ArticlePloS one2016
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.
Article in PloS one, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers, 2 of them syntheses that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
22 citing papers in PubMed, 2 syntheses or guidelines pooled it, 37 citations in OpenAlex.
- The landscape of GWAS validation; systematic review identifying 309 validated non-coding variants across 130 human diseases.BMC medical genomics · 2022Pooled it
- The pharmacogenetics of rosuvastatin and implications for treatment: a systematic review.PharmacogenomicsPooled it
- A multi-domain algorithm towards precision nutrition: integrating genetic risk scores and phenotypic diversity in the elderly, the MyFOOD4Senior study.Genes & nutrition · 2026Article
- Functional interrogation of candidate cis-regulatory elements at the LDLR locus.PLoS genetics · 2026Article
- Association between LDL-R (exon 8 C.1171 G > A) polymorphisms and response to antiviral therapy in hepatitis C virus infection.Scientific reports · 2026Article
- Variants in candidate genes and their interactions with smoking on the risk of acute coronary syndromeBiomedica : revista del Instituto Nacional de Salud · 2025Article
- The Impact of SNP Score on Low-Density Lipoprotein Cholesterol Concentration and Coronary Artery Disease.International journal of molecular sciences · 2025Article
- Pharmacologic and Genetic Downregulation of Proprotein Convertase Subtilisin/Kexin Type 9 and Survival From Sepsis.Critical care explorations · 2023Article
- Calling and Phasing of Single-Nucleotide and Structural Variants of theInternational journal of molecular sciences · 2023Article
- Genetic Factors for Coronary Heart Disease and Their Mechanisms: A Meta-Analysis and Comprehensive Review of Common Variants from Genome-Wide Association Studies.Diagnostics (Basel, Switzerland) · 2022Review
- Whole genome sequence analysis of blood lipid levels in >66,000 individuals.Nature communications · 2022Article
- Genetic Variants in Transcription Factor Binding Sites in Humans: Triggered by Natural Selection and Triggers of Diseases.International journal of molecular sciences · 2021Review
- A minor allele of the haplotype located in the 19q13 loci is associated with a decreased risk of hyper-LDL-cholesterolemia, and a balanced diet and high protein intake can reduce the risk.Lipids in health and disease · 2020Article
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- Identifying genetic markers associated with susceptibility to cardiovascular diseases.Future science OA · 2019Review
- Nutrigenetic Contributions to Dyslipidemia: A Focus on Physiologically Relevant Pathways of Lipid and Lipoprotein Metabolism.Nutrients · 2018Review
- Genetic Risk in Coronary Artery Disease.Arquivos brasileiros de cardiologia · 2018Article
- Article
- Usefulness of the genetic risk score to identify phenocopies in families with familial hypercholesterolemia?European journal of human genetics : EJHG · 2018Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
backgroundThe 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.
methodsThe 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.
resultsThe 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.
conclusionBoth 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.
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