Evolutioninthe Pharmacogenetics and Pharmacogenomics of Inflammatory Bowel Disease - Order Slowly Rises from the Chaos

D.   M.   Poppers; E.   J.   Scherl

Abstract

The management of inflammatory bowel disease (IBD) remains challenging due to the varied clinical manifes-tations of Crohns disease (CD) and ulcerative colitis (UC). The development of new modalities in therapy is promising, with immunomodulator-based approaches rising to a more prominent position in our armamentarium. Mutations in a vari-ety of genes have been shown to be associated with IBD and specific phenotypes of disease. The CARD15/NOD2 protein has been associated with the sensing of, and tolerance to, intraluminal bacteria. Patients with specific NOD2 mutations have an increased risk for the development of CD, and certain mutations have been associated with specific disease sub-types, including fibrostenotic and penetrating disease, and the likelihood of surgical intervention. Mutations in the Toll-like receptor 4 (TLR4) gene have been associated with inflammatory or stenotic disease. Other susceptibility loci, includ-ing OCTN and the IBD loci, are associated with increased severity and ear ly onset of disease. The elucidation of muta-tions in enzymatic pathways might predict who will respond to specific pharmacotherapies, and those at risk for treat-ment-associated adverse effects. Single nucleotide polymorphisms in the thiopurine methyltransferase (TPMT) gene, with lowered enzymatic activities, may predict patients who require lower doses of immunomodulatory therapies and those who are at increased risk for myelosuppression and hepatitis. Patients with mutations in the N-acetyltransferases may be at increased risk for adverse effects of aminosalicylates. Overall, our understanding of the genetics of susceptibility, and of the likelihood of response to specific therapies, may be beneficial in refining the medical approach to the complex man-agement of IBD.

Keywords: CYP450 mutations, nucleotide binding and oligomerization domain (NOD), N-acetyltransferase, Thiopurine methyltransferase, Muramyl dipeptide

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