New genetic risk factors for type 2 diabetes identified
17 May 2007
In the most comprehensive look at genetic risk factors for type 2
diabetes to date, researchers in the US and Finland have identified at least
four new genetic variants associated with increased risk of diabetes and
confirmed existence of another six. In total, the genomes of 32,554 people
from Finland, Poland, Sweden, the United Kingdom and the United States were
tested.
The researchers were from the University of Michigan, the National Human
Genome Research Institute, the University of Southern California, the
University of North Carolina, and Finland’s National Health Institute, The
findings have been published in the online edition of the journal Science.
“This achievement represents a major milestone in our battle against
diabetes. It will accelerate efforts to understand the genetic risk factors
for this disease, as well as explore how these genetic factors interact with
each other and with lifestyle factors,” said National Institutes of Health
(NIH) Director Elias A. Zerhouni, M.D. “Such research is opening the door to
the era of personalized medicine. Our current one-size-fits-all approach
will soon give way to more individualized strategies based on each person’s
unique genetic make-up.”
These findings distinguish at least 10 genetic variants confidently
associated with increased susceptibility to type 2 diabetes — a disease that
affects nearly 21 million in the United States, and the incidence of the
disease has skyrocketed in the last 30 years. Diabetes is a major cause of
heart disease and stroke, as well as the most common cause in US adults of
blindness, kidney failure and amputations not related to trauma.
“These genetic risk factors will make it more likely that we can predict
who is at risk for the disease,” says Richard Bergman, Ph.D., the chair of
the department of physiology and biophysics at the Keck School of Medicine
of USC. “We know type 2 takes a long time to develop and if we can identify
those at risk of the disease, we may be able to prevent or delay the risk of
disease in these people.”
Researchers used a relatively new, comprehensive strategy known as a
genome-wide association study by using two groups of participants: a large
group of people with the disease being studied and a large group of
otherwise similar people without the disease. Utilizing DNA purified from
blood or cells, researchers quickly survey each participant’s complete set
of DNA, or genome, for strategically selected markers of genetic variation.
In the latest work, researchers began by scanning the genomes of more
than 2,300 Finnish people who took part in the Finland-United States
Investigation Of NIDDM Genetics (FUSION) and Finrisk 2002 studies. About
half of the participants had type 2 diabetes and the other half had normal
blood glucose levels.
To validate their findings, the researchers compared their initial
results with results from genome scans of 3,000 Swedish and Finnish
participants in the Diabetes Genetics Initiative and 5,000 British
participants in the Wellcome Trust Case Control Consortium.
After identifying promising leads through this approach, the three
research teams jointly replicated their findings using smaller, more focused
sets of genetic markers in additional groups totalling more than 22,000
people from Finland, Poland, Sweden, the United Kingdom and the United
States. All told, the genomes of 32,554 people were tested for the study,
making it one of the largest genome-wide association efforts conducted to
date.
“This is a very exciting time for the genetics of type 2 diabetes. There
are real signals in the genome for the disease. Many are unexpected or
unexplained and each one accounts for only a small risk,” says Tom Buchanan,
M.D., professor of medicine at USC. “However, together they account for a
lot of risk. Our challenge now, a challenge that the USC Diabetes Group has
already begun to undertake in human studies, is to figure out how the risk
genes work and how they work together with environmental factors to cause
diabetes. The FUSION results are a big step for genetics, but an even bigger
opportunity for understanding one of the most common and most rapidly
increasing diseases of the developed world.”
The researchers identified four new diabetes-associated variations, as well
as confirmed previous findings that associated six other genetic variants
with increased diabetes risk. The newly identified diabetes-associated
variations lie in or near:
- IGF2BP2. This gene codes for a protein called insulin-like growth
factor 2 mRNA binding protein 2. Insulin-like growth factor 2 is thought
to play a role in regulating insulin action.
- CDKAL1. This gene codes for a protein called CDK5 regulatory subunit
associated protein1-like1. The protein may affect the activity of the
cyclin dependent kinase 5 (CDK5) protein, which stimulates insulin
production and may influence other processes in the pancreas’s
insulin-producing cells, known as beta cells. In addition, excessive
activity of CDK5 in the pancreas may lead to the degeneration of beta
cells.
- CDKN2A and CDKN2B. The proteins produced by these two genes inhibit
the activity of cyclin-dependent protein kinases, including one that has
been shown to influence the growth of beta cells in mice. Interestingly,
these genes have been heavily studied for their role in cancer, but
their contribution to diabetes comes as a complete surprise.
- Chromosome 11. One intriguing association is located in a region of
chromosome 11 not known to contain any genes. Researchers speculate that
the variant sequences may regulate the activity of genes located
elsewhere in the genome, but more work is needed to determine the exact
relationships to pathways involved in type 2 diabetes.
Bergman, Buchanan and Richard Watanabe, Ph.D., associate professor of
preventive medicine at USC were instrumental in helping decipher some of
these results. “We were able to provide the important physiologic and
clinical feedback necessary to guide the hunt for the genes,” says Watanabe.
“In addition, compared to the other centers, USC's contribution was unique
in that it was multi-dimensional. We provided support in terms of performing
assays, providing the biologic perspective, and performing data analysis and
interpretation. It speaks to the diverse talent and expertise in diabetes
research that exists at USC.”
The researchers emphasized that their predictions of disease risk need to
be interpreted with caution because the diabetes group in their sample was
“enriched” with people who had affected siblings and because the healthy
group excluded people who had impaired glucose tolerance or impaired fasting
glucose.
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