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  • 1
    Abstract: Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.
    Type of Publication: Journal article published
    PubMed ID: 27252175
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  • 2
    Abstract: Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.
    Type of Publication: Journal article published
    PubMed ID: 27252175
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  • 3
    Publication Date: 2014-07-22
    Description: The Greenlandic population, a small and historically isolated founder population comprising about 57,000 inhabitants, has experienced a dramatic increase in type 2 diabetes (T2D) prevalence during the past 25 years. Motivated by this, we performed association mapping of T2D-related quantitative traits in up to 2,575 Greenlandic individuals without known diabetes. Using array-based genotyping and exome sequencing, we discovered a nonsense p.Arg684Ter variant (in which arginine is replaced by a termination codon) in the gene TBC1D4 with an allele frequency of 17%. Here we show that homozygous carriers of this variant have markedly higher concentrations of plasma glucose (beta = 3.8 mmol l(-1), P = 2.5 x 10(-35)) and serum insulin (beta = 165 pmol l(-1), P = 1.5 x 10(-20)) 2 hours after an oral glucose load compared with individuals with other genotypes (both non-carriers and heterozygous carriers). Furthermore, homozygous carriers have marginally lower concentrations of fasting plasma glucose (beta = -0.18 mmol l(-1), P = 1.1 x 10(-6)) and fasting serum insulin (beta = -8.3 pmol l(-1), P = 0.0014), and their T2D risk is markedly increased (odds ratio (OR) = 10.3, P = 1.6 x 10(-24)). Heterozygous carriers have a moderately higher plasma glucose concentration 2 hours after an oral glucose load than non-carriers (beta = 0.43 mmol l(-1), P = 5.3 x 10(-5)). Analyses of skeletal muscle biopsies showed lower messenger RNA and protein levels of the long isoform of TBC1D4, and lower muscle protein levels of the glucose transporter GLUT4, with increasing number of p.Arg684Ter alleles. These findings are concomitant with a severely decreased insulin-stimulated glucose uptake in muscle, leading to postprandial hyperglycaemia, impaired glucose tolerance and T2D. The observed effect sizes are several times larger than any previous findings in large-scale genome-wide association studies of these traits and constitute further proof of the value of conducting genetic association studies outside the traditional setting of large homogeneous populations.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Moltke, Ida -- Grarup, Niels -- Jorgensen, Marit E -- Bjerregaard, Peter -- Treebak, Jonas T -- Fumagalli, Matteo -- Korneliussen, Thorfinn S -- Andersen, Marianne A -- Nielsen, Thomas S -- Krarup, Nikolaj T -- Gjesing, Anette P -- Zierath, Juleen R -- Linneberg, Allan -- Wu, Xueli -- Sun, Guangqing -- Jin, Xin -- Al-Aama, Jumana -- Wang, Jun -- Borch-Johnsen, Knut -- Pedersen, Oluf -- Nielsen, Rasmus -- Albrechtsen, Anders -- Hansen, Torben -- England -- Nature. 2014 Aug 14;512(7513):190-3. doi: 10.1038/nature13425. Epub 2014 Jun 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] The Bioinformatics Centre, Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark [2] Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA [3]. ; 1] The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark [2]. ; Steno Diabetes Center, 2820 Gentofte, Denmark. ; National Institute of Public Health, University of Southern Denmark, 1353 Copenhagen, Denmark. ; The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Integrative Physiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark. ; Department of Integrative Biology, University of California, Berkeley, California 94720, USA. ; Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, 1350 Copenhagen, Denmark. ; The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark. ; 1] The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Integrative Physiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark [2] Department of Molecular Medicine and Surgery, Karolinska Institute, 171 77 Stockholm, Sweden. ; Research Centre for Prevention and Health, Glostrup University Hospital, 2600 Glostrup, Denmark. ; BGI-Shenzhen, Shenzhen 518083, China. ; 1] BGI-Shenzhen, Shenzhen 518083, China [2] The Department of Genetic Medicine, Faculty of Medicine and Princess Al Jawhara Albrahim Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia. ; 1] The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark [2] BGI-Shenzhen, Shenzhen 518083, China [3] The Department of Genetic Medicine, Faculty of Medicine and Princess Al Jawhara Albrahim Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia [4] Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark [5] Macau University of Science and Technology, Macau 999078, China. ; Holbaek Hospital, 4300 Holbaek, Denmark. ; 1] Department of Integrative Biology, University of California, Berkeley, California 94720, USA [2] Department of Statistics, University of California, Berkeley, California 94720, USA. ; The Bioinformatics Centre, Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark. ; 1] The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark [2] Faculty of Health Sciences, University of Southern Denmark, 5000 Odense, Denmark.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043022" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Blood Glucose/analysis ; Codon, Nonsense/genetics ; Diabetes Mellitus, Type 2/*genetics ; GTPase-Activating Proteins/*genetics ; Gene Frequency ; *Genetic Variation ; Genome-Wide Association Study ; Genotype ; Greenland ; Humans ; Insulin/blood ; Insulin Resistance/*genetics ; Middle Aged ; Muscle, Skeletal/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2015-09-19
    Description: The indigenous people of Greenland, the Inuit, have lived for a long time in the extreme conditions of the Arctic, including low annual temperatures, and with a specialized diet rich in protein and fatty acids, particularly omega-3 polyunsaturated fatty acids (PUFAs). A scan of Inuit genomes for signatures of adaptation revealed signals at several loci, with the strongest signal located in a cluster of fatty acid desaturases that determine PUFA levels. The selected alleles are associated with multiple metabolic and anthropometric phenotypes and have large effect sizes for weight and height, with the effect on height replicated in Europeans. By analyzing membrane lipids, we found that the selected alleles modulate fatty acid composition, which may affect the regulation of growth hormones. Thus, the Inuit have genetic and physiological adaptations to a diet rich in PUFAs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fumagalli, Matteo -- Moltke, Ida -- Grarup, Niels -- Racimo, Fernando -- Bjerregaard, Peter -- Jorgensen, Marit E -- Korneliussen, Thorfinn S -- Gerbault, Pascale -- Skotte, Line -- Linneberg, Allan -- Christensen, Cramer -- Brandslund, Ivan -- Jorgensen, Torben -- Huerta-Sanchez, Emilia -- Schmidt, Erik B -- Pedersen, Oluf -- Hansen, Torben -- Albrechtsen, Anders -- Nielsen, Rasmus -- R01-HG003229/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2015 Sep 18;349(6254):1343-7. doi: 10.1126/science.aab2319.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Evolution, and Environment, University College London, London WC1E 6BT, UK. Department of Integrative Biology, University of California-Berkeley, Berkeley, CA 94720, USA. ; The Bioinformatics Centre, Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark. ; The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark. ; Department of Integrative Biology, University of California-Berkeley, Berkeley, CA 94720, USA. ; National Institute of Public Health, University of Southern Denmark, 1353 Copenhagen, Denmark. Greenland Center for Health Research, University of Greenland, Nuuk, Greenland. ; National Institute of Public Health, University of Southern Denmark, 1353 Copenhagen, Denmark. Steno Diabetes Center, 2820 Gentofte, Denmark. ; Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, 1350 Copenhagen, Denmark. ; Department of Genetics, Evolution, and Environment, University College London, London WC1E 6BT, UK. Department of Anthropology, University College London, London WC1H 0BW, UK. ; Research Centre for Prevention and Health, Capital Region of Denmark, Copenhagen, Denmark. Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Denmark. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. ; Department of Medicine, Lillebaelt Hospital, Vejle, Denmark. ; Department of Clinical Biochemistry, Lillebaelt Hospital, Vejle, Denmark. Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark. ; Research Centre for Prevention and Health, Capital Region of Denmark, Copenhagen, Denmark. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Faculty of Medicine, University of Aalborg, Aalborg, Denmark. ; School of Natural Sciences, University of California-Merced, Merced, CA 95343, USA. ; Faculty of Medicine, University of Aalborg, Aalborg, Denmark. Department of Cardiology, Aalborg University Hospital, 9100 Aalborg, Denmark. ; The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark. torben.hansen@sund.ku.dk albrecht@binf.ku.dk rasmus_nielsen@berkeley.edu. ; The Bioinformatics Centre, Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark. torben.hansen@sund.ku.dk albrecht@binf.ku.dk rasmus_nielsen@berkeley.edu. ; Department of Integrative Biology, University of California-Berkeley, Berkeley, CA 94720, USA. Department of Statistics, University of California-Berkeley, Berkeley, CA 94720, USA. torben.hansen@sund.ku.dk albrecht@binf.ku.dk rasmus_nielsen@berkeley.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26383953" target="_blank"〉PubMed〈/a〉
    Keywords: Acclimatization/*genetics ; Alleles ; Arctic Regions ; Body Height/genetics ; Body Weight/genetics ; Chromosomes, Human, Pair 11/genetics ; Climate ; *Diet, High-Fat ; Fatty Acids, Omega-3/*administration & dosage/analysis ; Female ; Genetic Loci ; Genome, Human/genetics ; Genome-Wide Association Study ; Greenland ; Humans ; Inuits/*genetics ; Linkage Disequilibrium ; Male ; Membrane Lipids/analysis/genetics ; Polymorphism, Single Nucleotide ; Selection, Genetic
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2013-08-30
    Description: We are facing a global metabolic health crisis provoked by an obesity epidemic. Here we report the human gut microbial composition in a population sample of 123 non-obese and 169 obese Danish individuals. We find two groups of individuals that differ by the number of gut microbial genes and thus gut bacterial richness. They contain known and previously unknown bacterial species at different proportions; individuals with a low bacterial richness (23% of the population) are characterized by more marked overall adiposity, insulin resistance and dyslipidaemia and a more pronounced inflammatory phenotype when compared with high bacterial richness individuals. The obese individuals among the lower bacterial richness group also gain more weight over time. Only a few bacterial species are sufficient to distinguish between individuals with high and low bacterial richness, and even between lean and obese participants. Our classifications based on variation in the gut microbiome identify subsets of individuals in the general white adult population who may be at increased risk of progressing to adiposity-associated co-morbidities.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Le Chatelier, Emmanuelle -- Nielsen, Trine -- Qin, Junjie -- Prifti, Edi -- Hildebrand, Falk -- Falony, Gwen -- Almeida, Mathieu -- Arumugam, Manimozhiyan -- Batto, Jean-Michel -- Kennedy, Sean -- Leonard, Pierre -- Li, Junhua -- Burgdorf, Kristoffer -- Grarup, Niels -- Jorgensen, Torben -- Brandslund, Ivan -- Nielsen, Henrik Bjorn -- Juncker, Agnieszka S -- Bertalan, Marcelo -- Levenez, Florence -- Pons, Nicolas -- Rasmussen, Simon -- Sunagawa, Shinichi -- Tap, Julien -- Tims, Sebastian -- Zoetendal, Erwin G -- Brunak, Soren -- Clement, Karine -- Dore, Joel -- Kleerebezem, Michiel -- Kristiansen, Karsten -- Renault, Pierre -- Sicheritz-Ponten, Thomas -- de Vos, Willem M -- Zucker, Jean-Daniel -- Raes, Jeroen -- Hansen, Torben -- MetaHIT consortium -- Bork, Peer -- Wang, Jun -- Ehrlich, S Dusko -- Pedersen, Oluf -- England -- Nature. 2013 Aug 29;500(7464):541-6. doi: 10.1038/nature12506.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉INRA, Institut National de la Recherche Agronomique, US1367 Metagenopolis, 78350 Jouy en Josas, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23985870" target="_blank"〉PubMed〈/a〉
    Keywords: Adiposity ; Adult ; Bacteria/classification/genetics/*isolation & purification ; Biomarkers/*metabolism ; Body Mass Index ; Case-Control Studies ; Diet ; Dyslipidemias/microbiology ; Energy Metabolism ; Europe/ethnology ; European Continental Ancestry Group ; Female ; Gastrointestinal Tract/*microbiology ; Genes, Bacterial ; Humans ; Inflammation/microbiology ; Insulin Resistance ; Male ; *Metagenome/genetics ; Obesity/metabolism/microbiology ; Overweight/metabolism/microbiology ; Phylogeny ; Thinness/microbiology ; Weight Gain ; Weight Loss
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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