Identification of the functional variant(s) that explain the low-Density lipoprotein receptor (LDLR) GWAS SNP rs6511720 association with lower LDL-C and Risk of CHD

26Citations
Citations of this article
33Readers
Mendeley users who have this article in their library.

Abstract

Background The Low-Density Lipoprotein Receptor (LDLR) SNP rs6511720 (G>T), located in intron-1 of the gene, has been identified in genome-wide association studies (GWAS) as being associated with lower plasma levels of LDL-C and a lower risk of coronary heart disease (CHD). Whether or not rs6511720 is itself functional or a marker for a functional variant elsewhere in the gene is not known. Methods The association of LDLR SNP rs6511720 with incidence of CHD and levels of LDL-C was determined by reference to CARDIoGRAM, C4D and Global lipids genetics consortium (GLGC) data. SNP annotation databases were used to identify possible SNP function and prioritization. Luciferase reporter assays in the liver cell line Huh7 were used to measure the effect of variant genotype on gene expression. Electrophoretic Mobility Shift Assays (EMSAs) were used to identify the Transcription Factors (TFs) involved in gene expression regulation. Results The phenotype-genotype analysis showed that the rs6511720 minor allele is associated with lower level of LDL-C [beta = -0.2209, p = 3.85 x10-262 ], and lower risk of CHD [log (OR) = 0.1155, p = 1.04 x10-7 ]. Rs6511720 is in complete linkage. Rs6511720 is in complete linkage disequilibrium (LD) with three intron-1 SNPs (rs141787760, rs60173709, rs57217136). Luciferase reporter assays in Huh7 cells showed that the rare alleles of both rs6511720 and rs57217136 caused a significant increase in LDLR expression compared to the common alleles (+29% and +24%, respectively). Multiplex Competitor-EMSAs (MC-EMSA) identified that the transcription factor serum response element (SRE) binds to rs6511720, while retinoic acid receptor (RAR) and signal transducer and activator of transcription 1 (STAT1) bind to rs57217136. Conclusion Both LDLR rs6511720 and rs57217136 are functional variants. Both these minor alleles create enhancer-binding protein sites for TFs and may contribute to increased LDLR expression, which is consequently associated with reduced LDL-C levels and 12% lower CHD risk.

References Powered by Scopus

Biological, clinical and population relevance of 95 loci for blood lipids

3019Citations
N/AReaders
Get full text

Histone H3K27ac separates active from poised enhancers and predicts developmental state

2993Citations
N/AReaders
Get full text

Capturing chromosome conformation

2801Citations
N/AReaders
Get full text

Cited by Powered by Scopus

Sesamol: a powerful functional food ingredient from sesame oil for cardioprotection

80Citations
N/AReaders
Get full text

The landscape of GWAS validation; systematic review identifying 309 validated non-coding variants across 130 human diseases

33Citations
N/AReaders
Get full text

Whole genome sequence analysis of blood lipid levels in >66,000 individuals

32Citations
N/AReaders
Get full text

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Cite

CITATION STYLE

APA

Fairoozy, R. H., White, J., Palmen, J., Kalea, A. Z., & Humphries, S. E. (2016). Identification of the functional variant(s) that explain the low-Density lipoprotein receptor (LDLR) GWAS SNP rs6511720 association with lower LDL-C and Risk of CHD. PLoS ONE, 11(12). https://doi.org/10.1371/journal.pone.0167676

Readers' Seniority

Tooltip

PhD / Post grad / Masters / Doc 12

57%

Researcher 5

24%

Professor / Associate Prof. 2

10%

Lecturer / Post doc 2

10%

Readers' Discipline

Tooltip

Biochemistry, Genetics and Molecular Bi... 10

50%

Medicine and Dentistry 5

25%

Agricultural and Biological Sciences 4

20%

Chemistry 1

5%

Article Metrics

Tooltip
Mentions
News Mentions: 1

Save time finding and organizing research with Mendeley

Sign up for free