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

BMC Medical Genomics

Miguel Pocoví¹  Fernando Civeira⁴  Jose C Rodríguez-Rey³  Emilio Ros⁵  Jose A Casasnovas¹  Montserrat Cofán⁵  Montserrat León¹  Marta Ledesma¹  Soraya Rebollar²  Rocio Mateo-Gallego⁴  Javier Pérez-López³  Isabel De Castro-Orós⁴ 

[1]Aragon Workers Health Study, Zaragoza, Spain

[2]Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, C. Pedro Cerbuna 12, 50009 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 Lípidos y Laboratorio de Investigación Molecular, Hospital Universitario Miguel Servet, Instituto Aragonés de Ciencias de la Salud (IACS), Zaragoza, Spain

[5]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

关键词: LDLR;    Polygenic;    Gene regulation;    Variant;    Hypercholesterolemia;    LDL-cholesterol;   

Others  :  797068
DOI  :  10.1186/1755-8794-7-17

 received in 2013-12-17, accepted in 2014-03-31,  发布年份 2014

【 摘 要 】

Background

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.

Methods

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.

Results

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.

Conclusion

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.

【 授权许可】

   
2014 De Castro-Orós et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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