title: Inheritance of rare functional GCKR variants and their contribution to triglyceride levels in families.
abstract: Significant resources have been invested in sequencing studies to investigate the role of rare variants in complex disease etiology. However, the diagnostic interpretation of individual rare variants remains a major challenge, and may require accurate variant functional classification and the collection of large numbers of variant carriers. Utilizing sequence data from 458 individuals with hypertriglyceridemia and 333 controls with normal plasma triglyceride levels, we investigated these issues using GCKR, encoding glucokinase regulatory protein. Eighteen rare non-synonymous GCKR variants identified in these 791 individuals were comprehensively characterized by a range of biochemical and cell biological assays, including a novel high-throughput-screening-based approach capable of measuring all variant proteins simultaneously. Functionally deleterious variants were collectively associated with hypertriglyceridemia, but a range of in silico prediction algorithms showed little consistency between algorithms and poor agreement with functional data. We extended our study by obtaining sequence data on family members; however, functional variants did not co-segregate with triglyceride levels. Therefore, despite evidence for their collective functional and clinical relevance, our results emphasize the low predictive value of rare GCKR variants in individuals and the complex heritability of lipid traits.
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford OX3 7LE, UK, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Rees
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford OX3 7LE, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Raimondo
authors.affiliation: Departments of Medicine and Biochemistry, Schulich School of Medicine and Dentistry, Robarts Research Institute, University of Western Ontario, London, ON N6A 3K6, Canada.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Departments of Medicine and Biochemistry, Schulich School of Medicine and Dentistry, Robarts Research Institute, University of Western Ontario, London, ON N6A 3K6, Canada.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Ban
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
authors.forename: Mindy I
authors.initials: MI
authors.lastname: Davis
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford OX3 7LE, UK.
authors.forename: Amy
authors.initials: A
authors.lastname: Barrett
authors.affiliation: Institute for Medical Biochemistry & Molecular Biology, University of Rostock, Rostock 18057, Germany and.
authors.forename: Jessica
authors.initials: J
authors.lastname: Ranft
authors.affiliation: Institute for Medical Biochemistry & Molecular Biology, University of Rostock, Rostock 18057, Germany and.
authors.forename: David
authors.initials: D
authors.lastname: Jagdhuhn
authors.affiliation: Institute for Medical Biochemistry & Molecular Biology, University of Rostock, Rostock 18057, Germany and.
authors.forename: Rica
authors.initials: R
authors.lastname: Waterstradt
authors.affiliation: Institute for Medical Biochemistry & Molecular Biology, University of Rostock, Rostock 18057, Germany and.
authors.forename: Simone
authors.initials: S
authors.lastname: Baltrusch
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
authors.forename: Anton
authors.initials: A
authors.lastname: Simeonov
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Francis S
authors.initials: FS
authors.lastname: Collins
authors.affiliation: Departments of Medicine and Biochemistry, Schulich School of Medicine and Dentistry, Robarts Research Institute, University of Western Ontario, London, ON N6A 3K6, Canada.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford OX3 7LE, UK, NIHR Oxford Biomedical Research Centre, ORH Trust, OCDEM, Churchill Hospital, Oxford OX3 7LE, UK anna.gloyn@drl.ox.ac.uk.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Gloyn
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000465:Algorithms; D000818:Animals; D019556:COS Cells; D016022:Case-Control Studies; D002522:Chlorocebus aethiops; D014644:Genetic Variation; D006367:HeLa Cells; D006801:Humans; D006953:Hyperlipoproteinemia Type IV / Q000097:blood / Q000235:genetics*; D051379:Mice; D008958:Models, Molecular; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D017422:Sequence Analysis, DNA; D014280:Triglycerides / Q000097:blood*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C485100:GCKR protein, human; D014280:Triglycerides