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Dr. Moran is a pediatric gastroenterologist who practices clinically in the Pediatric Inflammatory Bowel Disease Programs at MassGeneral Hospital for Children and Newton Wellesley Hospital. He conducts clinical and basic science research to better understand the cause of inflammatory bowel disease (IBD).

Studying the Genetics of Early-Onset Inflammatory Bowel Disease

23/Aug/2012

Christopher J. Moran, MD

Christopher J. Moran, MD; Pediatric Gastroenterologist, Massachusetts General Hospital for Children, Brigham & Women’s Hospital, and Newton Wellesley Hospital; Instructor in Pediatrics, Harvard Medical School

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder in which patients have inappropriate inflammation in various parts of the gastrointestinal tract.  IBD can be further subdivided into Crohn’s disease (which can affect all segments of the gastrointestinal tract) and ulcerative colitis (which predominantly affects the large intestine).  25% of patients with IBD in the United States were diagnosed during childhood.  The treatment for IBD typically includes immunosuppressive medications that possess increased risk of both infection and cancer.  By nature, children who start strong immunosuppressive agents may need to live with the consequences of these treatment choices made in early life.  As the cause of IBD (in children and adults) is poorly understood, the available treatments do not adequately target the causal event of IBD but rather suppress inflammation at a late stage.  The goal of my research is to better understand the cause of IBD. 

Recent reports of children with mutations in the receptor for interleukin-10 (IL-10) have described a very aggressive form of Crohn’s disease.1  These patients failed treatment with immunomodulators, corticosteroids, and anti-TNF monoclonal antibodies and required multiple bowel resections.  These patients with mutations in the genes encoding IL-10 receptor (IL-10R) received allogeneic stem cell transplantation with resolution of their IBD symptoms. 

Although these reports were limited to infants with IBD, the role that mutations in IL-10R genes might play in older IBD patients was unknown.  We postulated that milder mutations in IL-10R may contribute to very early-onset IBD (VEO-IBD).  Therefore, we performed deep sequencing of the coding regions of IL-10R genes (IL-10RA and IL-10RB) in a cohort of patients diagnosed with IBD as children.  We identified a patient with infantile-onset IBD that was homozygous for an IL-10R mutation, who ultimately received an allogeneic stem cell transplantation.  We also identified 2 polymorphisms in IL-10RA that were associated with an increased risk of developing very early onset ulcerative colitis (VEO-UC).2  These 2 polymorphisms were found to be inherited as a haplotype and doubled the risk of VEO-UC (<5yo).  Subsequently, we validated the association in an independent cohort of children.  Although these polymorphisms were not sufficient to cause IBD, they highlight the need to better define subsets of patients with IBD.  As therapies for IBD become more specialized, the ability to identify genetic polymorphisms to allow for tailoring of therapy to the individual will be remarkably useful.  This project was funded by the Crohn’s and Colitis Foundation of America.

The current focus of my research is to identify causative genetic markers found in very early onset IBD.  In addition to my work, there is an expanding series of cases of infantile-onset IBD in the literature of loss-of-function IL-10R mutations. 

Although these IL-10R mutations appear sufficient to cause IBD, they only represent a portion of the genetic risk for developing IBD in children, especially out of the infantile age group.  I am expanding the search for causal genetic variants in very early onset IBD with the use of whole exome sequencing.  This strategy has the advantage over candidate gene analysis (such as my IL-10R research) in that allows analysis of alleles throughout an individual’s exome.  The overall goal is to both improve our understanding of the inciting events of VEO-IBD and to improve our ability to stratify patients with VEO-IBD into more distinct subsets to allow for tailoring of therapy.

In addition to my genetic research, I continue to be active in research collaborations investigating the upper gastrointestinal clinico-pathologic findings of pediatric IBD, optimizing the evaluation of children suspected to have IBD, and the microbiome of pediatric IBD.  


References:

 

1. Glocker EO, Kotlarz D, Boztug K, et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med 2009;361(21):2033-45.

2. Moran CJ, Walters TD, Guo CH, et al. IL-10R polymorphisms are associated with very-early-onset ulcerative colitis. Inflamm Bowel Dis 2012.

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