A decade ago, finding genes that contribute to human diseases was labor-intensive, time-consuming and prohibitively expensive. But today, cutting-edge research tools are changing all that, and two School of Medicine researchers are at the forefront of the revolution.

Last month, in the journal Science, Josephine J. Hoh, Ph.D., associate professor of epidemiology and ophthalmology, and Judy H. Cho, M.D., associate professor of medicine, reported that their research teams had homed in on genes involved in two genetically complex human disorders: age-related macular degeneration (AMD), the leading cause of vision loss and blindness in the elderly in the developed world, and Crohn’s disease (CD), an inflammatory disorder of the gastrointestinal tract.

The key to the research strategy used by Hoh and Cho is the natural variability in the 3 billion “letters” in the human genome, the genetic instruction book that encodes all the proteins in the body. Compare the genomes of a large group of people and you’ll find single-letter differences at about one in every 1,300 letters. In all, there are about 10 million sites sprinkled throughout the human genome where common variations occur. Most of these variations, which are known as single-nucleotide polymorphisms, or SNPs (pronounced “snips”), have no relevance to health. But some SNPs may influence one’s risk of developing a particular disease.

Genetic variations lying close to one another on a chromosome are often inherited together in chunks. By looking for chunks of variations that are always found in people with a particular disease but rarely in healthy individuals, scientists can narrow the search for disease genes and eventually pinpoint their locations. To effectively scan the SNPs in the entire genomes of large groups of people, however, one must compare hundreds of thousands of variations, which would have been impossible until quite recently.

Last year, Hoh’s research group was among the first to complete such a whole-genome analysis by combining the SNP information compiled in public databases with the power of microarrays—silicon or plastic chips that are coated with hundreds of thousands of precisely arranged microscopic fragments of DNA.

The chip the Hoh team used allowed them to rapidly compare the genomes of more than 100 people with or without AMD for 100,000 different SNPs. As reported in the April 15, 2005, issue of Science, the researchers pinpointed a single-letter variation strongly associated with the so-called “dry” form of AMD, a common form of the disease that causes vision loss but which rarely leads to complete blindness.

Using the same approach, Hoh and colleagues have now identified a variation associated with the “wet” form of AMD, a rarer but far more damaging form of the disorder in which a proliferation of leaky blood vessels causes irreversible damage to the retina. In the November 10, 2006, issue of Science, the team reports that people who had inherited a particular SNP from both parents near a gene called HTRA1 are 11 times more likely to get AMD than those lacking the variant.

The disease-associated SNP discovered by Hoh’s team seems to increase the expression of the gene, but she cautions that her results do not definitively establish that the variation itself causes AMD. The SNP may just lie close to some other disease-promoting genetic variation, she says, and it is still not clear how overexpression of HTRA1 would cause the blood vessel growth characteristic of the disease. However, previous research has demonstrated that HTRA1 protein is present in the eyes of patients with wet AMD.

“It’s a long way, probably many years, to prove it,” Hoh says, but she adds that every clue is valuable when tackling poorly understood disorders like AMD. Hoh says that we know very little about the biological pathways causing AMD and that identifying potential disease-promoting genes like HTRA1 may lead to a greater understanding of those pathways.

Cho, the new director of the medical school’s Inflammatory Bowel Disease (IBD) Center, chairs the steering committee of the National Institute of Diabetes and Digestive and Kidney Disorders IBD Genetics Research Consortium, an alliance of seven academic centers in the United States and Canada that combines resources and genomic data to efficiently pursue disease genes.

In the October 26, 2006, online issue of Science, Cho and other consortium members published results from a study comparing DNA from 547 CD patients and 548 healthy people. The team used microarray technology that simultaneously examines more than 300,000 SNPs in the genome—80 percent of the known SNPs in populations of European ancestry, who are most susceptible to CD—and identified a variation in the healthy people that is absent in those with CD.

The SNP, in a gene known as IL23R, tamps down the expression of a receptor for interleukin-23 (IL-23), a protein that promotes inflammation. Cho speculates the SNP protects healthy people from CD by interfering with the protein’s function, and she suggests that developing drugs to block the IL-23 may provide a new therapy for CD.
“We knew this was an unbelievably hot finding,” says Cho, who believes that whole-genome analyses will lead to important advances in treating previously intractable diseases.