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A Splice Region Variant in LDLR Lowers Non-high Density Lipoprotein Cholesterol and Protects against Coronary Artery Disease.
Gretarsdottir, Solveig; Helgason, Hannes; Helgadottir, Anna; Sigurdsson, Asgeir; Thorleifsson, Gudmar; Magnusdottir, Audur; Oddsson, Asmundur; Steinthorsdottir, Valgerdur; Rafnar, Thorunn; de Graaf, Jacqueline; Daneshpour, Maryam S; Hedayati, Mehdi; Azizi, Fereidoun; Grarup, Niels; Jørgensen, Torben; Vestergaard, Henrik; Hansen, Torben; Eyjolfsson, Gudmundur; Sigurdardottir, Olof; Olafsson, Isleifur; Kiemeney, Lambertus A; Pedersen, Oluf; Sulem, Patrick; Thorgeirsson, Gudmundur; Gudbjartsson, Daniel F; Holm, Hilma; Thorsteinsdottir, Unnur; Stefansson, Kari.
Afiliação
  • Gretarsdottir S; deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
  • Helgason H; deCODE Genetics/Amgen, Inc., Reykjavik, Iceland; School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
  • Helgadottir A; deCODE Genetics/Amgen, Inc., Reykjavik, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
  • Sigurdsson A; deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
  • Thorleifsson G; deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
  • Magnusdottir A; deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
  • Oddsson A; deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
  • Steinthorsdottir V; deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
  • Rafnar T; deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
  • de Graaf J; Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
  • Daneshpour MS; Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, I. R. Iran.
  • Hedayati M; Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, I. R. Iran.
  • Azizi F; Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, I. R. Iran.
  • Grarup N; The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Jørgensen T; Research Centre for Prevention and Health, The Capital Region of Denmark, Copenhagen, Denmark; Faculty of Medicine, University of Aalborg, Aalborg, Denmark; Institute of Public Health and Medical Science, University of Copenhagen, Copenhagen, Denmark.
  • Vestergaard H; The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Hansen T; The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
  • Eyjolfsson G; The Laboratory in Mjodd, RAM, Reykjavik, Iceland.
  • Sigurdardottir O; Department of Clinical Biochemistry, Akureyri Hospital, Akureyri, Iceland.
  • Olafsson I; Department of Clinical Biochemistry, Landspitali, National University Hospital, Reykjavik, Iceland.
  • Kiemeney LA; Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
  • Pedersen O; The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Sulem P; deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
  • Thorgeirsson G; Faculty of Medicine, University of Iceland, Reykjavik, Iceland; Division of Cardiology, Department of Internal Medicine, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland.
  • Gudbjartsson DF; deCODE Genetics/Amgen, Inc., Reykjavik, Iceland; School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
  • Holm H; deCODE Genetics/Amgen, Inc., Reykjavik, Iceland; Division of Cardiology, Department of Internal Medicine, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland.
  • Thorsteinsdottir U; deCODE Genetics/Amgen, Inc., Reykjavik, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
  • Stefansson K; deCODE Genetics/Amgen, Inc., Reykjavik, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
PLoS Genet ; 11(9): e1005379, 2015 Sep.
Article em En | MEDLINE | ID: mdl-26327206
ABSTRACT
Through high coverage whole-genome sequencing and imputation of the identified variants into a large fraction of the Icelandic population, we found four independent signals in the low density lipoprotein receptor gene (LDLR) that associate with levels of non-high density lipoprotein cholesterol (non-HDL-C) and coronary artery disease (CAD). Two signals are novel with respect to association with non-HDL-C and are represented by non-coding low frequency variants (between 2-4% frequency), the splice region variant rs72658867-A in intron 14 and rs17248748-T in intron one. These two novel associations were replicated in three additional populations. Both variants lower non-HDL-C levels (rs72658867-A, non-HDL-C effect = -0.44 mmol/l, Padj = 1.1 × 10⁻8° and rs17248748-T, non-HDL-C effect = -0.13 mmol/l, Padj = 1.3 × 10⁻¹²) and confer protection against CAD (rs72658867-A, OR = 0.76 and Padj = 2.7 × 10⁻8 and rs17248748-T, OR = 0.92 and Padj = 0.022). The LDLR splice region variant, rs72658867-A, located at position +5 in intron 14 (NM_000527c.2140+5G>A), causes retention of intron 14 during transcription and is expected to produce a truncated LDL receptor lacking domains essential for function of the receptor. About half of the transcripts generated from chromosomes carrying rs72658867-A are characterized by this retention of the intron. The same variant also increases LDLR mRNA expression, however, the wild type transcripts do not exceed levels in non-carriers. This demonstrates that sequence variants that disrupt the LDL receptor can lower non-HDL-C and protect against CAD.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doença da Artéria Coronariana / Receptores de LDL / Splicing de RNA / Colesterol Limite: Humans Idioma: En Revista: PLoS Genet Assunto da revista: GENETICA Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Islândia

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doença da Artéria Coronariana / Receptores de LDL / Splicing de RNA / Colesterol Limite: Humans Idioma: En Revista: PLoS Genet Assunto da revista: GENETICA Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Islândia