Genes May Link Disparate Diseases

Diseases that strike different parts of the body—and that don’t seem to resemble each other at all—may actually have a lot in common.

Scientists have identified the genetic basis for many separate diseases. Now, some researchers are looking at how the genes interact with each other. They are finding that a genetic abnormality behind one illness may also cause other, seemingly unrelated disorders. Sometimes diseases are tangentially linked, having just one gene in common. But the greater the number of shared genetic underpinnings a group of diseases has, the greater the likelihood a patient with one of the illnesses will contract another.

Researchers have found evidence, for example, that there is a close genetic relationship between Crohn’s disease, a gastrointestinal condition, and Type 2 diabetes, despite the fact the two conditions affect the body in very distinct ways. Other illnesses with apparently close genetic links are rheumatoid arthritis and Type 1 diabetes, the form of the disease that usually starts in childhood, says Joseph Loscalzo, chairman of the department of medicine at Brigham and Women’s Hospital in Boston.

This network approach, known among scientists as systems biology, could change the way medical specialists view and treat disease, according to some researchers. Rather than only looking to repair the parts of the body that are directly affected by illness, “we should be looking at what the wiring diagram [inside of cells] looks like,” says Albert-László Barabási, a physicist at Northeastern University’s Center for Complex Network Research in Boston.

Research work in the field is being done by geneticists, biologists and physicists at several universities and drug makers. The aim is to map how genes and the proteins they produce interact within cells in order to gain a better understanding of what goes wrong in the body to cause disease.

The information could help better predict a person’s risk of developing diseases, researchers say. It also could aid drug development. By figuring out which proteins are most critical to the normal functioning of the body, pharmaceutical companies could target those key proteins to treat disease. In some cases, drug companies may want to avoid interfering with key proteins to avoid too many unintended side effects, says Marc Vidal, director of the Center for Cancer Systems Biology at Dana-Farber Cancer Institute in Boston.

Since all the DNA in the human body was first sequenced in 2000, some 4,000 diseases with a known genetic basis have been identified, according to the National Institutes of Health. But only about 250 of those diseases have treatments, leaving many genetic puzzles left to untangle.

Scientists have long known that proteins and other molecules in the body don’t act alone. In order for the body to operate efficiently, biological substances must bind to or pass chemical messages to each other to start and stop working. The system is complex: Each gene is thought to produce, on average, five separate substances, mostly proteins, and these products interact with each other. When a protein, or group of proteins, malfunctions, it appears to give rise to a variety of distinct illnesses.

Dr. Barabási and his colleagues set out to see which diseases shared genetic underpinnings. They used information from a vast database at Johns Hopkins University in Baltimore that pulled together research from around the world on diseases and genes they were linked to. The scientists then mapped out a network indicating which diseases were seemingly connected to each other through common genes.

Of the 1,284 diseases mapped, nearly 900 had genetic links to at least one other disease. And 516 of these formed a so-called disease cluster, in which illnesses, mainly cancers, were linked to each other through multiple genetic connections.

Among the findings: Deafness shared at least one of 41 genes with over 20 other diseases, suggesting that it sits centrally in a cluster of other diseases. These include cardiomyopathy, a condition in which the heart muscle deteriorates; and ectodermal dysplasia, an abnormal development of the skin, hair, nails or teeth. Colon cancer shared at least one of 34 genes with 50 other diseases. Also in the cancer cluster were squamous cell carcinoma, a type of skin cancer, and throat cancer, but these had fewer genetic links between them. The work was published in the Proceedings of the National Academy of Sciences in 2007.

Because the diseases in the cluster were linked at the level of the cellular network, “the breakdown of one gene can lead to many apparently unrelated diseases,” says Dr. Barabási.

Another study by Dr. Barabási’s team aimed to see if their database analysis of genetically linked diseases was borne out in real life. The researchers analyzed more than 32 million Medicare hospital claims.

When patients developed multiple conditions, they were more likely to get illnesses that had close genetic links to their original disease than they were to get other disorders.

The study, published in 2009 in one of the journals of the Public Library of Science, PLoS Computational Biology, also showed that patients who developed diseases that tend to coincide with many others were more likely to die sooner than people whose diseases were more tangentially connected.

Using the data, the researchers estimated people’s likelihood of getting a second disease. A patient with ischemic heart disease, for example, has a 60% greater risk of getting Type 2 diabetes than an average healthy person.

Other biological processes also link seemingly unrelated diseases. In work published in 2008 in the Proceedings of the National Academy of Sciences, Dr. Barabási’s team identified a cluster of diseases, including diabetes and anemia, or coronary heart disease and hypertension, that appear to share common metabolic pathways, such as how chemicals are broken down or used in the body.

Dr. Vidal is currently working with Dr. Barabási and other researchers to map out all the possible protein interactions within a human cell. Dr. Vidal says about 20% of the project is finished, making it already the most complete map of the human protein network. The researchers also are developing protein-network maps for other organisms, including a yeast cell and Caenorhabditis elegans, a tiny worm with some 19,000 genes, about the same number as humans.

To test the role played by key proteins, or hubs, the researchers selectively deleted proteins or genes in the organisms and observed what happened. In the yeast cell, they found only about a quarter of the genes and proteins appeared to be essential, in that they connected to large numbers of other proteins and substances. The organism died when these hubs were removed, Dr. Vidal says.

This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.