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Crohn's GWAS Points to Genetic Differences Between Disease Risk, Prognosis

NEW YORK (GenomeWeb) – The genetic factors influencing Crohn's disease outcomes appear to be largely distinct from those associated with risk of the inflammatory bowel disease, a new study suggests.

Researchers from the UK and New Zealand compared array-based genotyping profiles for thousands of Crohn's disease patients whose symptoms were more or less severe. As they reported in Nature Genetics today, the investigators identified four loci that were significantly linked to Crohn's disease prognosis — a set that was distinct from the loci already implicated in Crohn's disease risk.

"This shows us that the genetic architecture of disease outcome is very different to that of disease risk," senior author Kenneth Smith, a medicine researcher at the University of Cambridge School of Clinical Medicine, said in a statement.

A series of past genome-wide association studies have found variants that are over-represented in individuals with Crohn's disease and/or other IBDs. And in other Nature Genetics papers published today, independent teams described new genetic risk loci for IBD identified through GWAS meta-analyses, along with clues to genetic architecture for IBD using a combination of GWAS data and genome sequencing data for thousands of individuals with Crohn's disease or ulcerative colitis.

Less is known about the genetic factors that might contribute to IBD severity, Smith and his colleagues explained, noting that prognostic features can vary significantly between individuals, but appears to have a heritable component.

"Genetic studies have been very successful at identifying genetic risk factors for Crohn's disease, but have told us virtually nothing about why one person will get only mild disease while someone else might need surgery to treat their condition," co-first author and Cambridge researcher James Lee said in the statement. "We do know, though, that family members who have the disease often tend to see it progress in a similar way. This suggested to us that genetics was likely to be involved in prognosis."

The researchers compared genotyping profiles for 1,762 individuals with Crohn's disease who had poor prognoses — marked by frequent flare ups or disease recurrence after treatment — with patterns found in 972 Crohn's disease cases with relatively good prognoses. Nearly 2,800 more cases of intermediate prognosis phenotype were excluded from the analysis.

The search led to significant prognosis-related associations at four loci: sites in an enhancer for the chromosome 6 gene FOXO3, upstream of IGFBP1 on chromosome 7, near the region of chromosome 6 that contains major histocompatibility (MHC) genes, and in the XACT gene on the X chromosome.

The researchers noted that these sites in the genome were distinct from the set of 170 loci implicated in Crohn's disease development in the past. And their analyses indicated that information at these known risk loci did not coincide with the course of an individual's Crohn's disease, based on information for individuals in the prognostic cohorts considered.

The authors also noted that analyzing the genetic data of individuals with well-documented clinical features and phenotypes may hold the potential for understanding new aspects of other conditions as well.

"[T]his work illustrates the value of reanalyzing existing GWAS data using carefully selected sub-phenotypes," they wrote. "Indeed, providing sufficiently detailed clinical data are available, this approach should be broadly applicable and could yield important new insights into multiple diseases."