Mutual Effect of rs688 and rs5925 in Regulating Low-Density Lipoprotein Receptor Splicing

Abstract

Analysis of the low-density lipoprotein receptor (LDLR) gene based on the rs688 and rs5925 genetic polymorphisms has provided evidence suggesting that haplotypes related to rs688 and rs5925 are associated with ischemic cerebrovascular diseases. Both rs688 and rs5925 have been empirically identified as exon-splicing enhancers in silico, and rs688 has been shown to be a functional polymorphism that modulates LDLR exon 12 splicing efficiency both in vitro and in vivo. The aim of this study was to evaluate whether rs688 and rs5925 and their haplotypes may alter the splicing efficiency of exons 12 and 13 both in vivo and in vitro. When the minigenes were evaluated for splicing efficiency, we found that converting rs688C to the T allele reduced exon 12 splicing efficiency. In parallel, converting rs688T to the C allele increased the efficiency of exon 12 inclusion. The apparent difference in splicing efficiency was 9.36%±2.58% between the C and T alleles. When rs688C existed in the minigene, the major and minor rs5925 alleles were also sufficient to account for the differences in splicing efficiency of LDLR involving exon 13. The apparent splicing efficiency difference was 5.43%±2.87%. Sequential mutations of rs688 and rs5925 were performed to generate four different haplotypes in the LDLR minigene system. The splicing efficiencies for the haplotypes CC, CT, TC, and TT were 79.60%±1.38%, 76.68%±0.85%, 69.02%±1.79%, and 68.54%±1.38%, respectively. The splicing efficiency of the four haplotype groups differed significantly. In vivo analysis of human leukocyte samples was also compatible with in vitro analysis, indicating a mutual effect between rs688 and rs5925 in regulating LDLR splicing efficiency.

LDLR Gene Polymorphisms (rs5925 and rs1529729) Are Associated with Susceptibility to Coronary Artery Disease in a South Indian Population

“…It was indicated that the GA genotype of the rs5925 polymorphism is associated with decreased susceptibility to CAD with an OR = 0.45 (95% CI, 0.27–0.75), RR = 0.65 (0.47–0.88), P = 0.002. The rs5925 polymorphism (in cooperation with the rs688 polymorphism) has been shown to regulate the splicing efficiency of the LDLR gene [29]. This result may be consistent with a study that showed that the rs5925 polymorphism is associated with the thickness of the carotid-intima media in Slovenian type 2 diabetes T2D patients [30].…”

“…We suggest that the T allele of the rs1529729 polymorphism and the GA genotype of the rs5925 polymorphism protect against CAD by increasing the expression of LDLR at the hepatocyte surface such that LDL-C uptake and metabolism is enhanced. In support of this suggestion, the rs5925 polymorphism has been described as an exon-splicing enhancer [29]. However, the effect of rs1529729 and rs5925 polymorphisms on LDLR expression should be to be elucidated in a future study.…”

Post-Traumatic Stress Disorder Is Associated with Elevated Plasma Cholesterol in Female TT Homozygotes of LDLR rs5925

“…This polymorphism variation is sufficient to explain the differences of LDLR involving exon 13 in splicing efficiency. The C allele can result in enhanced exon 13 splicing efficacy in LDLR [38]. Therefore, the effects LDLR rs5925 observed in the present study on the prevalence of PTSD and plasma lipid profiles in the male and female subjects with or without PTSD may be due to the difference of splicing efficiency.…”

Polimorfismos de los genes LEP, LDLR, APOA4, sus relaciones con sobrepeso, obesidad y riesgo de enfermedades crónicas en adultos del estado Sucre, Venezuela

“…Tratándose de cambios en el intrón (rs885765) o en regiones no traducidas del gen (rs55903358 y rs5742911), es posible que su papel sea regulador; por su parte, los cambios dentro de los exones (rs688 y rs5925) son sinónimos; sin embargo, hay estudios que revelan su influencia sobre la modulación del proceso de corte y empalme del gen, produciendo diferencias en los niveles del colesterol LDL (54,55).…”