title: Do Genetic Factors Modify the Relationship Between Obesity and Hypertriglyceridemia? Findings From the GLACIER and the MDC Studies.
abstract: BACKGROUND
  Obesity is a major risk factor for dyslipidemia, but this relationship is highly variable. Recently published data from 2 Danish cohorts suggest that genetic factors may underlie some of this variability.
  
  
  RESULTS
  We tested whether established triglyceride-associated loci modify the relationship of body mass index (BMI) and triglyceride concentrations in 2 Swedish cohorts (the Gene-Lifestyle Interactions and Complex Traits Involved in Elevated Disease Risk [GLACIER Study; N=4312] and the Malmö Diet and Cancer Study [N=5352]). The genetic loci were amalgamated into a weighted genetic risk score (WGRSTG) by summing the triglyceride-elevating alleles (weighted by their established marginal effects) for all loci. Both BMI and the WGRSTG were strongly associated with triglyceride concentrations in GLACIER, with each additional BMI unit (kg/m(2)) associated with 2.8% (P=8.4×10(-84)) higher triglyceride concentration and each additional WGRSTG unit with 2% (P=7.6×10(-48)) higher triglyceride concentration. Each unit of the WGRSTG was associated with 1.5% higher triglyceride concentrations in normal weight and 2.4% higher concentrations in overweight/obese participants (Pinteraction=0.056). Meta-analyses of results from the Swedish cohorts yielded a statistically significant WGRSTG×BMI interaction effect (Pinteraction=6.0×10(-4)), which was strengthened by including data from the Danish cohorts (Pinteraction=6.5×10(-7)). In the meta-analysis of the Swedish cohorts, nominal evidence of a 3-way interaction (WGRSTG×BMI×sex) was observed (Pinteraction=0.03), where the WGRSTG×BMI interaction was only statistically significant in females. Using protein-protein interaction network analyses, we identified molecular interactions and pathways elucidating the metabolic relationships between BMI and triglyceride-associated loci.
  
  
  CONCLUSIONS
  Our findings provide evidence that body fatness accentuates the effects of genetic susceptibility variants in hypertriglyceridemia, effects that are most evident in females.
authors: From the Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit (A.A., T.V.V., A.P., F.R., P.W.F.) and Department of Clinical Sciences, Diabetes & Cardiovascular Disease-Genetic Epidemiology (I.A.S., C.-A.S., M.O.-M.), Lund University, Malmö, Sweden; Department of Systems Medicine, Steno Diabetes Center, Gentofte, Denmark (A.A.); Department of Biobank Research (G.H., F.R.) and Department of Public Health & Clinical Medicine (P.W.F.), Umeå University, Umeå, Sweden; Human Genetics Programme, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton (I.B.); NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science (I.B.) and University of Cambridge, Metabolic Research Laboratories Institute of Metabolic Science (I.B.), Addenbrooke's Hospital, Cambridge, United Kingdom; Department of Genetics, Physical Anthropology & Animal Physiology, University of the Basque Country (UPV/EHU), Bilbao, Spain (A.P.); and Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA (P.W.F.). Paul.Franks@med.lu.se aqai@steno.dk.
authors: Ashfaq
authors: A
authors: Ali
authors: From the Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit (A.A., T.V.V., A.P., F.R., P.W.F.) and Department of Clinical Sciences, Diabetes & Cardiovascular Disease-Genetic Epidemiology (I.A.S., C.-A.S., M.O.-M.), Lund University, Malmö, Sweden; Department of Systems Medicine, Steno Diabetes Center, Gentofte, Denmark (A.A.); Department of Biobank Research (G.H., F.R.) and Department of Public Health & Clinical Medicine (P.W.F.), Umeå University, Umeå, Sweden; Human Genetics Programme, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton (I.B.); NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science (I.B.) and University of Cambridge, Metabolic Research Laboratories Institute of Metabolic Science (I.B.), Addenbrooke's Hospital, Cambridge, United Kingdom; Department of Genetics, Physical Anthropology & Animal Physiology, University of the Basque Country (UPV/EHU), Bilbao, Spain (A.P.); and Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA (P.W.F.).
authors: Tibor V
authors: TV
authors: Varga
authors: From the Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit (A.A., T.V.V., A.P., F.R., P.W.F.) and Department of Clinical Sciences, Diabetes & Cardiovascular Disease-Genetic Epidemiology (I.A.S., C.-A.S., M.O.-M.), Lund University, Malmö, Sweden; Department of Systems Medicine, Steno Diabetes Center, Gentofte, Denmark (A.A.); Department of Biobank Research (G.H., F.R.) and Department of Public Health & Clinical Medicine (P.W.F.), Umeå University, Umeå, Sweden; Human Genetics Programme, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton (I.B.); NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science (I.B.) and University of Cambridge, Metabolic Research Laboratories Institute of Metabolic Science (I.B.), Addenbrooke's Hospital, Cambridge, United Kingdom; Department of Genetics, Physical Anthropology & Animal Physiology, University of the Basque Country (UPV/EHU), Bilbao, Spain (A.P.); and Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA (P.W.F.).
authors: Ivana A
authors: IA
authors: Stojkovic
authors: From the Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit (A.A., T.V.V., A.P., F.R., P.W.F.) and Department of Clinical Sciences, Diabetes & Cardiovascular Disease-Genetic Epidemiology (I.A.S., C.-A.S., M.O.-M.), Lund University, Malmö, Sweden; Department of Systems Medicine, Steno Diabetes Center, Gentofte, Denmark (A.A.); Department of Biobank Research (G.H., F.R.) and Department of Public Health & Clinical Medicine (P.W.F.), Umeå University, Umeå, Sweden; Human Genetics Programme, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton (I.B.); NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science (I.B.) and University of Cambridge, Metabolic Research Laboratories Institute of Metabolic Science (I.B.), Addenbrooke's Hospital, Cambridge, United Kingdom; Department of Genetics, Physical Anthropology & Animal Physiology, University of the Basque Country (UPV/EHU), Bilbao, Spain (A.P.); and Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA (P.W.F.).
authors: Christina-Alexandra
authors: CA
authors: Schulz
authors: From the Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit (A.A., T.V.V., A.P., F.R., P.W.F.) and Department of Clinical Sciences, Diabetes & Cardiovascular Disease-Genetic Epidemiology (I.A.S., C.-A.S., M.O.-M.), Lund University, Malmö, Sweden; Department of Systems Medicine, Steno Diabetes Center, Gentofte, Denmark (A.A.); Department of Biobank Research (G.H., F.R.) and Department of Public Health & Clinical Medicine (P.W.F.), Umeå University, Umeå, Sweden; Human Genetics Programme, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton (I.B.); NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science (I.B.) and University of Cambridge, Metabolic Research Laboratories Institute of Metabolic Science (I.B.), Addenbrooke's Hospital, Cambridge, United Kingdom; Department of Genetics, Physical Anthropology & Animal Physiology, University of the Basque Country (UPV/EHU), Bilbao, Spain (A.P.); and Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA (P.W.F.).
authors: Göran
authors: G
authors: Hallmans
authors: From the Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit (A.A., T.V.V., A.P., F.R., P.W.F.) and Department of Clinical Sciences, Diabetes & Cardiovascular Disease-Genetic Epidemiology (I.A.S., C.-A.S., M.O.-M.), Lund University, Malmö, Sweden; Department of Systems Medicine, Steno Diabetes Center, Gentofte, Denmark (A.A.); Department of Biobank Research (G.H., F.R.) and Department of Public Health & Clinical Medicine (P.W.F.), Umeå University, Umeå, Sweden; Human Genetics Programme, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton (I.B.); NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science (I.B.) and University of Cambridge, Metabolic Research Laboratories Institute of Metabolic Science (I.B.), Addenbrooke's Hospital, Cambridge, United Kingdom; Department of Genetics, Physical Anthropology & Animal Physiology, University of the Basque Country (UPV/EHU), Bilbao, Spain (A.P.); and Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA (P.W.F.).
authors: Inês
authors: I
authors: Barroso
authors: From the Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit (A.A., T.V.V., A.P., F.R., P.W.F.) and Department of Clinical Sciences, Diabetes & Cardiovascular Disease-Genetic Epidemiology (I.A.S., C.-A.S., M.O.-M.), Lund University, Malmö, Sweden; Department of Systems Medicine, Steno Diabetes Center, Gentofte, Denmark (A.A.); Department of Biobank Research (G.H., F.R.) and Department of Public Health & Clinical Medicine (P.W.F.), Umeå University, Umeå, Sweden; Human Genetics Programme, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton (I.B.); NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science (I.B.) and University of Cambridge, Metabolic Research Laboratories Institute of Metabolic Science (I.B.), Addenbrooke's Hospital, Cambridge, United Kingdom; Department of Genetics, Physical Anthropology & Animal Physiology, University of the Basque Country (UPV/EHU), Bilbao, Spain (A.P.); and Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA (P.W.F.).
authors: Alaitz
authors: A
authors: Poveda
authors: From the Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit (A.A., T.V.V., A.P., F.R., P.W.F.) and Department of Clinical Sciences, Diabetes & Cardiovascular Disease-Genetic Epidemiology (I.A.S., C.-A.S., M.O.-M.), Lund University, Malmö, Sweden; Department of Systems Medicine, Steno Diabetes Center, Gentofte, Denmark (A.A.); Department of Biobank Research (G.H., F.R.) and Department of Public Health & Clinical Medicine (P.W.F.), Umeå University, Umeå, Sweden; Human Genetics Programme, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton (I.B.); NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science (I.B.) and University of Cambridge, Metabolic Research Laboratories Institute of Metabolic Science (I.B.), Addenbrooke's Hospital, Cambridge, United Kingdom; Department of Genetics, Physical Anthropology & Animal Physiology, University of the Basque Country (UPV/EHU), Bilbao, Spain (A.P.); and Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA (P.W.F.).
authors: Frida
authors: F
authors: Renström
authors: From the Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit (A.A., T.V.V., A.P., F.R., P.W.F.) and Department of Clinical Sciences, Diabetes & Cardiovascular Disease-Genetic Epidemiology (I.A.S., C.-A.S., M.O.-M.), Lund University, Malmö, Sweden; Department of Systems Medicine, Steno Diabetes Center, Gentofte, Denmark (A.A.); Department of Biobank Research (G.H., F.R.) and Department of Public Health & Clinical Medicine (P.W.F.), Umeå University, Umeå, Sweden; Human Genetics Programme, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton (I.B.); NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science (I.B.) and University of Cambridge, Metabolic Research Laboratories Institute of Metabolic Science (I.B.), Addenbrooke's Hospital, Cambridge, United Kingdom; Department of Genetics, Physical Anthropology & Animal Physiology, University of the Basque Country (UPV/EHU), Bilbao, Spain (A.P.); and Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA (P.W.F.).
authors: Marju
authors: M
authors: Orho-Melander
authors: From the Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit (A.A., T.V.V., A.P., F.R., P.W.F.) and Department of Clinical Sciences, Diabetes & Cardiovascular Disease-Genetic Epidemiology (I.A.S., C.-A.S., M.O.-M.), Lund University, Malmö, Sweden; Department of Systems Medicine, Steno Diabetes Center, Gentofte, Denmark (A.A.); Department of Biobank Research (G.H., F.R.) and Department of Public Health & Clinical Medicine (P.W.F.), Umeå University, Umeå, Sweden; Human Genetics Programme, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton (I.B.); NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science (I.B.) and University of Cambridge, Metabolic Research Laboratories Institute of Metabolic Science (I.B.), Addenbrooke's Hospital, Cambridge, United Kingdom; Department of Genetics, Physical Anthropology & Animal Physiology, University of the Basque Country (UPV/EHU), Bilbao, Spain (A.P.); and Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA (P.W.F.). Paul.Franks@med.lu.se aqai@steno.dk.
authors: Paul W
authors: PW
authors: Franks
mesh_terms: D015992:Body Mass Index; D005260:Female; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015228:Hypertriglyceridemia / Q000097:blood / Q000150:complications* / Q000235:genetics*; D008019:Life Style; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000097:blood / Q000150:complications* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D012727:Sex Characteristics; D014280:Triglycerides / Q000097:blood
chemical_list: D014280:Triglycerides
keywords: bioinformatics; genetic epidemiology; genetics; obesity; triglycerides