title: A rare splice donor mutation in the haptoglobin gene associates with blood lipid levels and coronary artery disease.
abstract: Common sequence variants at the haptoglobin gene (HP) have been associated with blood lipid levels. Through whole-genome sequencing of 8,453 Icelanders, we discovered a splice donor founder mutation in HP (NM_001126102.1:c.190 + 1G > C, minor allele frequency = 0.56%). This mutation occurs on the HP1 allele of the common copy number variant in HP and leads to a loss of function of HP1. It associates with lower levels of haptoglobin (P = 2.1 × 10-54), higher levels of non-high density lipoprotein cholesterol (β = 0.26 mmol/l, P = 2.6 × 10-9) and greater risk of coronary artery disease (odds ratio = 1.30, 95% confidence interval: 1.10-1.54, P = 0.0024). Through haplotype analysis and with RNA sequencing, we provide evidence of a causal relationship between one of the two haptoglobin isoforms, namely Hp1, and lower levels of non-HDL cholesterol. Furthermore, we show that the HP1 allele associates with various other quantitative biological traits.
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|Faculty of Medicine.
authors.forename: Eythor
authors.initials: E
authors.lastname: Bjornsson
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
authors.forename: Hannes
authors.initials: H
authors.lastname: Helgason
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Gisli
authors.initials: G
authors.lastname: Halldorsson
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|Faculty of Medicine.
authors.forename: Anna
authors.initials: A
authors.lastname: Helgadottir
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Arnaldur
authors.initials: A
authors.lastname: Gylfason
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Birte
authors.initials: B
authors.lastname: Kehr
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Adalbjorg
authors.initials: A
authors.lastname: Jonasdottir
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Aslaug
authors.initials: A
authors.lastname: Jonasdottir
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Asgeir
authors.initials: A
authors.lastname: Sigurdsson
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Asmundur
authors.initials: A
authors.lastname: Oddsson
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Gudmar
authors.initials: G
authors.lastname: Thorleifsson
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Olafur Th
authors.initials: OT
authors.lastname: Magnusson
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Solveig
authors.initials: S
authors.lastname: Gretarsdottir
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Florian
authors.initials: F
authors.lastname: Zink
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Ragnar P
authors.initials: RP
authors.lastname: Kristjansson
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Margret
authors.initials: M
authors.lastname: Asgeirsdottir
authors.affiliation: Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Department of Laboratory Medicine, Nijmegen, The Netherlands.
authors.forename: Dorine W
authors.initials: DW
authors.lastname: Swinkels
authors.affiliation: Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
authors.forename: Lambertus A
authors.initials: LA
authors.lastname: Kiemeney
authors.affiliation: The Laboratory in Mjodd, Reykjavik, Iceland.
authors.forename: Gudmundur I
authors.initials: GI
authors.lastname: Eyjolfsson
authors.affiliation: Department of Clinical Biochemistry, Akureyri Hospital, Akureyri, Iceland.
authors.forename: Olof
authors.initials: O
authors.lastname: Sigurdardottir
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Gisli
authors.initials: G
authors.lastname: Masson
authors.affiliation: Department of Clinical Biochemistry.
authors.forename: Isleifur
authors.initials: I
authors.lastname: Olafsson
authors.affiliation: Faculty of Medicine.|Division of Cardiology, Department of Internal Medicine, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland.
authors.forename: Gudmundur
authors.initials: G
authors.lastname: Thorgeirsson
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|Division of Cardiology, Department of Internal Medicine, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland.
authors.forename: Hilma
authors.initials: H
authors.lastname: Holm
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|Faculty of Medicine.
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Gudbjartsson
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Sulem
authors.affiliation: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|Faculty of Medicine.
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
mesh_terms: D000328:Adult; D000483:Alleles; D001483:Base Sequence; D003324:Coronary Artery Disease / Q000235:genetics* / Q000378:metabolism; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D056726:Genetic Association Studies / Q000379:methods; D014644:Genetic Variation; D006242:Haptoglobins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007055:Iceland; D008055:Lipids / Q000097:blood / Q000235:genetics; D008074:Lipoproteins / Q000235:genetics; D008297:Male; D009154:Mutation; D016017:Odds Ratio; D022821:RNA Splice Sites / Q000235:genetics; D012307:Risk Factors
chemical_list: C485359:HP protein, human; D006242:Haptoglobins; D008055:Lipids; D008074:Lipoproteins; D022821:RNA Splice Sites