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

Isabel De Castro-Orós,Miguel Pocoví,Emilio Ros,Jose C Rodríguez-Rey,Marta Ledesma,Fernando Civeira,Montserrat León,Soraya Rebollar,Jose A Casasnovas,Rocio Mateo-Gallego,Javier Pérez-López,Montserrat Cofán

doi:10.1186/1755-8794-7-17

Abstract

BackgroundGWAS 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.MethodsFour-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.ResultsThe 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.ConclusionOur 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.

Highlights

Genome Wide Association Studies (GWAS) have consistently revealed that LDLR locus variability influences LDL-cholesterol in general population
It has been recently published that a substantial number of subjects with familial hypercholesterolemia (FH) without a known mutation have increased the number of polymorphisms associated with higher lowdensity lipoprotein cholesterol (LDL-C) levels, they might have a polygenic cause [6,7]
The major conclusions drawn from this study are that, the LDLR g.3131C > T polymorphism in the 5’ region of the LDLR is responsible for a major effect on LDL-C concentration because of the increase in the transcriptional activity of the LDLR gene, and indicates that the LDLR variation is associated with polygenic hypercholesterolemia (PH)

Summary

Introduction

GWAS have consistently revealed that LDLR locus variability influences LDL-cholesterol in general population. We hypothesized that genetic variants in this region are responsible for the LDLR association with LDL-cholesterol found in GWAS. Severe primary hypercholesterolemias are often monogenic disorders, such as familial hypercholesterolemia (FH) associated with mutations in coding regions of LDLR, APOB, or PCSK9 genes [1,2,3,4]. No functional defects are detected in these genes in most subjects with primary hypercholesterolemia, albeit, in comparison with FH, a milder phenotype and lower family penetrance are usually present. Most of these subjects receive a diagnosis of polygenic hypercholesterolemia (PH), and it is believed that common genetic variants in the population are responsible for this phenotype [5]. It has been recently published that a substantial number of subjects with FH without a known mutation have increased the number of polymorphisms associated with higher LDL-C levels, they might have a polygenic cause [6,7]

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Results

Discussion

Conclusion