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

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...

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Autores: Castro Orós, Isabel de, Pérez López, Javier, Mateo Gallego, Rocío, Rebollar González, Soraya, Ledesma Fuentes, Marta, León Latrea, Montserrat, Cofán Pujol, Montserrat, Casasnovas Lenguas, José A., Ros Rahola, Emilio, Rodríguez Rey, José Carlos, Civeira Murillo, Fernando, Pocoví Mieras, Miguel
Tipo de recurso: artículo
Fecha de publicación:2014
País:España
Institución:Universidad de Cantabria (UC)
Repositorio:UCrea Repositorio Abierto de la Universidad de Cantabria
Idioma:inglés
OAI Identifier:oai:repositorio.unican.es:10902/4731
Acceso en línea:http://hdl.handle.net/10902/4731
Access Level:acceso abierto
Palabra clave:LDL-cholesterol
Hypercholesterolemia
Variant
Gene regulation
Polygenic
LDLR
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spelling A genetic variant in the LDLR promoter is responsible for part of the LDL-cholesterol variability in primary hypercholesterolemiaCastro Orós, Isabel dePérez López, JavierMateo Gallego, RocíoRebollar González, SorayaLedesma Fuentes, MartaLeón Latrea, MontserratCofán Pujol, MontserratCasasnovas Lenguas, José A.Ros Rahola, EmilioRodríguez Rey, José CarlosCiveira Murillo, FernandoPocoví Mieras, MiguelLDL-cholesterolHypercholesterolemiaVariantGene regulationPolygenicLDLRBACKGROUND: 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.Acknowledgements. Grants from the Spanish Ministry of Economy and Competitiveness PI12/ 00637, PI01/01087, PI12/01231, PI12/01703, RIC RD12/0042/0055, IPT-2011-0817-010000, Aragon Workers’ Health Study (AWHS) and CIBERobn. AWHS is an initiative of CNIC and IACS, Spain. RIC and CIBERobn are initiatives of ISCIII, Spain.BioMed CentralUniversidad de Cantabria20142014-04-07journal articlehttp://purl.org/coar/resource_type/c_6501NAhttp://purl.org/coar/version/c_be7fb7dd8ff6fe43info:eu-repo/semantics/articlehttp://hdl.handle.net/10902/4731BMC Medical Genomics. 2014 Apr 7;7:17reponame:UCrea Repositorio Abierto de la Universidad de Cantabriainstname:Universidad de Cantabria (UC)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Atribución 3.0 Españahttp://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:repositorio.unican.es:10902/47312026-06-02T12:39:31Z
dc.title.none.fl_str_mv A genetic variant in the LDLR promoter is responsible for part of the LDL-cholesterol variability in primary hypercholesterolemia
title A genetic variant in the LDLR promoter is responsible for part of the LDL-cholesterol variability in primary hypercholesterolemia
spellingShingle A genetic variant in the LDLR promoter is responsible for part of the LDL-cholesterol variability in primary hypercholesterolemia
Castro Orós, Isabel de
LDL-cholesterol
Hypercholesterolemia
Variant
Gene regulation
Polygenic
LDLR
title_short A genetic variant in the LDLR promoter is responsible for part of the LDL-cholesterol variability in primary hypercholesterolemia
title_full A genetic variant in the LDLR promoter is responsible for part of the LDL-cholesterol variability in primary hypercholesterolemia
title_fullStr A genetic variant in the LDLR promoter is responsible for part of the LDL-cholesterol variability in primary hypercholesterolemia
title_full_unstemmed A genetic variant in the LDLR promoter is responsible for part of the LDL-cholesterol variability in primary hypercholesterolemia
title_sort A genetic variant in the LDLR promoter is responsible for part of the LDL-cholesterol variability in primary hypercholesterolemia
dc.creator.none.fl_str_mv Castro Orós, Isabel de
Pérez López, Javier
Mateo Gallego, Rocío
Rebollar González, Soraya
Ledesma Fuentes, Marta
León Latrea, Montserrat
Cofán Pujol, Montserrat
Casasnovas Lenguas, José A.
Ros Rahola, Emilio
Rodríguez Rey, José Carlos
Civeira Murillo, Fernando
Pocoví Mieras, Miguel
author Castro Orós, Isabel de
author_facet Castro Orós, Isabel de
Pérez López, Javier
Mateo Gallego, Rocío
Rebollar González, Soraya
Ledesma Fuentes, Marta
León Latrea, Montserrat
Cofán Pujol, Montserrat
Casasnovas Lenguas, José A.
Ros Rahola, Emilio
Rodríguez Rey, José Carlos
Civeira Murillo, Fernando
Pocoví Mieras, Miguel
author_role author
author2 Pérez López, Javier
Mateo Gallego, Rocío
Rebollar González, Soraya
Ledesma Fuentes, Marta
León Latrea, Montserrat
Cofán Pujol, Montserrat
Casasnovas Lenguas, José A.
Ros Rahola, Emilio
Rodríguez Rey, José Carlos
Civeira Murillo, Fernando
Pocoví Mieras, Miguel
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidad de Cantabria
dc.subject.none.fl_str_mv LDL-cholesterol
Hypercholesterolemia
Variant
Gene regulation
Polygenic
LDLR
topic LDL-cholesterol
Hypercholesterolemia
Variant
Gene regulation
Polygenic
LDLR
description 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.
publishDate 2014
dc.date.none.fl_str_mv 2014
2014-04-07
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
NA
http://purl.org/coar/version/c_be7fb7dd8ff6fe43
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10902/4731
url http://hdl.handle.net/10902/4731
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución 3.0 España
http://creativecommons.org/licenses/by/3.0/es/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución 3.0 España
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv BioMed Central
publisher.none.fl_str_mv BioMed Central
dc.source.none.fl_str_mv BMC Medical Genomics. 2014 Apr 7;7:17
reponame:UCrea Repositorio Abierto de la Universidad de Cantabria
instname:Universidad de Cantabria (UC)
instname_str Universidad de Cantabria (UC)
reponame_str UCrea Repositorio Abierto de la Universidad de Cantabria
collection UCrea Repositorio Abierto de la Universidad de Cantabria
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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