MAGIC Study Pulls New Genetic Rabbits from the Diabetes Hat
What's Hot in July/August 2011
by Jeremy Cherfas
Diabetes is one of the fastest-growing non-communicable diseases in the world. It affected an estimated 2.8% of world population in 2000 and is projected to almost double, to 4.4%, by 2030. Up to 95% of cases are type 2 diabetes, which is characterized both by insufficient insulin production (measured by an index called HOMA-B) and resistance to the effects of insulin (HOMA-IR). High levels of blood glucose and blood insulin during fasting are also indicative of diabetes.
Type 1 diabetes, which generally manifests at a much lower age than type 2 diabetes, is commonly thought of as "genetic" diabetes, while type 2 diabetes is more "environmental," associated with certain types of diet and sedentary lifestyles. Thanks to a massive meta-analysis of genome-wide association studies (GWAS), the genetic basis for type 2 diabetes is now considerably clearer.
The Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) was established specifically to look for genetic associations with those traits in people without diabetes, and one of MAGIC’s first two papers is at #9 in the current Top Ten.
It follows the by-now almost familiar pattern of genome-wide association studies. First, look for associations between single-nucleotide polymorphisms (SNPs) as genetic markers and markers of disease: fasting glucose, fasting insulin, HOMA-B and HOMA-IR. Then take the SNPs and follow up in new groups of subjects to confirm and further explore the associations. Step one was a meta-analysis of 2.5 million SNPs in 21 GWAS cohorts—adding up to more than 46,000 people who did not have diabetes and who had been tested for insulin and glucose function. This resulted in 25 lead candidate SNPs, which were tested in a further 76,000 people to reveal 10 new markers associated with impaired glucose or insulin function.
View the
Special Topic of Diabetes. The baseline time span
for this database is 1999-February 28, 2009. The resulting database
contained 50,145 (10 years) and 14,506 (2 years) papers; 117,289
authors; 150 nations; 2,937 journals; and 22,269 institutions.
The study also confirmed another eight SNPs that had been previously identified. A further comparison of the new markers in diabetic and non-diabetic people showed that five were linked to increased risk of type 2 diabetes.
Most of the new markers are linked to insulin secretion, with only one linked to insulin resistance. This suggests that pancreatic beta cells, which secrete insulin, may play a greater role in type 2 diabetes than previously thought. By the same token, with only one genetic marker associated with insulin resistance, perhaps the environment plays a greater part in insulin resistance, although fewer genes and rarer variants may also be to blame. And the fact that not all the markers linked to regulation of blood glucose are associated with diagnosed type 2 diabetes is also intriguing. The mere fact of higher blood glucose during fasting is probably less important for progression to type 2 diabetes than the mechanism by which blood glucose is raised.
The authors also cautiously note that they "cannot rule out" the possibility that there may be genetic variants that protect the individual from developing type 2 diabetes, even though fasting glucose levels are higher than normal.
A close look at the specifics of the genes nearest to the SNP markers reveals some interesting ideas about possible mechanisms. ADCY5, for example, which is linked to increased risk of type 2 diabetes, codes for an enzyme that catalyzes the formation of cyclic AMP, and in pancreatic beta cells cAMP activates insulin synthesis and secretion. FADS1, another risk factor, encodes fatty acid desaturase 1.
The products of FADS1 (and nearby FADS2 and FADS3) can boost the release of insulin caused by elevated blood glucose. As the authors comment of all the SNPs, "within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing, and circadian regulation." A box in the paper explores these various suggestive possibilities, and underpins the authors’ final conclusion, that "in-depth physiological investigation" of the 10 new loci associated with glycemic traits "should further our understanding of glucose homeostasis in humans and may reveal new pathways for diabetes therapeutics." That does indeed seem certain, and possibly underlies the paper’s high citation count.
Even without new therapeutics, the evidence of genetic variants associated with increased risk of developing type 2 diabetes could potentially be used to screen people and advise those with a greater risk to change their ways. However, given the known links between type 2 diabetes and behaviour—particularly what people eat and how much they exercise—it seems at least possible that a better understanding of how to help people at risk of type 2 diabetes to change their behavior in protective directions could have a more immediate, and possibly more effective, impact than waiting for deeper understanding and new therapeutics. But of course, that wouldn’t be nearly as magical.
Dr. Jeremy Cherfas is Science Writer at Bioversity International, Rome, Italy.
What's Hot in Biology | |||
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Rank | Paper |
Cites This Period Jan-Feb 11 |
Rank Last Period Nov-Dec 10 |
1 | J. M.L. Ebos, et al., "Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis," Cancer Cell, 15(3): 232-9, 3 March 2009. [Sunnybrook Health Sci. Ctr., Toronto, Canada; U. Toronto, Canada; Sunnybrook Odette Cancer Ctr., Toronto; Pfizer, La Jolla, CA] *416IC | 31 | † |
2 | M. Paez-Ribes, et al., "Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis," Cancer Cell, 15(3): 220-31, 3 March 2009. [Catalan Inst. Oncology, L’Hospitalet de Llobregat, Spain; U. Calif., San Francisco; Osaka Med. Ctr. Cancer & Cardio. Dis., Japan; U. Barcelona, Spain] *416IC | 30 | † |
3 | C. Choudhary, et al., "Lysine acetylation targets protein complexes and co-regulates major cellular functions," Science, 325(5942): 834-40, 14 August 2009. [Max Planck Inst. Biochem., Martinsried, Germany; U. Copenhagen, Denmark] *487AK | 26 | 8 |
4 | E. Lieberman-Aiden, et al., "Comprehensive mapping of long-range interactions reveals folding principles of the human genome," Science, 326(5950): 289-93, 9 October 2009. [5 U.S. institutions] *504EX | 25 | † |
5 | L.A. Hindorff, et al., "Potential etiologic and functional implications of genome-wide association loci for human diseases and traits," PNAS, 106(23): 9362-7, 9 June 2009. [NIH, Bethesda, MD] *456CN | 24 | 3 |
6 | Y. Tanaka, et al., "Genome-wide association of IL28B with response to pegylated interferon-a and ribavirin therapy for chronic hepatitis C," Nature Genetics, 41(10): 1105-9, October 2009. [17 Japanese institutions] *500UG | 24 | 7 |
7 | E.D. Pleasance, et al., "A comprehensive catalogue of somatic mutations from a human cancer genome," Nature, 463(7278): 191-6, 14 January 2010. [7 institutions worldwide] *543MQ | 23 | † |
8 | D.E. Harrison, et al., "Rapamycin fed late in life extends lifespan in genetically heterogeneous mice," Nature, 460(7253): 392-5, 16 July 2009. [7 U.S. institutions] *470MO | 22 | 4 |
9 | J. Dupuis, et al., "New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk," Nature Genetics, 42(2): 105-16, February 2010. [176 institutions worldwide] *549WB | 22 | † |
10 | J. Schmutz, et al., "Genome sequence of the palaeopolyploid soybean," Nature, 463(7278): 178-83, 14 January 2010. [17 U.S. institutions] *543MQ | 22 | † |
SOURCE: Thomson Reuters Hot Papers Database. Read the Legend. |
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Chemical structure of open-chain glucose, from the Wiki Commons.