17 January 2010

From biological basics to diabetes discovery

Researchers uncover novel genetic markers for diabetes-related traits

Manhattan plots of the association P values.

Manhattan plots of the association P values.

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In two major studies published in Nature Genetics today, researchers use biological understanding to dissect the genetics of diabetes. An international team comprising researchers from more than 100 institutions analysed vast suites of genetic data from more than 100,000 people of European descent to uncover the associations.

In the first study, the team identified ten novel genetic markers for biological traits underlying type 2 diabetes. In a companion paper the same consortium identified three new variants that are associated with raised levels of glucose seen in a common test for type 2 diabetes. The results help to unravel the complex biological story of type 2 diabetes: as well as revealing five new associations that influence directly the risk of diabetes, this research will drive studies to understand the biology of disease and to search for treatments to alleviate the burden caused by the disease.

The team are working to understand the normal metabolism of glucose as well as diseases of glucose metabolism, such as diabetes. They seek to uncover new genetic variants that are risk factors for the development of diabetes, as well as identifying genes that influence variation in the healthy range. Diabetes occurs when our bodies fail to produce sufficient insulin or when our cells fail to recognise and react to the insulin produced, resulting in abnormally high blood glucose or sugar levels.

The research was done by the Meta-Analyses of Glucose and Insulin-related Traits Consortium (MAGIC) who examined several commonly used measures including levels of fasting glucose and insulin and blood sugar levels two hours after an oral sugar challenge.

They searched data from population studies of people without diabetes to examine the links between glucose levels and SNPs - single letter changes in the genome that can act as markers for particular physical traits or disease. They found nine new genetic regions associated with fasting glucose, 16 regions associated with insulin production but only a single region associated with insulin resistance.

"We were delighted that we were able to find so many SNPs associated with raised levels of glucose," says Dr Inês Barroso, from the Wellcome Trust Sanger Institute, "but amazed that we found only one strong association with levels of insulin. We don't think this is a technical difference, but that the genetics is telling us that the two measures, insulin and glucose, have different architectures, with fewer genes, rarer variants or greater environmental influence affecting insulin resistance."

" The genetics is telling us that the two measures, insulin and glucose, have different architectures, with fewer genes, rarer variants or greater environmental influence affecting insulin resistance. "

Dr Inês Barroso

The team have strong evidence that other genetic factors remain to be found: their study explains about ten per cent of the genetic effect on fasting glucose. They believe that there will be rarer variants with a larger impact that would not be found by a study such as this.

Many of the diabetes-risk loci had not previously been identified in case-control studies, which compare patients with apparently healthy people. The genome-wide approach used here is a valuable complementary method to find variants that influence disease risk. Importantly, the participants were apparently healthy people, rather than patients, which suggests that important genetic determinants can be found in larger groups of unaffected people, rather than the sometimes restricted groups of patients.

This study not only provides further information about new loci that are associated with glucose levels and diabetes risk, but provides light into the different biological pathways that lead to diabetes. Professor Mark McCarthy of Oxford University says "Our knowledge of type 2 diabetes is slowly being added to with these genetic studies as we are beginning to unravel the complex pathways that lead to the common endpoint of disease."

In the detailed analysis of the glucose challenge, the team found three novel genetic associations, the most prominent of which was with a gene called GIPR-A. Normally, this gene produces a protein that is part of the normal hormone response to feeding, acting to stimulate release of insulin and thus control levels of glucose. The variant is associated with impaired response to the glucose meal and elevated levels of glucose. GIPR sits at a key decision point in glucose metabolism.

"Today's findings are the result of a tremendous group effort involving hundreds of scientists including large consortia in the UK in major institutions working together," says Professor Nick Wareham of the MRC Epidemiology Unit at the University of Cambridge Institute of Metabolic Science. "Traits associated with diseases like type 2 diabetes are so common that it becomes exceptionally difficult to find the genetic regions underlying the physical features and to make that connection solidly. In the face of common diseases, we need to work together in large teams to share and analyse the vast suites of data available. The availability of funding for such consortia from the Wellcome Trust, Medical Research Council and other funders including Diabetes UK has made such work possible and allowed the UK to be at the forefront of these efforts."

Notes to Editors

Type 2 diabetes

The threat posed by type 2 diabetes appears to be on the rise. Estimates suggest that between 170 million and 285 million people worldwide have type 2 diabetes, The World Health Organization suggests that, without urgent action, deaths caused by diabetes could double in the next ten years.

Type 2 diabetes represents 95 per cent of all diabetes cases and is defined as raised levels of glucose in the blood measured either when fasting or 2 hours after a glucose 'meal' (oral glucose challenge). The characteristics of type 2 diabetes are resistance to the effects of insulin and impairment to the working of the beta cells of the pancreas that produce insulin.

Type 2 diabetes is strongly associated with obesity, a history of diabetes, impaired glucose metabolism and population of origin. Type 1 diabetes is an autoimmune disease in which the body's defences attack the insulin-producing beta-cells of the pancreas.

Publication details

  • Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge.

    Saxena R, Hivert MF, Langenberg C, Tanaka T, Pankow JS, Vollenweider P, Lyssenko V, Bouatia-Naji N, Dupuis J, Jackson AU, Kao WH, Li M, Glazer NL, Manning AK, Luan J, Stringham HM, Prokopenko I, Johnson T, Grarup N, Boesgaard TW, Lecoeur C, Shrader P, O'Connell J, Ingelsson E, Couper DJ, Rice K, Song K, Andreasen CH, Dina C, Köttgen A, Le Bacquer O, Pattou F, Taneera J, Steinthorsdottir V, Rybin D, Ardlie K, Sampson M, Qi L, van Hoek M, Weedon MN, Aulchenko YS, Voight BF, Grallert H, Balkau B, Bergman RN, Bielinski SJ, Bonnefond A, Bonnycastle LL, Borch-Johnsen K, Böttcher Y, Brunner E, Buchanan TA, Bumpstead SJ, Cavalcanti-Proença C, Charpentier G, Chen YD, Chines PS, Collins FS, Cornelis M, J Crawford G, Delplanque J, Doney A, Egan JM, Erdos MR, Firmann M, Forouhi NG, Fox CS, Goodarzi MO, Graessler J, Hingorani A, Isomaa B, Jørgensen T, Kivimaki M, Kovacs P, Krohn K, Kumari M, Lauritzen T, Lévy-Marchal C, Mayor V, McAteer JB, Meyre D, Mitchell BD, Mohlke KL, Morken MA, Narisu N, Palmer CN, Pakyz R, Pascoe L, Payne F, Pearson D, Rathmann W, Sandbaek A, Sayer AA, Scott LJ, Sharp SJ, Sijbrands E, Singleton A, Siscovick DS, Smith NL, Sparsø T, Swift AJ, Syddall H, Thorleifsson G, Tönjes A, Tuomi T, Tuomilehto J, Valle TT, Waeber G, Walley A, Waterworth DM, Zeggini E, Zhao JH, GIANT consortium, MAGIC investigators, Illig T, Wichmann HE, Wilson JF, van Duijn C, Hu FB, Morris AD, Frayling TM, Hattersley AT, Thorsteinsdottir U, Stefansson K, Nilsson P, Syvänen AC, Shuldiner AR, Walker M, Bornstein SR, Schwarz P, Williams GH, Nathan DM, Kuusisto J, Laakso M, Cooper C, Marmot M, Ferrucci L, Mooser V, Stumvoll M, Loos RJ, Altshuler D, Psaty BM, Rotter JI, Boerwinkle E, Hansen T, Pedersen O, Florez JC, McCarthy MI, Boehnke M, Barroso I, Sladek R, Froguel P, Meigs JB, Groop L, Wareham NJ and Watanabe RM

    Nature genetics 2010;42;2;142-8

  • New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

    Dupuis J, Langenberg C, Prokopenko I, Saxena R, Soranzo N, Jackson AU, Wheeler E, Glazer NL, Bouatia-Naji N, Gloyn AL, Lindgren CM, Mägi R, Morris AP, Randall J, Johnson T, Elliott P, Rybin D, Thorleifsson G, Steinthorsdottir V, Henneman P, Grallert H, Dehghan A, Hottenga JJ, Franklin CS, Navarro P, Song K, Goel A, Perry JR, Egan JM, Lajunen T, Grarup N, Sparsø T, Doney A, Voight BF, Stringham HM, Li M, Kanoni S, Shrader P, Cavalcanti-Proença C, Kumari M, Qi L, Timpson NJ, Gieger C, Zabena C, Rocheleau G, Ingelsson E, An P, O'Connell J, Luan J, Elliott A, McCarroll SA, Payne F, Roccasecca RM, Pattou F, Sethupathy P, Ardlie K, Ariyurek Y, Balkau B, Barter P, Beilby JP, Ben-Shlomo Y, Benediktsson R, Bennett AJ, Bergmann S, Bochud M, Boerwinkle E, Bonnefond A, Bonnycastle LL, Borch-Johnsen K, Böttcher Y, Brunner E, Bumpstead SJ, Charpentier G, Chen YD, Chines P, Clarke R, Coin LJ, Cooper MN, Cornelis M, Crawford G, Crisponi L, Day IN, de Geus EJ, Delplanque J, Dina C, Erdos MR, Fedson AC, Fischer-Rosinsky A, Forouhi NG, Fox CS, Frants R, Franzosi MG, Galan P, Goodarzi MO, Graessler J, Groves CJ, Grundy S, Gwilliam R, Gyllensten U, Hadjadj S, Hallmans G, Hammond N, Han X, Hartikainen AL, Hassanali N, Hayward C, Heath SC, Hercberg S, Herder C, Hicks AA, Hillman DR, Hingorani AD, Hofman A, Hui J, Hung J, Isomaa B, Johnson PR, Jørgensen T, Jula A, Kaakinen M, Kaprio J, Kesaniemi YA, Kivimaki M, Knight B, Koskinen S, Kovacs P, Kyvik KO, Lathrop GM, Lawlor DA, Le Bacquer O, Lecoeur C, Li Y, Lyssenko V, Mahley R, Mangino M, Manning AK, Martínez-Larrad MT, McAteer JB, McCulloch LJ, McPherson R, Meisinger C, Melzer D, Meyre D, Mitchell BD, Morken MA, Mukherjee S, Naitza S, Narisu N, Neville MJ, Oostra BA, Orrù M, Pakyz R, Palmer CN, Paolisso G, Pattaro C, Pearson D, Peden JF, Pedersen NL, Perola M, Pfeiffer AF, Pichler I, Polasek O, Posthuma D, Potter SC, Pouta A, Province MA, Psaty BM, Rathmann W, Rayner NW, Rice K, Ripatti S, Rivadeneira F, Roden M, Rolandsson O, Sandbaek A, Sandhu M, Sanna S, Sayer AA, Scheet P, Scott LJ, Seedorf U, Sharp SJ, Shields B, Sigurethsson G, Sijbrands EJ, Silveira A, Simpson L, Singleton A, Smith NL, Sovio U, Swift A, Syddall H, Syvänen AC, Tanaka T, Thorand B, Tichet J, Tönjes A, Tuomi T, Uitterlinden AG, van Dijk KW, van Hoek M, Varma D, Visvikis-Siest S, Vitart V, Vogelzangs N, Waeber G, Wagner PJ, Walley A, Walters GB, Ward KL, Watkins H, Weedon MN, Wild SH, Willemsen G, Witteman JC, Yarnell JW, Zeggini E, Zelenika D, Zethelius B, Zhai G, Zhao JH, Zillikens MC, DIAGRAM Consortium, GIANT Consortium, Global BPgen Consortium, Borecki IB, Loos RJ, Meneton P, Magnusson PK, Nathan DM, Williams GH, Hattersley AT, Silander K, Salomaa V, Smith GD, Bornstein SR, Schwarz P, Spranger J, Karpe F, Shuldiner AR, Cooper C, Dedoussis GV, Serrano-Ríos M, Morris AD, Lind L, Palmer LJ, Hu FB, Franks PW, Ebrahim S, Marmot M, Kao WH, Pankow JS, Sampson MJ, Kuusisto J, Laakso M, Hansen T, Pedersen O, Pramstaller PP, Wichmann HE, Illig T, Rudan I, Wright AF, Stumvoll M, Campbell H, Wilson JF, Anders Hamsten on behalf of Procardis Consortium, MAGIC investigators, Bergman RN, Buchanan TA, Collins FS, Mohlke KL, Tuomilehto J, Valle TT, Altshuler D, Rotter JI, Siscovick DS, Penninx BW, Boomsma DI, Deloukas P, Spector TD, Frayling TM, Ferrucci L, Kong A, Thorsteinsdottir U, Stefansson K, van Duijn CM, Aulchenko YS, Cao A, Scuteri A, Schlessinger D, Uda M, Ruokonen A, Jarvelin MR, Waterworth DM, Vollenweider P, Peltonen L, Mooser V, Abecasis GR, Wareham NJ, Sladek R, Froguel P, Watanabe RM, Meigs JB, Groop L, Boehnke M, McCarthy MI, Florez JC and Barroso I

    Nature genetics 2010;42;2;105-16

Funding

A full list of funding agencies is available at the Nature Genetics website.

Participating Centres

A full list of participating centres is available at the Nature Genetics website.

Oxford University

Oxford University's Medical Sciences Division is one of the largest biomedical research centres in Europe. It represents almost one-third of Oxford University's income and expenditure, and two-thirds of its external research income. Oxford's world-renowned global health programme is a leader in the fight against infectious diseases (such as malaria, HIV/AIDS, tuberculosis and avian flu) and other prevalent diseases (such as cancer, stroke, heart disease and diabetes). Key to its success is a long-standing network of dedicated Wellcome Trust-funded research units in Asia (Thailand, Laos and Vietnam) and Kenya, and work at the MRC Unit in The Gambia. Long-term studies of patients around the world are supported by basic science at Oxford and have led to many exciting developments, including potential vaccines for tuberculosis, malaria and HIV, which are in clinical trials.
http://www.medsci.ox.ac.uk

The Medical Research Council Epidemiology Unit

The Medical Research Council supports the best scientific research to improve human health. Its work ranges from molecular level science to public health medicine and has led to pioneering discoveries in our understanding of the human body and the diseases which affect us all.
www.mrc.ac.uk

The goal of the MRC Epidemiology Unit is to study the genetic, development and environmental determinants of obesity, diabetes and related metabolic disorders and to contribute to the scientific basis of prevention.
www.mrc-epid.cam.ac.uk

The Wellcome Trust Sanger Institute

The Wellcome Trust Sanger Institute, which receives the majority of its funding from the Wellcome Trust, was founded in 1992. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome as well as genomes of model organisms and more than 90 pathogen genomes. In October 2006, new funding was awarded by the Wellcome Trust to exploit the wealth of genome data now available to answer important questions about health and disease.

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The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests.

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