotype and T allele are associated with an increased susceptibility to coronary artery disease patients. LDLR-rs688C > T gene variation can be used as a predisposing genetic marker for coronary artery disease. Further studies with larger sample sizes are necessary to confirm our findings.

Interaction between Sex and LDLR rs688 Polymorphism on Hyperlipidemia among Taiwan Biobank Adult Participants

“…According to findings from previous studies, the LDLR rs688 T/T genotype and T allele are associated with lipid traits [20,21] and heightened risk of coronary artery diseases [11,13]. Our data showed that the risk of hyperlipidemia was significantly lower in men with the T/T genotype as noted above.…”

“…Associations have also been reported between the T allele of the rs688 polymorphism and elevated total and LDL-cholesterol, particularly in pre-menopausal women [11,12]. It has been established that the rs688 C/T allele would greatly alter LDLR exon 12 splicing efficiency in women, especially those considered to be menopausal [11]. This in part may be the reason why the T allele was the significant risk allele for hyperlipidemia among women in our study.…”

“…In a previous study, cholesterol values for rs688 C/T and T/T carriers were both significantly higher than the C/C carriers, but not different from each other [12]. Associations have also been reported between the T allele of the rs688 polymorphism and elevated total and LDL-cholesterol, particularly in pre-menopausal women [11,12]. It has been established that the rs688 C/T allele would greatly alter LDLR exon 12 splicing efficiency in women, especially those considered to be menopausal [11].…”

“…Effects of genetic factors on hyperlipidemia may be direct or indirect in that, they may be mediated either by other genetic factors or by environmental and lifestyle choices. The low-density lipoprotein receptor (LDLR) gene is one of those genes that play an important role in maintaining cellular cholesterol homeostasis [10,11]. Several mutations in this gene have been reported to influence exons, splicing sites, and the promoter regions [11], and have also been recognized as a primary cause for familial hypercholesterolemia [12], a condition that has been associated with defective LDL uptake and degradation [4].…”

“…One of the LDLR variants, rs688, has shown significant associations with coronary heart disease [13] as well as with higher plasma cholesterol levels (approximately 4%-10%) in different populations [12,[14][15][16][17][18]. Furthermore, the rs688 T/T genotype has shown associations with hyperlipidemia [11] and Alzheimer's disease [19] in a sex-dependent manner. Moreover, it was reportedly associated with higher total and LDL-cholesterol, particularly in pre-menopausal women [12].…”