Common mutations linked to common obesity in Europeans (7/8/2008)

Scientists have discovered two common genetic mutations in people of European ancestry, which affect the production of several hormones controlling our appetite. The mutations have a significant effect on the risk of common obesity, according to research published today (6 July) in Nature Genetics.

The PCSK1 gene codes for the proconvertase enzyme, which is responsible for producing fully functioning versions of hormones such as insulin, glugagon and melanocortin. These are all involved in controlling the rate of metabolism.

Changes in the PCSK1 gene cause relatively minor abnormalities in the proconvertase enzyme that it codes for. But the effect on the hormones is significant, as they all play a major role in regulating weight.

Scientists from Imperial College London collaborated with teams from France, Denmark, Sweden and Germany to test the genomes of over 13,000 people. They discovered a significant association between the genetic mutations in PCSK1 and a tendency to develop obesity in both adults and children.

"This is the first time that we have found a strong link between common mutations and common obesity in the PCSK1 gene," says Professor Philippe Froguel, leading author of the research from the French National Research Institute and the Department of Genomic Medicine at Imperial College London.

"We know that common forms of obesity depend on variations in multiple genes, so this is an important addition to the list of genes we need to consider as therapeutic targets for treatment in the future."

These new results build on the previous discovery from Professor Froguel's group that the receptor for the hormone melanocotrin 4 also plays a significant role in obesity.

"Common nonsynonymous variants in PCSK1 confer risk of obesity", Nature Genetics, Sunday 6 July 2008

Michael Benzinou (1,2), John W M Creemers (3), Helene Choquet (2), Stephane Lobbens (2), Christian Dina (2), Emmanuelle Durand (2), Audrey Guerardel (2), Philippe Boutin (2), Beatrice Jouret (4), Barbara Heude (5), Beverley Balkau (5), Jean Tichet (6), Michel Marre (7â€"9), Natascha Potoczna (6), Fritz Horber (10), Catherine Le Stunff (11), Sebastien Czernichow (12), Annelli Sandbaek (13), Torsten Lauritzen (13), Knut Borch-Johnsen (14,15), Gitte Andersen (14), Wieland Kiess (16), Antje Körner (16), Peter Kovacs17, Peter Jacobson (18), Lena M S Carlsson (18), Andrew J Walley (1), Torben Jørgensen (19), Torben Hansen (14), Oluf Pedersen (14,15), David Meyre (2) & Philippe Froguel (1,2).

(1) Genomic Medicine, Imperial College London, Hammersmith Hospital, UK (2) Centre National de la Recherche Scientifique (CNRS) 8090-Institute of Biology, Pasteur Institute, Lille, France (3) Department of Human Genetics, University of Leuven, Belgium (4) Institut National de la Sante´ et de la Recherche Médicale (NSERM) U563, Children’s Hospital, Toulouse, France (5) INSERM, U780-IFR69, Villejuif; Univ Paris Sud, Faculty of Medicine, Le Kremlin-Bicêtre, France (6) The Regional Institute for Health, Tours, France (7) INSERM U695, Paris, France (8) Université Paris Diderot - Paris 7, Paris, France (9) Department of Endocrinology-Diabetology and Nutrition, Bichat Claude Bernard Hospital, Paris, France (10) Klinik Lindberg, Winterthur, Switzerland (11) Department of Pediatric Endocrinology and INSERM U561, Saint Vincent de Paul Hospital, Rene´ Descartes University, Paris, France (12) INSERM U557, Institut Scientifique de Recherche Agronomique (INRA) U1125, CNAM EA3200, Université Paris 13, CRNH IdF, & Hoˆ pital Avicenne (AP-HP), Bobigny, F-93017 France (13) Department of General Practice, University of Aarhus, Aarhus, Denmark. (14) Steno Diabetes Center, DK-2820 Gentofte, Copenhagen, Denmark. (15) Faculty of Health Science, University of Aarhus, Aarhus, Denmark (16) University Hospital for Children and Adolescents, University of Leipzig, Germany (17) Department of Internal Medicine III, Interdisciplinary Centre for Clinical Research, University of Leipzig, Germany (18) Department of Molecular and Clinical Medicine Institute of Medicine, The Sahlgrenska Academy, Go¨teborg University, Go¨teborg, Sweden (19) Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark

Note: This story has been adapted from a news release issued by the Imperial College London

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