Gene-searching method homes in on therapeutic targets for Crohn's disease

An international team of researchers has discovered new genes involved in Crohn's disease using a statistical tool to identify genes interacting on the same biological pathways and highly automated gene-hunting techniques that scan the whole genome.

Research over the past few years has identified many of the genes with the strongest effects, but other genes with important roles are overlooked because they may produce weaker or ambiguous signals in the large-scale studies.

"Our pathway-based approach aggregates information from multiple sources to detect modest effects from genes associated with each other," said study leader Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics at Children's Hospital of Philadelphia.

Currently the workhorse of gene hunting is genome-wide association (GWA), which uses automated analytic equipment to sweep through the full range of all 23 human chromosomes and detect the most significant gene variants associated with a given disease. Those variants, each a change in a single DNA base, are called single nucleotide polymorphisms (SNPs).

However, individual GWA studies often do not have the statistical power to detect subtle but important variants that are involved in disease development. By using an algorithm developed by Kai Wang, PhD, also at the Center for Applied Genomics, Hakonarson's study team created a pathway-based approach that seeks out interacting or related genes along the same biological pathway.

That pathway, the interleukin 12/interleukin 23 (IL12/IL23) pathway, governs cell receptors involved in the development of Crohn's disease. Previous work by other researchers has shown that monoclonal antibodies blocking the IL12 or IL23 receptor show some clinical success in treating Crohn's disease.

"As we better understand the gene pathways operating in Crohn's disease, we are uncovering more potential targets for effective drug treatments," said pediatric gastroenterologist Robert Baldassano, MD, a study co-author and the director of the Center for Pediatric Inflammatory Bowel Disease at Children's Hospital. He added that developing targeted therapies based on gene pathways might allow doctors to tailor treatments to a patient's genetic profile.

The study team initially analyzed DNA from 1,758 patients with Crohn's disease and 1,480 control subjects, all of European ancestry. They were able to replicate their results in three additional groups that included patients of both European and African American ancestry. Their study was the first to use a pathway-based approach to analyze GWA without deciding beforehand to concentrate on a specific pathway.

The researchers said the emerging gene data may open the doors to more effective treatments. "Blocking cell receptors at some points on a biological pathway may produce clinical improvements but with side effects to the immune system," said Baldassano. "If we can block other molecules further downstream on a pathway, we may achieve better treatments that may be more specific to an individual patient with fewer side effects."

Funding for the study came from the National Center for Research Resources of the National Institutes of Health, the Primary Children's Medical Center Foundation and from an Institute Development Award from the Children's Hospital of Philadelphia.

Wang K. Amer J Human Genetics. 2009;84;1-7.