Researchers Identify New Genetic Risk Factors
for Type 2 Diabetes
Landmark Study Shows At Least 10 Genetic Variants
Are Associated With Adult Onset Diabetes
In the most comprehensive look at genetic risk factors for type
2 diabetes to date, a U.S.-Finnish team, working in close collaboration
with two other groups, has identified at least four new genetic
variants associated with increased risk of diabetes and confirmed
existence of another six. The findings of the three groups, published
simultaneously today in the online edition of the journal Science,
boost to at least 10 the number of genetic variants confidently
associated with increased susceptibility to type 2 diabetes — a
disease that affects more than 200 million people worldwide.
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"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."
Led by Michael Boehnke, Ph.D., of the University of Michigan's
School of Public Health, Ann Arbor; Francis Collins, M.D., Ph.D.,
of the National Human Genome Research Institute; Richard Bergman,
Ph.D., of the University of Southern California, Los Angeles; Karen
Mohlke, Ph.D. of the University of North Carolina, Chapel Hill;
and Jaakko Tuomilehto, M.D., Ph.D. of the University of Helsinki
and National Public Health Institute in Finland; the U.S.-Finnish
team received major support from the National Institute of Diabetes
and Digestive and Kidney Diseases (NIDDK) and NHGRI's Division
of Intramural Research, both part of the NIH. The laboratory analysis
of genetic variants in the first stage of the study was conducted
by the Center for Inherited Disease Research, using funding from
NIH and The Johns Hopkins University in Baltimore.
The research was carried out in conjunction with the work of two
other teams: the Diabetes Genetics Initiative, which is a collaboration
of the Broad Institute of Harvard and MIT, Cambridge, Mass.; Lund
University, Malmo, Sweden; and Novartis, Basel, Switzerland; and
the Wellcome Trust Case Control Consortium/U.K. Type 2 Diabetes
Genetics Consortium. The Diabetes Genetics Initiative was led by
David Altshuler, M.D., Ph.D., Broad Institute; Leif Groop, M.D.,
Ph.D., Lund University; and Thomas Hughes, Ph.D., Novartis. The
British team was led by Mark McCarthy, M.D., FRCP, Oxford University
and Andrew Hattersley, D.M., FRCP, Peninsula Medical School, Plymouth.
"It's been a formidable challenge to identify the complex genetic
factors involved in common diseases, such as type 2 diabetes. Now,
thanks to the tools and technologies generated by the sequencing
of the human genome and subsequent mapping of common human genetic
variations, we finally are making significant progress," said NHGRI
Director Collins, who led the NIH component of the Human Genome
Project.
Type 2 diabetes affects nearly 21 million people in the United
States and the incidence of the disease has skyrocketed in the
U.S. and many other developed nations over the last 30 years. Diabetes
is a major cause of heart disease and stroke, as well as the most
common cause in U.S. adults of blindness, kidney failure and amputations
not related to trauma.
NIDDK Director Griffin P. Rodgers, M.D., said, "These genetic
findings are exciting news for diabetes research. While more work
remains to be done, the newly identified genetic variants may point
us in the direction of valuable new drug targets for the prevention
or treatment of type 2 diabetes."
Previously known as adult onset or non-insulin dependent diabetes
(NIDDM), type 2 diabetes usually appears after age 40, often in
overweight, sedentary individuals. However, an increasing number
of younger people and even children are developing the disease,
which is characterized by the resistance of target tissues to respond
to insulin and a gradual failure of insulin-secreting cells in
the pancreas.
In addition to lifestyle factors like obesity, poor diet and lack
of exercise, doctors have long known that heredity plays a significant
role in the risk of developing type 2 diabetes. People who have
a parent or sibling with type 2 diabetes face a 3.5-times greater
risk than people without a family history of the disease. However,
researchers have only recently begun to zero in on particular genetic
variants that increase or decrease susceptibility to the disease.
To make their discoveries, researchers used a relatively new,
comprehensive strategy known as a genome-wide association study. "Genome-wide
association studies offer a powerful way to uncover the genetic
variations that contribute to diabetes, as well as other common
conditions, such as asthma, arthritis, heart disease, cancer and
mental illnesses," Dr. Boehnke said. "Once susceptibility genes
are identified, researchers then can use this information to develop
better approaches to detecting, treating and preventing disease."
To conduct a genome-wide association study, researchers use 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.
If certain genetic variations are found more frequently in people
with the disease compared to healthy people, the variations are
said to be associated with the disease. The associated genetic
variations can serve as a strong pointer to the region of the genome
where the genetic risk factor resides. However, the first variants
detected may not themselves directly influence disease susceptibility,
and the actual causative variant may lie nearby. This means researchers
often need to take additional steps, such as sequencing every DNA
base pair in that particular region of the genome, to identify
the exact genetic variant that affects disease risk.
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.
"We thank all the Finnish citizens who participated in this study.
Their generosity has created a lasting legacy that will help to
reduce the terrible toll that diabetes is taking on the world’s
health," said Dr. Tuomilehto of the Diabetes Unit in Finland’s
National Public Health Institute.
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, led
by Peter Donnelly, D.Phil., Oxford University. 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 totaling 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 phenomenal accomplishment, in terms of both the breadth
and depth of the research. By pulling together and sharing their
data, these three groups were able to achieve far more than any
one of them could have done alone," said Eric D. Green, M.D., Ph.D.,
director of NHGRI’s Division of Intramural Research. "This is scientific
collaboration at its best."
Ultimately, 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.
The genetic variants associated with diabetes that were confidently
confirmed by the new research are: TCF7L2, SLC30A8, HHEX, PPARG,
KCNJ11 and FTO. A variant in FTO was recently
associated with increased risk of obesity. (T. Frayling et al. A
Common Variant in the FTO Gene Is Associated with Body Mass
Index and Predisposes to Childhood and Adult Obesity. Science
Express, Published online April 12, 2007) The latest study found
that variations in or near the FTO gene are also associated
with greater risk of type 2 diabetes, which is likely related to
an increased predisposition to obesity.
When the genomes of the Finnish participants were scanned for
all 10 diabetes-associated genetic variants, researchers could
identify individuals whose genetic profiles placed them at increased
risk for type 2 diabetes — including one subset of people
who faced a risk four times higher than those at the lowest genetic
risk. This “could potentially have value in a personalized preventive
medicine program,” the researchers wrote.
However, 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.
For more information about genome-wide association studies, go
to http://www.genome.gov/20019523.
For more information about diabetes, go to: http://diabetes.niddk.nih.gov/dm/pubs/overview/index.htm.
NHGRI and NIDDK are two of the 27 institutes and centers at the
National Institutes of Health, which is an agency of the Department
of Health and Human Services. The NHGRI Division of Intramural
Research develops and implements technology to understand, diagnose
and treat genomic and genetic diseases. Additional information
about NHGRI can be found at www.genome.gov.
The NIDDK conducts and supports research in diabetes and other
endocrine and metabolic diseases; digestive diseases, nutrition,
and obesity; and kidney, urologic and hematologic diseases. Additional
information about NIDDK can be found at www.niddk.nih.gov.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.
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