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The Genetics of Type 2 Diabetes: No Longer a
Nightmare Scenario
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by David W. Sharp
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Medicine Top Ten
Papers
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Rank
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Papers
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Cites Nov-Dec
07
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Rank
Sep-Oct 07
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1
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C.L. Ogden, et al., "Prevalence of
overweight and obesity in the United States,
1999-2004," JAMA, 295(13): 1549-55, 5
April 2006. [Ctrs. for Disease Control, Atlanta, GA]
*028RG
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104
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1
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2
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S.E. Nissen, K. Wolski, "Effect of rosiglitazone on
the risk of myocardial infarction and death from
cardiovascular causes," New Engl. J.
Med., 356(24): 2457-71, 14 June 2007. [Cleveland
Clinic, OH] *178DR
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52
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†
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3
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J.A. Bonner, et al., "Radiotherapy plus
cetuximab for squamous-cell carcinoma of the head and
neck," New Engl. J. Med., 354(6): 567-78,
9 February 2006. [11 institutions worldwide] *010HF
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42
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†
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4
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R. Sladek, et al., "A
genome-wide association study identifies novel risk
loci for type 2
diabetes," Nature,
445(7130): 881-5, 22 February 2007. [14 institutions
worldwide] *138CR
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41
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†
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5
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R.J. Motzer, et al., "Sunitinib versus
interferon alfa in metastatic renal-cell
carcinoma," New Engl. J. Med., 356(2):
115-24, 11 January 2007. [10 institutions worldwide] *124NE
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40
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7
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6
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T. Sjöblom, et al., "The consensus
coding sequences of
human breast and colorectal
cancers," Science, 314(5797): 268-74,
13 October 2006. [11 U.S. institutions] *093TV
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39
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3
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7
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A. Sandler, et al.,
"Paclitaxel-carboplatin alone or with bevacizumab
for non-small-cell lung cancer," New Engl. J.
Med., 355(24): 2542-50, 14 December 2006. [7 U.S.
institutions] *116BZ
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39
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10
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8
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L.J. Scott, et al., "A genome-wide
association study of type 2 diabetes in Finns detects
multiple susceptibility variants,"
Science, 316(5829): 1341-5, 1 June 2007. [12 U.S.
and Finland institutions] *173PS
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35
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†
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9
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G. Van den Berghe, et al., "Intensive
insulin therapy in the medical ICU," New Engl.
J. Med., 354(5): 449-61, 2 February 2006. [Catholic U.
Leuven, Belgium] *008DC
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34
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†
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10
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R.H. Duerr, et al., "A genome-wide
association study identifies IL23R as an
inflammatory bowel disease gene,"
Science, 314(5804): 1461-3, 1 December 2006. [18
U.S. and Canadian institutions] *110UF
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34
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6
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SOURCE: Thomson Reuters's
Hot Papers Database. Read the
Legend.
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Single-gene disorders due to the inheritance of one dominant defective gene
or two recessive ones are rare but have been well explored, an example
being cystic fibrosis. Several far more common conditions, such as asthma,
depression, and type 2 diabetes (T2D), are perceived to "run in families,"
but teasing out the complex genetics of these disorders used to be
thought of as near impossible. Access to the whole human genome,
advances in automated genotyping, and novel techniques of statistical
analysis, together with international collaborations, the sharing of
data on a wide scale, and painstaking attempts to confirm findings in
independent samples, have combined to alter that situation, and rapidly.
Two papers in the current Top Ten (#4, #8) illustrate the point for T2D.
Paper #4 almost made it last time (landing at #11) and had accumulated 102
citations at the most recent count. Paper #8, with 68 total citations, was
one of three related papers in the same issue of Science. Of the
other two, one has recorded 59 citations as of this period (E. Zeggini,
et al., Science, 316[5827]:1336-41, 2007) while the other
(R. Saxena, et al., Science, 316[5827]: 1331-6, 2007) has
yet to achieve Hot Paper status.
Genome-wide studies—and both papers #4 and #8 report investigations
of this type—look at single nucleotide polymorphisms (SNPs), and the
risk loci identified may be coding (for proteins) or non-coding. Dr. Robert
Sladek and his colleagues (#4) identified five significant loci, including
an already widely replicated one, TCF7L2, controlling a
transcription factor associated with insulin sensitivity. Another was the
zinc transporter SLC30A8, which is expressed exclusively in
insulin-producing pancreatic beta-cells. Dr. Laura J. Scott and her
co-workers (#8) also report new loci and confirm older ones, including
TCF7L2 and SLC30A8. Their findings brought the number of
"T2D loci confidently identified to at least 10." That this is a
fast-moving field is shown by the paper, with almost 100 authors, released
by Nature Genetics at the end of March, 2008 (E. Zeggini, et
al., Nat. Genet. Epub, March 30, 2008), which takes that total to 16.
By the time this issue of Science Watch appears, this number too
may be out of date.
Risks are often expressed as odds ratios, and genetics is no exception.
With T2D, and for the loci attracting attention, the odds ratios are low
(often in the range 1.1 to 1.3) but highly significant statistically. Even
for the most amply confirmed locus, TCF7L2, when subjected to a
meta-analysis of what was then 28 studies (S. Cauchi, et al.,
J. Mol. Med. 85[7]:777-82, 2007), the odds ratio was only 1.46,
the probability of this association being due to chance being vanishingly
small. However, such modest effects on risk should not be a surprise, says
Prof. Mark McCarthy (University of Oxford, U.K.). "We knew we were dealing
with multifactorial traits, whereby risk is governed by the combined
effects of many genetic variants and many environmental exposures, such
that the effect of any single one is small," he tells Science
Watch.
In any case, "effect size has little to do with biological impact,"
McCarthy explains. The genetic variants now being identified "are simply
accidents of nature…and have been tolerated through generations."
Even though "most will have only a subtle effect on the function/expression
of the genes they influence," what they can reveal about the mechanisms of
normal and abnormal glucose homeostasis may prove very important
therapeutically. An early credible locus was KCNJ11, in fact
chosen because it encodes a target for powerful drugs. Here the odds ratio
for T2D risk may be only 1.2 but this does not mean that "a drug designed
to target its product doesn’t have a big effect," says McCarthy.
Science Watch did not ask Prof. McCarthy about the use of these
findings as a test for predicting the likelihood of an individual
developing type 2 diabetes (as opposed to the development of new treatments
for the disease). That predictive testing is at least theoretically
feasible is hinted at by calculations done in Cleveland, Ohio, at Case
Western Reserve University (Q. Lu, R.C. Elston, Am. J. Hum. Genet.
82[3]: 641-51, 2008).
Mr. David W. Sharp, M.A. (Cambridge), formerly deputy editor of
The Lancet, is a freelance writer in Minchinhampton, U.K.
Keywords: diabetes, type 2 diabetes, genome-wide
association study, genotyping, SNPs, Robert Sladek, Laura J. Scott, Mark
McCarthy
What's Hot In... : What's Hot In Medicine Menu : The Genetics of Type 2 Diabetes: No Longer a Nightmare Scenario - May/Jun 2008
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