Pharmacogenetics of inflammatory bowel disease.
Therapeutic outcome in inflammatory bowel disease has traditionally been related to disease activity. Recent data suggest that individual differences in drug disposition and metabolism, some of which are genetically determined, may play a significant role in the outcome of therapy for inflammatory diseases. Polymorphisms in the thiopurine methyl transferase gene (TPMT) are known to influence the outcome of therapy with azathioprine although pharmacogenetic analysis of outcome has not entered routine clinical use. The outcome of therapy with drugs such as steroids may be influenced by a wide range of genetic factors including polymorphisms in the multi-drug resistance 1 gene (MDR1), polymorphisms in glucocorticoid receptor genes and potentially other as yet undefined polymorphisms regulating the inflammatory process. Multiple polymorphisms have been identified in MDR1 but their direct contribution to changes in expression and function have not as yet been defined. Lastly, as novel biological agents such as infliximab become established in clinical practice, it is clear that their therapeutic efficacy will likely be modified by polymorphisms downstream of their target molecules. New diagnostic and therapeutic algorithms are needed to directly determine the functional importance of the influence of host genetic factors on choice and dosage scheduling of therapy.
Kelleher
Dermot
D
Department of Clinical Medicine and Dublin Molecular Medicine Centre, Trinity College Dublin, Ireland.
Farrell
Richard
R
McManus
Ross
R
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001379:Azathioprine / Q000494:pharmacology; D005765:Gastrointestinal Agents / Q000494:pharmacology; D014644:Genetic Variation; D006801:Humans; D007249:Inflammation; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000235:genetics*; D000069285:Infliximab; D008780:Methyltransferases / Q000235:genetics; D008954:Models, Biological; D010597:Pharmacogenetics / Q000379:methods*; D011110:Polymorphism, Genetic; D011965:Receptors, Glucocorticoid / Q000235:genetics; D013256:Steroids / Q000378:metabolism / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000911:Antibodies, Monoclonal; D005765:Gastrointestinal Agents; D011965:Receptors, Glucocorticoid; D013256:Steroids; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine