title: Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach.
abstract: Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a disorder characterized by coronary heart disease (CHD) at young age. We aimed to apply an extreme sampling method to enhance the statistical power to identify novel genetic risk variants for CHD in individuals with FH. We selected cases and controls with an extreme contrast in CHD risk from 17,000 FH patients from the Netherlands, whose functional LDLR mutation was unequivocally established. The genome-wide association (GWA) study was performed on 249 very young FH cases with CHD and 217 old FH controls without CHD (above 65 years for males and 70 years of age for females) using the Illumina HumanHap550K chip. In the next stage, two independent samples (one from the Netherlands and one from Italy, Norway, Spain, and the United Kingdom) of FH patients were used as replication samples. In the initial GWA analysis, we identified 29 independent single nucleotide polymorphisms (SNPs) with suggestive associations with premature CHD (P<1 × 10(-4)). We examined the association of these SNPs with CHD risk in the replication samples. After Bonferroni correction, none of the SNPs either replicated or reached genome-wide significance after combining the discovery and replication samples. Therefore, we conclude that the genetics of CHD risk in FH is complex and even applying an 'extreme genetics' approach we did not identify new genetic risk variants. Most likely, this method is not as effective in leveraging effect size as anticipated, and may, therefore, not lead to significant gains in statistical power.
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Jorie
authors.initials: J
authors.lastname: Versmissen
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Daniëlla M
authors.initials: DM
authors.lastname: Oosterveer
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Mojgan
authors.initials: M
authors.lastname: Yazdanpanah
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Abbas
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authors.lastname: Dehghan
authors.affiliation: deCODE Genetics, Reykjavik, Iceland.
authors.forename: Hilma
authors.initials: H
authors.lastname: Hólm
authors.affiliation: Deutsches Hertzzentrum München, Technische Universität München, München, Germany.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Erdman
authors.affiliation: 1] Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands [2] Novosibirsk State University, Novosibirsk, Russia.
authors.forename: Yurii S
authors.initials: YS
authors.lastname: Aulchenko
authors.affiliation: deCODE Genetics, Reykjavik, Iceland.
authors.forename: Gudmar
authors.initials: G
authors.lastname: Thorleifsson
authors.affiliation: Deutsches Hertzzentrum München, Technische Universität München, München, Germany.
authors.forename: Heribert
authors.initials: H
authors.lastname: Schunkert
authors.affiliation: Department of Vascular Medicine, Amsterdam Medical Center, Amsterdam, The Netherlands.
authors.forename: Roeland
authors.initials: R
authors.lastname: Huijgen
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Ranitha
authors.initials: R
authors.lastname: Vongpromek
authors.affiliation: 1] Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands [2] Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Department of Vascular Medicine, Amsterdam Medical Center, Amsterdam, The Netherlands.
authors.forename: Joep C
authors.initials: JC
authors.lastname: Defesche
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Monique
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authors.lastname: Mulder
authors.affiliation: Unilever R&D, Colworth Science Park, Sharnbrook, UK.
authors.forename: Tony
authors.initials: T
authors.lastname: Dadd
authors.affiliation: Icelandic Heart Association and Department of Cardiology, Landspitali-University Hospital, Reykjavik, Iceland.
authors.forename: Hróbjartur D
authors.initials: HD
authors.lastname: Karlsson
authors.affiliation: Nutrition and Genomics Laboratory, Jean Mayer USDA HNRCA at Tufts University, Boston, MA, USA.
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authors.lastname: Ordovas
authors.affiliation: Stichting Opsporing Erfelijke Hypercholesterolemie, Amsterdam, The Netherlands.
authors.forename: Iris
authors.initials: I
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authors.affiliation: Unilever R&D, Colworth Science Park, Sharnbrook, UK.
authors.forename: Amelia
authors.initials: A
authors.lastname: Jarman
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Albert
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authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Leonie
authors.initials: L
authors.lastname: van Vark-van der Zee
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Adriana C
authors.initials: AC
authors.lastname: Blommesteijn-Touw
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Jaap
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authors.lastname: Kwekkeboom
authors.affiliation: Department of Cardiology, Sint Franciscus Gasthuis Hospital, Rotterdam, The Netherlands.
authors.forename: Anho H
authors.initials: AH
authors.lastname: Liem
authors.affiliation: Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Frans J
authors.initials: FJ
authors.lastname: van der Ouderaa
authors.affiliation: Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Calandra
authors.affiliation: Department of Internal Medicine, University of Genova, Genova, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Bertolini
authors.affiliation: Department of Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy.
authors.forename: Maurizio
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authors.lastname: Averna
authors.affiliation: Lipid Clinic, Oslo University Hospital, Oslo, Norway.
authors.forename: Gisle
authors.initials: G
authors.lastname: Langslet
authors.affiliation: Lipid Clinic, Oslo University Hospital, Oslo, Norway.
authors.forename: Leiv
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authors.affiliation: 1] Lipid Clinic, Endocrinology and Nutrition Service, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Hospital Clínic, Barcelona, Spain [2] CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
authors.forename: Emilio
authors.initials: E
authors.lastname: Ros
authors.affiliation: Hospital de Guipúzcoa, San Sebastián, Guipúzcoa, España.
authors.forename: Fátima
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authors.lastname: Almagro
authors.affiliation: Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Peter W
authors.initials: PW
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authors.affiliation: Lipids Unit and Molecular Research Unit, Hospital Universitario Miguel Servet, Zaragoza, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Civeira
authors.affiliation: Unitat de Recerca en Lípids i Arteriosclerosi (URLA), Hospital Universitari Sant Joan de Reus, Reus, Spain.
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authors.lastname: Masana
authors.affiliation: Unitat de Lípids i Arteriosclerosi, Servei de Medicina Interna, Hospital Universitari de Bellvitge, Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Pintó
authors.affiliation: Department of Cardiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Maarten L
authors.initials: ML
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authors.affiliation: 1] Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands [2] Department of Cardiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
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authors.initials: AF
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authors.affiliation: Unilever R&D, Colworth Science Park, Sharnbrook, UK.
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authors.initials: MR
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authors.affiliation: Department of Clinical Epidemiology and Biostatistics, Amsterdam Medical Center, Amsterdam, The Netherlands.
authors.forename: Aeilko H
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authors.affiliation: Novartis Insitutes of Biomedical Research, Cambridge, MA, USA.
authors.forename: Keith J
authors.initials: KJ
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authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Arne
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authors.lastname: Schaefer
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Neil
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Jacqueline C M
authors.initials: JC
authors.lastname: Witteman
authors.affiliation: Cardiovascular Genetics, BHF Laboratories, Institute Cardiovascular Science, University College London, London, UK.
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
authors.affiliation: Department of Vascular Medicine, Amsterdam Medical Center, Amsterdam, The Netherlands.
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
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authors.lastname: Sijbrands
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D016022:Case-Control Studies; D015897:Comorbidity; D003327:Coronary Disease / Q000453:epidemiology / Q000209:etiology*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000150:complications* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011973:Receptors, LDL / Q000235:genetics; D012306:Risk; D012307:Risk Factors; D055815:Young Adult
chemical_list: D011973:Receptors, LDL