PHILADELPHIA, July 15 /PRNewswire-USNewswire/ -- Pediatrics researchers
at The Children's Hospital of Philadelphia and McGill University in
Montreal have identified a gene variant that raises a child's risk for type
1 diabetes, formerly called juvenile diabetes. As investigators continue to
pinpoint genes contributing to diabetes, they have their eyes on providing
a scientific basis for designing better treatments and preventive measures
for the disease.
    The research adds a new gene and new knowledge to the four genes
previously discovered for type 1 diabetes, in which the immune system
destroys insulin-producing beta cells in the pancreas and makes patients
dependent on frequent insulin injections to keep the body's blood sugar
under control. As the project continues, the study team expects to identify
additional genes (perhaps as many as 15 or 20) thought to interact with
each other in the disease.
    The study appeared July 15 in an advance online letter in the journal
Nature.
    "The genotyping technology we now have available has revolutionized the
way we can ask and answer research questions," said the study's lead
author, Hakon Hakonarson, M.D., Ph.D., the director of the Center for
Applied Genomics at The Children's Hospital of Philadelphia. "Unlike the
previous technology, which was quite limited and dealt largely with
relatively rare gene variants, we can now detect common genetic variants
that are important in large numbers of individuals, and begin to understand
how multiple genes interact in complex diseases such as diabetes."
    In the discovery phase of the study, the investigators examined the
genomes of 1,046 children with type 1 diabetes. These DNA samples came from
patients and families followed in pediatric diabetes clinics in
Philadelphia and four Canadian cities. Specifically, the researchers
compared the genomes of 563 patients with type 1 diabetes with those of
1,146 matched control subjects. Those results were combined with those
obtained from an independent analysis of 483 family trios, in which the
genomes of a child with the disease and both parents were examined.
    The researchers confirmed the four previously identified locations for
genes contributing to type 1 diabetes, but also uncovered a new type 1
diabetes locus on chromosome 16, occupied by a gene called KIAA0350. The
team then replicated this discovery in yet another independent cohort of
1,333 children with the disease from the Type 1 Diabetes Genetics
Consortium, which includes children of European descent in Europe, North
America and Australia, as well as in 390 additional type 1 diabetes family
trios from Canada.
    Constantin Polychronakos, M.D., director of Pediatric Endocrinology at
McGill University and senior author of the study, said that better
knowledge of genes that predispose to type 1 diabetes may later enable
physicians to screen newborns to predict those at high risk for the
disease.
    The gene implicated in the current research, KIAA0350, is known to be
active almost exclusively in immune cells. Although scientists do not
currently know the exact function of the protein the gene encodes, other
research has predicted that it produces a protein called C-type lectin that
is located on the surface of immune cells and binds to groups of sugars in
the body.
    "The role of KIAA0350 needs to be investigated," said Hakonarson.
"However, a special cell type called a natural killer (NK) cell expresses
this gene abundantly, although at different levels based on these gene
variants. Our hypothesis is that a special mutation in KIAA0350 may
influence the sugar binding of the protein, and trigger an autoimmune
response that activates these NK cells in such a way that they attack and
destroy the islet cells in the pancreas, resulting in type 1 diabetes. A
particular version of the gene protects against this inappropriate
autoimmune response, while a different version of the gene makes it more
likely to happen."
    Although much research remains to be done, better understanding of the
disease process may guide doctors to new and improved therapies. "If we
know the gene pathways that give rise to type 1 diabetes, we hope to
intervene early in life with targeted drugs or cell therapies to prevent
the disease from developing," said Polychronakos.
    The current research used a technique called genome-wide association,
in which highly automated analytic equipment rapidly scans each patient's
DNA for more than half a million genetic markers. It was performed at the
Center for Applied Genomics at Children's Hospital. The Center's tools
spell out a patient's genotype -- the specific pattern of variations among
an individual's 30,000 genes. Established in the summer of 2006, the center
is taking on one of the largest genotyping projects in the world, and is
the largest one dedicated to genetic analysis of childhood diseases.
    "This study is the first one that our center has published on a gene
associated with a complex childhood disease, but we have many projects
under way and several other papers in press," said Hakonarson. "Our goal at
the Center is to discover the major disease-causing variants and genes that
influence complex pediatric diseases, thus providing a scientific
foundation that is based in biology for translating those discoveries into
successful treatments."
    Among its current projects, the Center's investigators are focused on
identifying genes involved in pediatric asthma, allergy, obesity,
attention- deficit hyperactivity disorder, autism, inflammatory bowel
disease, hypertension, juvenile rheumatoid arthritis and the pediatric
cancer neuroblastoma. The Center recently contributed 4,000 DNA samples to
an industry-hosted database that serves as a free repository of control
samples for researchers seeking gene variations in diseases.
    Financial support for the study came from Genome Canada through the
Ontario Genomics Institute, the Juvenile Diabetes Research Foundation and
The Children's Hospital of Philadelphia. Hakonarson's and Polychronakos'
co- authors were affiliated with the University of Pennsylvania School of
Medicine, the University of Manitoba, the Children's Hospital of Eastern
Ontario, the University of Ottawa, and Markham-Stoufville Hospital of
Markham, Ontario.
    About The Children's Hospital of Philadelphia: The Children's Hospital
of Philadelphia was founded in 1855 as the nation's first pediatric
hospital. Through its long-standing commitment to providing exceptional
patient care, training new generations of pediatric healthcare
professionals and pioneering major research initiatives, Children's
Hospital has fostered many discoveries that have benefited children
worldwide. Its pediatric research program is among the largest in the
country, ranking third in National Institutes of Health funding. In
addition, its unique family-centered care and public service programs have
brought the 430-bed hospital recognition as a leading advocate for children
and adolescents. For more information, visit http://www.chop.edu.
    Contact: John Ascenzi
    Phone: (267) 426-6055
    Ascenzi@email.chop.edu

SOURCE Children's Hospital of Philadelphia