28 June 2010

Decoding diabetes

12 new genes linked to type 2 diabetes

Laser scanning confocal microscope image of the Islet of Langerhans isolated from rat pancreas. Beta-cells are stained green. Many of the genes identified in this study seem to be important in controlling the number of pancreatic beta-cells that an individual has.

Laser scanning confocal microscope image of the Islet of Langerhans isolated from rat pancreas. Beta-cells are stained green. Many of the genes identified in this study seem to be important in controlling the number of pancreatic beta-cells that an individual has. [Masur, Wikimedia Commons]

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Twelve new genes associated with type 2 diabetes have been identified in the largest study yet of the connections between differences in people's DNA and their risk of diabetes.

The international consortium of scientists, led by Professor Mark McCarthy of the University of Oxford, report their findings in the journal Nature Genetics - 10 years after the first draft of the human genome was announced on 26 June 2000.

"The signals we have identified provide important clues to the biological basis of type 2 diabetes," says Professor McCarthy of the Wellcome Trust Centre for Human Genetics at Oxford University. "The challenge will be to turn these genetic findings into better ways of treating and preventing the condition."

The identification of 12 new genes brings the total number of genetic regions known to be associated with type 2 diabetes to 38. The genes tend to be involved in the working of pancreatic cells that produce the hormone insulin (insulin is crucial for controlling levels of glucose in the blood), the control of insulin's action in the body, and in cell-cycle regulation.

The findings not only improve understanding of the processes underpinning type 2 diabetes, but give new biological pathways that can be explored as targets for new therapies.

"One important theme is that several of the genes seem to be important in controlling the number of pancreatic beta-cells that an individual has," says Professor McCarthy. (Beta-cells are the cells in the pancreas that produce insulin.) "This helps settle a long-standing controversy about the role of beta-cell numbers in type 2 diabetes risk, and points to the importance of developing therapies that are able to preserve or restore depleted numbers of beta-cells."

The consortium of researchers - from across the UK, Europe, USA and Canada - compared the DNA of over 8,000 people with type 2 diabetes with almost 40,000 people without the condition at almost 2.5 million locations across the genome. They then checked the genetic variations they found in another group including over 34,000 people with diabetes and almost 60,000 controls.

" That we have been able to expand the catalogue of genetic regions known to contribute to type 2 diabetes by nearly a third serves to highlight the importance of international collaboration to tease out new clues from large samples. "

Dr Eleftheria Zeggini

"That we have been able to expand the catalogue of genetic regions known to contribute to type 2 diabetes by nearly a third in a single study serves to highlight the importance of international collaboration to tease out new clues from large samples," says Dr Eleftheria Zeggini, from the Wellcome Trust Sanger Institute and an author on the study. "But many challenges remain. Each individual variant must be deciphered and its effects understood in the context of the complex tapestry of biological mechanisms underlying type 2 diabetes."

Although the study found 12 new genetic regions where the presence of a particular variation in DNA sequence leads to an increased susceptibility to type 2 diabetes, the individual effects are small. That is, possessing one of these gene variants leads to only a marginal (but clear) increase in the risk of developing the condition. Even in combination, their capacity to predict future risk of diabetes is modest. However, the potential impact of the findings in terms of new biology and possible therapeutic developments could be significant.

Dr Jim Wilson, Royal Society University Research Fellow at the University of Edinburgh and a member of the research team, said: "One very interesting finding is that the diabetes susceptibility genes also contain variants that increase the risk of unrelated diseases, including skin and prostate cancer, coronary heart disease and high cholesterol. This implies that different regulation of these genes can lead to many different diseases."

The researchers are now planning to use the availability of new tools for sequencing the whole human genome to explore further sources of DNA sequence variation that have been missed in previous efforts, in an effort to pin down the remaining genetic basis for type 2 diabetes.

Type 2 diabetes represents one of the most significant global challenges to health. The rapidly rising prevalence of this condition across the world is thought to reflect the impact of widespread changes in lifestyle and diet on genetically susceptible individuals. Currently-available therapies can mitigate the effects of diabetes, but improved approaches for prevention and treatment are urgently required.

"Gradually we are piecing together clues about why some people get diabetes and others don't, with the potential for developing better treatments and preventing onset of diabetes in the future," says Professor McCarthy.

Notes to Editors

Publication details

  • Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis.

    Voight BF, Scott LJ, Steinthorsdottir V, Morris AP, Dina C, Welch RP, Zeggini E, Huth C, Aulchenko YS, Thorleifsson G, McCulloch LJ, Ferreira T, Grallert H, Amin N, Wu G, Willer CJ, Raychaudhuri S, McCarroll SA, Langenberg C, Hofmann OM, Dupuis J, Qi L, Segrè AV, van Hoek M, Navarro P, Ardlie K, Balkau B, Benediktsson R, Bennett AJ, Blagieva R, Boerwinkle E, Bonnycastle LL, Bengtsson Boström K, Bravenboer B, Bumpstead S, Burtt NP, Charpentier G, Chines PS, Cornelis M, Couper DJ, Crawford G, Doney AS, Elliott KS, Elliott AL, Erdos MR, Fox CS, Franklin CS, Ganser M, Gieger C, Grarup N, Green T, Griffin S, Groves CJ, Guiducci C, Hadjadj S, Hassanali N, Herder C, Isomaa B, Jackson AU, Johnson PR, Jørgensen T, Kao WH, Klopp N, Kong A, Kraft P, Kuusisto J, Lauritzen T, Li M, Lieverse A, Lindgren CM, Lyssenko V, Marre M, Meitinger T, Midthjell K, Morken MA, Narisu N, Nilsson P, Owen KR, Payne F, Perry JR, Petersen AK, Platou C, Proença C, Prokopenko I, Rathmann W, Rayner NW, Robertson NR, Rocheleau G, Roden M, Sampson MJ, Saxena R, Shields BM, Shrader P, Sigurdsson G, Sparsø T, Strassburger K, Stringham HM, Sun Q, Swift AJ, Thorand B, Tichet J, Tuomi T, van Dam RM, van Haeften TW, van Herpt T, van Vliet-Ostaptchouk JV, Walters GB, Weedon MN, Wijmenga C, Witteman J, Bergman RN, Cauchi S, Collins FS, Gloyn AL, Gyllensten U, Hansen T, Hide WA, Hitman GA, Hofman A, Hunter DJ, Hveem K, Laakso M, Mohlke KL, Morris AD, Palmer CN, Pramstaller PP, Rudan I, Sijbrands E, Stein LD, Tuomilehto J, Uitterlinden A, Walker M, Wareham NJ, Watanabe RM, Abecasis GR, Boehm BO, Campbell H, Daly MJ, Hattersley AT, Hu FB, Meigs JB, Pankow JS, Pedersen O, Wichmann HE, Barroso I, Florez JC, Frayling TM, Groop L, Sladek R, Thorsteinsdottir U, Wilson JF, Illig T, Froguel P, van Duijn CM, Stefansson K, Altshuler D, Boehnke M, McCarthy MI, MAGIC investigators and GIANT Consortium

    Nature genetics 2010;42;7;579-89

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