Open Access Research article

A genetic variant in the LDLR promoter is responsible for part of the LDL-cholesterol variability in primary hypercholesterolemia

Isabel De Castro-Orós12*, Javier Pérez-López3, Rocio Mateo-Gallego2, Soraya Rebollar1, Marta Ledesma45, Montserrat León45, Montserrat Cofán6, Jose A Casasnovas45, Emilio Ros6, Jose C Rodríguez-Rey3, Fernando Civeira2 and Miguel Pocoví15

Author Affiliations

1 Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, C. Pedro Cerbuna 12, 50009 Zaragoza, Spain

2 Unidad de Lípidos y Laboratorio de Investigación Molecular, Hospital Universitario Miguel Servet, Instituto Aragonés de Ciencias de la Salud (IACS), Zaragoza, Spain

3 Departamento de Biología Molecular. Facultad de Medicina, Universidad de Cantabria and Instituto de Formación e Investigación Marques de Valdecilla (IFIMAV), Santander, Spain

4 Unidad de Investigación Cardiovascular, Instituto Aragonés de Ciencias de la Salud (IACS), Zaragoza, Spain

5 Aragon Workers Health Study, Zaragoza, Spain

6 Servei d’Endocrinologia i Nutrició, Institut d’Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Hospital Clínic, Barcelona and Ciber Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain

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BMC Medical Genomics 2014, 7:17  doi:10.1186/1755-8794-7-17

Published: 7 April 2014



GWAS have consistently revealed that LDLR locus variability influences LDL-cholesterol in general population. Severe LDLR mutations are responsible for familial hypercholesterolemia (FH). However, most primary hypercholesterolemias are polygenic diseases. Although Cis-regulatory regions might be the cause of LDL-cholesterol variability; an extensive analysis of the LDLR distal promoter has not yet been performed. We hypothesized that genetic variants in this region are responsible for the LDLR association with LDL-cholesterol found in GWAS.


Four-hundred seventy-seven unrelated subjects with polygenic hypercholesterolemia (PH) and without causative FH-mutations and 525 normolipemic subjects were selected. A 3103 pb from LDLR (-625 to +2468) was sequenced in 125 subjects with PH. All subjects were genotyped for 4 SNPs (rs17242346, rs17242739, rs17248720 and rs17249120) predicted to be potentially involved in transcription regulation by in silico analysis. EMSA and luciferase assays were carried out for the rs17248720 variant. Multivariable linear regression analysis using LDL-cholesterol levels as the dependent variable were done in order to find out the variables that were independently associated with LDL-cholesterol.


The sequencing of the 125 PH subjects did not show variants with minor allele frequency ≥ 10%. The T-allele from g.3131C > T (rs17248720) had frequencies of 9% (PH) and 16.4% (normolipemic), p < 0.00001. Studies of this variant with EMSA and luciferase assays showed a higher affinity for transcription factors and an increase of 2.5 times in LDLR transcriptional activity (T-allele vs C-allele). At multivariate analysis, this polymorphism with the lipoprotein(a) and age explained ≈ 10% of LDL-cholesterol variability.


Our results suggest that the T-allele at the g.3131 T > C SNP is associated with LDL-cholesterol levels, and explains part of the LDL-cholesterol variability. As a plausible cause, the T-allele produces an increase in LDLR transcriptional activity and lower LDL-cholesterol levels.

LDL-cholesterol; Hypercholesterolemia; Variant; Gene regulation; Polygenic; LDLR