Many Common Loci Associated With Early- and Adult-Onset Inflammatory Bowel Disease

Jacquelyn K. Beals, PhD

November 04, 2009

November 4, 2009 (Honolulu, Hawaii) — A genomewide association study (GWAS) has found that the genetic pathogenesis of early-onset inflammatory bowel disease (IBD) closely resembles that of adult-onset disease. Of particular interest is an allele on chromosome 16 involved in pathways already associated with IBD. Cells harboring this allele have decreased expression of interleukin (IL)-27, a cytokine involved in both innate and acquired immunity.

The peak age of onset for IBD is early adulthood (range, 10 to 30 years of age), but early-onset IBD arises in infants, toddlers, and preschool-aged children. IBD subtypes, including early-onset cases, are Crohn's disease (CD), ulcerative colitis (UC), and indeterminate colitis. The heritability of IBD is 40% to 50%, but environmental influences are also recognized.

Before GWAS, UC was associated with the major histocompatibility complex and CD was associated with NOD2 mutation, noted Marcin Imielinski, MD, PhD, from the Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, in Pennsylvania, during his presentation here at the American Society of Human Genetics 59th Annual Meeting.

Since the advent of GWAS, more than 32 loci have been identified for CD and 17 have been identified for UC, but about 80% of the genetic risk for IBD is still unidentified. Early-onset disease has a distinctive phenotype and has been considered a separate entity. "Early-onset CD patients tend to have more colonic involvement," Dr. Imielinski explained to Medscape Pathology. "Early-onset UC patients tend to have more extensive colonic involvement, and the disease is thought to be more severe — especially in the case of UC. So clinically, it's distinct," he said.

"Our study suggests that, genetically, it's quite highly related to adult-onset [IBD]," added Dr. Imielinski. "So I think the question is somewhat open still, but . . . on the genetic side, at least from our perspective, they are quite close."

The current GWAS looked for disease-susceptibility genes in 2413 early-onset IBD patients and 6197 genetically matched control subjects to investigate the relation between early-onset and adult-onset IBD and the underlying genetics.

Loci demonstrating significant CD association were identified in or near the IL27 gene on chromosome 16 (P = 1.27 × 10–8) and LNPEP-LRAP on chromosome 5 (P = 4.5 × 10–7). IBD-associated loci included SMAD3 on chromosome 15 (P = 6.67 × 10–7) and HORMAD2 on chromosome 21 (P = 9.99 × 10–7). The study also discovered a locus on chromosome 4 associated with UC onset before 8 years of age (P = 1.805 × 10–8).

Overall, of the 32 loci previously associated with adult-onset CD, 21 contribute significantly (after Bonferroni correction) to early-onset disease. Similarly, of 17 loci associated with adult-onset UC, 8 contribute significantly (after correction) to early-onset disease.

"That does lead into the obvious questions about whether or not . . . early-onset [IBD] is a different disease," Jonathan L. Haines, PhD, professor of human genetics, chief of the Division of Human Genomics, and director of the Center for Human Genetics Research, Vanderbilt University Medical Center in Nashville, Tennessee, told Medscape Pathology. "Are these genes specific to that, or is that just an easier way to find genes that affect [the disease] more generally? Some of that would depend on what the clinical phenotypes are," said Dr. Haines.

The investigators looked further at the locus on chromosome 16 (16p11.2), which had emerged in both the CD and IBD scans. The IL27 gene located here was involved in pathways already associated with IBD. This study found decreased IL-27 expression in cells that harbor this polymorphism, as well as lower colonic expression of IL27 in CD than in normal tissue (P = .028).

Dr. Imielinski noted in his presentation that IL27 is a promising gene candidate. This finding supports links to the Th17 pathway (Th17 responses are controlled by IL-27, among other cytokines, and are implicated in a number of auto-inflammatory disorders).

"As with all the GWAS findings up to now, I think the majority of the clinical implications are of discovering novel targets for therapeutics. And I think . . . the potential for these loci as pharmacogenomic risk-modifying factors, that hasn't really been explored," said Dr. Imielinski.

"For a clinician, just the evidence of family history is obviously going to be much more than any genetic test based on this. So from that perspective, it's somewhat sobering," Dr. Imielinski observed. "But for the therapeutic and pharmacogenomic aspects, I think there's still quite a bit of potential."

Dr. Imielinski has disclosed no relevant financial relationships. Dr. Haines reports receiving consulting fees or other remuneration from ArcticDx, and has held nonremunerative positions of influence (officer, board member, trustee, or public spokesperson) and has been an inventor/patent owner associated with ArcticDx and with Optherion.

American Society of Human Genetics (ASHG) 59th Annual Meeting: Abstract 274. Presented October 24, 2009.

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