title: Mutation in KERA identified by linkage analysis and targeted resequencing in a pedigree with premature atherosclerosis.
abstract: OBJECTIVE
  Genetic factors explain a proportion of the inter-individual variation in the risk for atherosclerotic events, but the genetic basis of atherosclerosis and atherothrombosis in families with Mendelian forms of premature atherosclerosis is incompletely understood. We set out to unravel the molecular pathology in a large kindred with an autosomal dominant inherited form of premature atherosclerosis.
  
  
  RESULTS
  Parametric linkage analysis was performed in a pedigree comprising 4 generations, of which a total of 11 members suffered from premature vascular events. A parametric LOD-score of 3.31 was observed for a 4.4 Mb interval on chromosome 12. Upon sequencing, a non-synonymous variant in KERA (c.920C>G; p.Ser307Cys) was identified. The variant was absent from nearly 28,000 individuals, including 2,571 patients with premature atherosclerosis. KERA, a proteoglycan protein, was expressed in lipid-rich areas of human atherosclerotic lesions, but not in healthy arterial specimens. Moreover, KERA expression in plaques was significantly associated with plaque size in a carotid-collar Apoe-/- mice (r2 = 0.69; p<0.0001).
  
  
  CONCLUSIONS
  A rare variant in KERA was identified in a large kindred with premature atherosclerosis. The identification of KERA in atherosclerotic plaque specimen in humans and mice lends support to its potential role in atherosclerosis.
authors.affiliation: Department of Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands; Department of Experimental Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Maiwald
authors.affiliation: Department of Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands.
authors.forename: Suthesh
authors.initials: S
authors.lastname: Sivapalaratnam
authors.affiliation: Department of Experimental Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands.
authors.forename: Mahdi M
authors.initials: MM
authors.lastname: Motazacker
authors.affiliation: Department of Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands.
authors.forename: Julian C
authors.initials: JC
authors.lastname: van Capelleveen
authors.affiliation: Division of Biopharmaceutics, Leiden/Amsterdam Centre for Drug Research, Leiden, the Netherlands; Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Ilze
authors.initials: I
authors.lastname: Bot
authors.affiliation: Division of Biopharmaceutics, Leiden/Amsterdam Centre for Drug Research, Leiden, the Netherlands; Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Saskia C
authors.initials: SC
authors.lastname: de Jager
authors.affiliation: Division of Biopharmaceutics, Leiden/Amsterdam Centre for Drug Research, Leiden, the Netherlands; Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Miranda
authors.initials: M
authors.lastname: van Eck
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, United Kingdom; National Health Service Blood and Transplant, Cambridge, United Kingdom.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jolley
authors.affiliation: Division of Biopharmaceutics, Leiden/Amsterdam Centre for Drug Research, Leiden, the Netherlands; Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
authors.forename: Johan
authors.initials: J
authors.lastname: Kuiper
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, United Kingdom; National Health Service Blood and Transplant, Cambridge, United Kingdom.
authors.forename: Jonathon
authors.initials: J
authors.lastname: Stephens
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, United Kingdom; National Health Service Blood and Transplant, Cambridge, United Kingdom.
authors.forename: Cornelius A
authors.initials: CA
authors.lastname: Albers
authors.affiliation: Amsterdam Institute of Molecules, Medicines and Systems, Division of Molecular and Computational Toxicology, Department of Chemistry and Pharmaceutical Sciences, VU University, Amsterdam, the Netherlands.
authors.forename: C Ruben
authors.initials: CR
authors.lastname: Vosmeer
authors.affiliation: Amsterdam Institute of Molecules, Medicines and Systems, Division of Molecular and Computational Toxicology, Department of Chemistry and Pharmaceutical Sciences, VU University, Amsterdam, the Netherlands.
authors.forename: Heleen
authors.initials: H
authors.lastname: Kruize
authors.affiliation: Amsterdam Institute of Molecules, Medicines and Systems, Division of Molecular and Computational Toxicology, Department of Chemistry and Pharmaceutical Sciences, VU University, Amsterdam, the Netherlands.
authors.forename: Daan P
authors.initials: DP
authors.lastname: Geerke
authors.affiliation: Department of Pathology, Academic Medical Centre, Amsterdam, the Netherlands.
authors.forename: Allard C
authors.initials: AC
authors.lastname: van der Wal
authors.affiliation: Department of Pathology, Academic Medical Centre, Amsterdam, the Netherlands.
authors.forename: Chris M
authors.initials: CM
authors.lastname: van der Loos
authors.affiliation: Department of Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands.
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.affiliation: Department of Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands.
authors.forename: Mieke D
authors.initials: MD
authors.lastname: Trip
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, United Kingdom; National Health Service Blood and Transplant, Cambridge, United Kingdom.
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
authors.affiliation: Department of Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands; Department of Experimental Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands.
authors.forename: Geesje M
authors.initials: GM
authors.lastname: Dallinga-Thie
authors.affiliation: Department of Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands.
authors.forename: G Kees
authors.initials: GK
authors.lastname: Hovingh
mesh_terms: D000368:Aged; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D056004:Molecular Dynamics Simulation; D009154:Mutation; D010375:Pedigree; D011487:Protein Conformation; D011509:Proteoglycans / Q000737:chemistry / Q000235:genetics*
chemical_list: D001057:Apolipoproteins E; C490948:KERA protein, human; D011509:Proteoglycans