Investigators Discover Genes Tied To Type 1 Diabetes, Crohn's Disease


Researchers at The Children's Hospital of Philadelphia have identified novel gene variants that raise a child's risk for two common and serious diseases.

In separate studies, investigators discovered genes for type 1 diabetes, formerly called juvenile diabetes, and Crohn's disease, a chronic and painful condition attributed to inflammation of the gastrointestinal tract.

The studies were conducted by or in collaboration with the Hospital's Center for Applied Genomics (CAG), which aims to identify the genes responsible for common childhood diseases. The center uses advanced automated technology to house one of the world's largest programs for genotyping, which involves detecting gene variations and linking them to particular illnesses.

Working with investigators from McGill University in Montreal, Children's Hospital researchers added a new gene and new knowledge to the four genes previously discovered for type 1 diabetes. The study appeared July 15 in an advance online letter in the journal Nature.

CAG Director Hakon Hakonarson, M.D., Ph.D., lead the diabetes study and anticipates that further investigation may yield as many as 15 or 20 additional genes thought to interact with each other in the disease. By pinpointing the genes contributing to diabetes, Dr. Hakonarson and his colleagues aim to provide a scientific basis for designing better treatments and preventive measures.

"The genotyping technology we now have available has revolutionized the way we can ask and answer research questions," says Dr. Hakonarson. "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."

The investigators examined the genomes of more than 1,000 children with type 1 diabetes. 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 replicated this discovery in an 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.

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.

Dr. Hakonarson believes a special mutation in KIAA0350 may influence the sugar binding of the protein, and trigger an autoimmune response that activates natural killer 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 more research remains to be done, a better understanding of the disease process may guide doctors to new and improved therapies, allowing physicians to intervene in early life with targeted drugs or cell therapies to prevent the disease from developing.

In the second genetic study, published in the August issue of the journal Gut, Children's Hospital investigators identified a gene variant that raises a child's risk of Crohn's disease.

The research reinforces previous results by German researchers, who found the same gene variant associated with the adult form of the disease. Given the complexity of the disease and the interplay of multiple genes and environmental factors, it is critical for investigators to sort out specific genes and replicate previous findings.

With colleagues from the University of Pennsylvania, the investigators compared the genomes of 143 children with Crohn's disease to genomes of 282 matched control subjects. The study team, led by Robert N. Baldassano, M.D., director of the Hospital's Center for Pediatric Inflammatory Bowel Disease, found that 64 percent of children with Crohn's disease had a specific variant form of the gene ATG16L1, compared with 52 percent of the healthy children.

The odds ratio for children with the gene variant was 1.62 compared to control children, meaning that those who have the variant were 62 percent more likely to have Crohn's disease than children with the more common allele.

A separate test that analyzed a Crohn's patient and both parents — called a trios — also found an association between the ATG16L1 gene variant and disease symptoms. This finding strengthened the results of the pediatric case-control study.

ATG16L1 plays an important role in the autophagosome pathway, a sequence of biological events involved in processing bacteria within cells. While the mechanisms are not fully understood, a mutation in the gene may weaken a cell's ability to degrade cellular waste products, including bacteria, according to Dr. Baldassano.

When unprocessed waste products pile up within the cell, they may stimulate the inflammatory response that characterizes Crohn's disease.

The investigators anticipate that further research will shed light on the disease process and guide the development of new and improved therapies.

"If an excess of bacteria is the problem, we may find antibiotics effective in treating this type of Crohn's disease," says Dr. Baldassano. "Other approaches may be to use immune- boosting drugs to blunt the inflammation, or determining whether particular foods interact with genetic susceptibilities to affect disease symptoms. Understanding gene influences gives us a more targeted way to look at disease physiology, and also may
suggest targets for treatment."

Baldassano and Hakonarson will continue to search for other gene variants associated with Crohn's disease and the closely related bowel disorder ulcerative colitis, and they have put together a pediatric consortium of approximately 3,000 pediatric IBD patients from Europe, Canada and the United States, who will be genotyped and analyzed at the Center for Applied Genomics in the coming weeks.

Both the diabetes and Crohn's disease research used genome-wide association approach, which involved scanning each patient's DNA for more than half a million genetic markers. The CAG performed the studies, its tools spelling out a patient's genotype — the specific pattern of variations among an individual's 30,000 genes.

These studies are among the first the CAG has published on genes associated with a complex childhood disease, Dr. Hakonarson says, although the center has numerous projects under way in numerous disease areas like asthma, autism, obesity, ADHD and neuroblastoma in its quest to find the genes that influence pediatric disease and translate those discoveries into successful treatments.