Date Approved

12-2018

Graduate Degree Type

Thesis

Degree Name

Health Sciences (M.H.S.)

Degree Program

Biomedical Sciences

First Advisor

Debra Burg, Ph.D

Second Advisor

Dave W. Chesla, PA-ASCP, MHA

Third Advisor

John Capodilupo, Ph.D

Academic Year

2018/2019

Abstract

Background: Inflammatory Bowel Disease (IBD) affects as many as 1.3 million Americans and includes both ulcerative colitis (UC) and Crohn’s disease (CD). Recent practices have moved towards using immunomodulators early in the course of disease to prevent disease progression. Patients have shown improved outcomes on immunomodulators compared to aminosalicylates, and reduced risk for tachyphylaxis compared to corticosteroid treatment. Thiopurine agents such as azathioprine and 6-mercaptopurine are immunomodulators often used to treat IBD. Unfortunately, many patients experience cytotoxicity from thiopurine use. Recent studies have shown that patients deficient in thiopurine-S-methyltransferase (TMPT), produce an overabundance of the therapeutic end product, 6-thioguanine nucleotide (6-TGN), causing toxicity leading to apoptosis in all types of immune cells. In this study we investigated whether pre-emptive genotyping for TPMT would allow customized doses of thiopurines based on TPMT status and whether knowing this genotyping would reduce the risk of adverse events without compromising disease control.

Methods: A retrospective study using an available data set identified 30 adults over 18 with CD or UC. Patients were included in the study if their TPMT genotype and phenotype, 6-TGN and 6- MeMPN levels, and disease exacerbation were recorded. Using Fisher’s Exact test for statistical analysis, genotype was compared to phenotype (enzyme activity), metabolite levels, and toxicity/exacerbation. Phenotype was compared to metabolite levels.

Results: Genotype and enzymatic activity were not independent of each other. Subjects with a mutant TPMT genotype were more likely to respond to thiopurine therapies. Genotype was not indicative of high risk for hepatotoxicity, and there was no significant relationship between enzyme activity and metabolite levels. Lastly, there was no relationship between genotype and toxicity.

Conclusions: Multiple studies have studied dose escalation based on genotype alone. However, genotype does not take into consideration confounding factors that might impact patient outcomes when using thiopurine therapy for IBD. This would include rare deficiency alleles, true phenotypic expression, other genetic polymorphisms, and most importantly polypharmacy. Thiopurine interaction with ASAs, benzoic acid derivatives, non-steroidal anti-inflammatory drugs, and methotrexate have been shown to influence TPMT enzyme activity. Whether this is due to allosteric inhibition or competitive inhibition has yet to be discovered.

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