Discovering the different genes that contribute to a complex disease is like searching in the proverbial haystack for an unknown number of needles--some much smaller than others, often blending into the background, and many of them widely separated from each other. But if some needles are linked to each other by fine threads, you might pull out clumps of them together.
Using a novel approach that combines a statistical tool that identifies genes interacting on the same biological pathways with highly automated gene-hunting techniques that scan the whole genome, an international team of researchers has discovered new genes involved in Crohn's disease. Crohn's disease is a chronic and painful condition caused by inflammation of the gastrointestinal tract. The researchers, led by scientists at The Children's Hospital of Philadelphia, say their approach broadens the power of gene discovery studies to ferret out potential targets for disease treatments.
In a complex disorder such as Crohn's disease, many different genes interact to cause the illness. Research over the past few years have identified many of the genes with the strongest effects, but many other genes with important roles may produce weaker or ambiguous signals in the large-scale studies, and go overlooked. "Our pathway-based approach aggregates information from multiple sources to detect modest effects from genes associated with each other," said study leader Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics at Children's Hospital.
The study appeared online today in the American Journal of Human Genetics. It will be published in the journal's print edition on March 13.
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, Ph.D., 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. "We applied our pathway-based approach to GWA data for Crohn's disease, but conducted the search without starting with a hypothesis focused on a specific suspected pathway," said Hakonarson. "Among hundreds of known biological pathways, the one that surfaced from the analysis as being most significant included genes already known to be relevant to the biology of Crohn's disease."
That pathway, the interleukin 12 (IL12) pathway, governs cell receptors involved in the development of Crohn's disease. Hakonarson added that the IL12 pathway might be more correctly referred to as the IL12/IL23 pathway, since IL12 receptor signaling converges with signaling on another receptor, IL23. Previous work by other researchers had shown that monoclonal antibodies that block 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, M.D., 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 performed the initial analysis in DNA from 1,758 patients with Crohn's disease and 1,480 control subjects, all of European ancestry. They repeated the study in three additional groups, of both European and African American ancestry, and were able to replicate their results. Their study was the first to use a pathway-based approach to analyze GWA, without deciding beforehand to concentrate on a specific pathway.
For children and adults with Crohn's disease, who suffer the debilitating effects of chronic gastrointestinal inflammation, 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."
John Ascenzi | EurekAlert!
Further reports about: > Crohn's disease > DNA > Genomics > IL12 > New gene-searching method > Pediatric Inflammatory Bowel Disease > algorithm K* > automated analytic equipment > biological pathways > effective treatment > gastrointestinal tract > gene variants > genetic discovery techniques > inflammation > interleukin 12 > painful condition
Ion treatments for cardiac arrhythmia — Non-invasive alternative to catheter-based surgery
20.01.2017 | GSI Helmholtzzentrum für Schwerionenforschung GmbH
Seeking structure with metagenome sequences
20.01.2017 | DOE/Joint Genome Institute
An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...
Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales
Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
19.01.2017 | Event News
10.01.2017 | Event News
09.01.2017 | Event News
20.01.2017 | Awards Funding
20.01.2017 | Materials Sciences
20.01.2017 | Life Sciences