New Approach Associates Multiple Pathway Genes With Crohn's Disease

Jacquelyn K Beals, PhD

February 28, 2009

February 28, 2009 — A pathway-based approach has demonstrated significant association between Crohn's disease (CD) and the interleukin (IL) 12/IL-23 pathway, which contains 20 genes. Many genes associated with CD susceptibility are contained in this pathway but do not demonstrate genomewide significance in single genomewide association (GWA) studies.

The report, published online February 26 in the American Journal of Human Genetics, describes the first use of a pathway-based analysis of GWA data without prior selection of a relevant pathway.

"We applied our pathway-based approach to GWA data for [CD], but conducted the search without starting with a hypothesis focused on a specific suspected pathway," said lead investigator Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics, Children's Hospital of Philadelphia, and Department of Pediatrics, University of Pennsylvania, Philadelphia, in a Children's Hospital press release.

Not surprisingly, the most significant pathway identified among hundreds of possibilities contained genes already recognized as important in CD biology. However, the contributions of many of these genes to CD susceptibility had only been detected through meta-analysis of multiple GWA studies.

"A major purpose of GWA studies is to find disease targets," Dr. Hakonarson told Medscape Pathology & Lab Medicine via email. "However, a gene harboring common variants with strong [odds ratio (OR)] and P values does not necessarily make a good drug target. On the other hand, other genes in the same pathway, even if not harboring common susceptibility alleles with strong OR, could be good therapeutic targets for drug intervention," Dr. Hakonarson pointed out. Genes with more modest effects are frequently missed in GWA studies.

The present pathway-based association study applied complex statistical analysis to individual genotype data that included all the single nucleotide polymorphisms (SNPs) in a GWA study. Raw data for CD and control groups were obtained from the Wellcome Trust Case Control Consortium (WTCCC); the 1748 patients with CD and 1480 control individuals were all of European ancestry. Analysis using the Affymetrix Mapping 500K platform found that the highest-ranked pathway in terms of CD association was the IL-12 pathway, containing 20 genes.

Several IL-12 pathway genes — JAK2, TYK2, IL12RB1, and IL12B — also belong to the IL-23 network. Within the combined IL-12/IL-23 pathway, JAK2 and IL12B were identified in a recent meta-analysis as CD susceptibility genes, although neither had been picked up in any individual GWA study. Even after these 2 susceptibility genes were removed from the analysis, the IL-12/IL-23 pathway showed significant association with CD (Z = 3.3; permutation P = 8 × 10−5).

The study was replicated in several GWA data sets, using the Illumina HumanHap550 platform. The first replication included 647 patients with CD and 4250 control subjects of European ancestry; association between CD and the IL-12/IL-23 pathway proved statistically significant (Z = 2.2; P = .013). The association was supported by a second replication in 1083 patients with CD and 2507 control individuals of European ancestry (Z = 3.3; P = .0004). The third replication used a GWA data set of 40 patients with CD and 527 control individuals, all of African-American ancestry; significant association was found between the IL-12/IL-23 pathway and CD (Z = 1.8; P = .03), despite the limited sample size.

Although individual SNPs showed widely different levels of association with CD across the GWA studies, the IL-12/IL-23 pathway was consistently associated with CD in analyses that used 2 array platforms and individuals of differing ancestry.

"Our study hassignificant implications with respect to CD biology and may broaden the options for therapy," the authors state. "Although GWA studies have been proven useful to identify common disease-susceptibility variants in specific human populations, biologically important genes do not necessarily contain common variants with high odds ratios.... [O]ther members in the IL12/IL23 pathway may also serve as functional candidates for detailed molecular studies or as promising therapeutic targets."

Dr. Hakonarson has disclosed no relevant financial relationships.

Am J Hum Genet. Published online February 26, 2009.

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