Crohn's disease (CD) and ulcerative colitis (UC) affect over 1.4 million Americans. Over the past 15 years, considerable progress has been made in the therapy of CD and UC with monoclonal antibodies against tumor necrosis factor ? (anti-TNF) representing the most significant therapeutic breakthrough. However, many patients fail to respond adequately. Recent genome wide associations studies (GWAS) have significantly increased our understanding of the pathogenesis of CD and UC. The role of these genetic variants in predicting response to anti-TNF therapy is yet to be defined adequately. In addition, significant safety concerns remain with the use of these agents with serious infections occurring in up to 10% of patients. There is a strong genetic component to susceptibility to infections, in particular involving polymorphisms in innate immunity. Given the key role of innate immunity in IBD pathogenesis, whether such shared polymorphisms also influence risk of infections on anti-TNF therapy has not been examined previously. Thus, the development of tools to define likelihood of treatment response and infections are a key unmet need in the field. Our overarching objective is to identify clinical and genetic predictors of both short-term and long-term response as well as infectious complications of anti-TNF therapy. To achieve these aims, we will utilize the complementary strengths of two large cohorts - a prospective registry cohort of over 1200 patients with CD or UC, and a novel EMR-based cohort of over 11,000 patients with CD or UC linked to a biospecimen repository. This proposal utilizes the mentorship and significant expertise in key areas including analytical genetics, translational immunology, and bioinformatics and allows the candidate to develop fundamental skills in these novel content areas and research methods. The access to expertise at the NIH-funded center Informatics for Integrating Biology and the Bedside, the Center for Study of Inflammatory Bowel Disease, and the Broad Institute is a key strength of this application. This career development award will be critical in providing training in bioinformatics and genetic epidemiology, thus contributing to the candidate's long-term goal of establishing an independent IBD research career with focus on defining at-risk cohorts and personalizing therapy. The training component of the award includes graduate-level courses in the relevant content areas in genetic epidemiology, and bioinformatics at the Harvard Medical School, School of Public Health, and Massachusetts Institute of Technology. The candidate will continue to actively engage with an established group of multidisciplinary researchers who have demonstrated the utility of the EMR-based approach to accurately define autoimmune diseases, link it to biospecimen collection, and use it successfully for genotyping-phenotype research. This will help foster collaborative development of future proposals as the work proposed in this application has the potential for applicability in other cohorts.

Public Health Relevance

The novel information gained from this study regarding genetic predictors of treatment response and infectious complications has the potential to transform clinical practice by leading to clinical trials focused on selected cohorts of patients most likely to respond to therapies with low risk of adverse events, thus preventing unnecessary exposure to potentially toxic therapies with low likelihood of benefit. Such work is a step toward developing personalized medicine approaches to tailor therapy based on likelihood of benefit and risk. The methodology developed here will also have applications in other EMR-based cohorts to investigate novel therapeutic agents and disease outcomes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZDK1-GRB-2 (O2))
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Podskalny, Judith M,
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Massachusetts General Hospital
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Ananthakrishnan, Ashwin N; Kwon, Jennifer; Raffals, Laura et al. (2015) Variation in treatment of patients with inflammatory bowel diseases at major referral centers in the United States. Clin Gastroenterol Hepatol 13:1197-200
Ananthakrishnan, Ashwin N (2015) Environmental risk factors for inflammatory bowel diseases: a review. Dig Dis Sci 60:290-8
Ananthakrishnan, Ashwin N; Cheng, Alice; Cagan, Andrew et al. (2015) Mode of childbirth and long-term outcomes in women with inflammatory bowel diseases. Dig Dis Sci 60:471-7
Ananthakrishnan, Ashwin N; Du, Mengmeng; Berndt, Sonja I et al. (2015) Red meat intake, NAT2, and risk of colorectal cancer: a pooled analysis of 11 studies. Cancer Epidemiol Biomarkers Prev 24:198-205
Ananthakrishnan, Ashwin N; Cagan, Andrew; Cai, Tianxi et al. (2015) Colonoscopy is associated with a reduced risk for colon cancer and mortality in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol 13:322-329.e1
Ananthakrishnan, Ashwin N; Cagan, Andrew; Gainer, Vivian S et al. (2014) Thromboprophylaxis is associated with reduced post-hospitalization venous thromboembolic events in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol 12:1905-10
Ananthakrishnan, Ashwin N; Khalili, Hamed; Konijeti, Gauree G et al. (2014) Long-term intake of dietary fat and risk of ulcerative colitis and Crohn's disease. Gut 63:776-84
Mouli, V P; Ananthakrishnan, A N (2014) Review article: vitamin D and inflammatory bowel diseases. Aliment Pharmacol Ther 39:125-36
Ananthakrishnan, Ashwin N; Nguyen, Deanna D; Sauk, Jenny et al. (2014) Genetic polymorphisms in metabolizing enzymes modifying the association between smoking and inflammatory bowel diseases. Inflamm Bowel Dis 20:783-9
Scoville, Elizabeth A; Konijeti, Gauree G; Nguyen, Deanna D et al. (2014) Venous thromboembolism in patients with inflammatory bowel diseases: a case-control study of risk factors. Inflamm Bowel Dis 20:631-6

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