The candidate is an accomplished gastroenterology fellow with formal training in epidemiological methods and a commitment to a career in clinical and translational research in the study of inflammatory bowel disease (IBD). The candidate's long-term career goal is to become an independently funded physician investigator, devoting more than 75% of his time to establish and maintain a clinical research program in inflammatory bowel disease (IBD). The candidate's short-term career goals are to 1) build large analytic datasets based upon administrative data collected in registries;2) design and interpret genetic data, including application of gene-environment interaction methodology;3) oversee the collection of new bio specimens and understand the complexities of efficient bio banking;4) acquire skills in the analysis and interpretation of high dimensional data sets, including genetic polymorphisms and gut micro biome sequence data;5) produce the data and publications necessary for a successful R01 application. This application outlines the institutional commitment, research plan, career development activities and key mentors involved to ensure the candidate accomplishes these goals. In prior work, the candidate has demonstrated that use of oral contraceptives (OC) is associated with an increased risk of developing CD. This finding, in agreement with several other prior studies, has convincingly established OC as an etiologic risk factor for CD. Nonetheless, data regarding an influence of OC on CD progression and potential biological mechanisms underlying associations with CD are lacking. In this proposal, the candidate seeks to fill this knowledge gap through a comprehensive examination of the complex interaction between OC, sex steroid biomarkers, genetic risk loci, and alterations in the intestinal microbial environment in the etiology and progression of CD. The specific goals of this study are to 1) estimate the relative and population attributable risk associated with OC of developing CD or developing CD-related complications among patients with CD using comprehensive Swedish nationwide registries;2) evaluate the interaction between OC and CD risk loci on incident CD and evaluate the relationship between prediagnostic plasma sex steroid hormones on risk of CD using two large, well-characterized cohorts which have provided detailed and updated lifestyle data for over 30 years;3) evaluate the effect of OC use on gut microbial composition and mucosal inflammation within clinic-based patient cohorts. As an integral part of this proposal, the candidate's career development will be complemented by participation in advanced coursework and research seminars to develop expertise in genetic epidemiology, plasma biomarker, and micro biome data analysis. A formal mentorship committee and advisory team, consisting of multidisciplinary experts in epidemiology, genetics, genetic epidemiology, and the micro biome will provide supervision, guidance, and assistance for the candidate to achieve his goals. The research environment, which includes the MGH Crohn's and Colitis Center, the NIH-supported Center for the Study of IBD, the Channing Laboratory of chronic disease epidemiology, the Harvard School of Public Health, and the Karolinska Institute, will provide a rich, collaborative, and intellectually stimulating atmosphereto ensure the candidate's success. Through this award, the candidate will emerge as an independent clinical investigator by contributing to our understanding of the role of OC in the etiopathogenesis of CD through a series of studies that bridge epidemiologic correlation with disease causation.

Public Health Relevance

Crohn's Disease (CD) is an inflammatory disorder of the gastrointestinal tract impacting nearly 600,000 Americans, resulting in substantial morbidity and direct and indirect health care costs. In this proposal, we will comprehensively investigate the role of oral contraceptives in relation to risk and progression of CD and examine the interplay between these agents, genetic predisposition, sex steroid biomarkers, and the gut micro biome. Our study has the potential to lead to clinical recommendations regarding the use of oral contraceptives among women at-risk for CD or with established CD and will offer new insights into CD etiopathogenesis.

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 (M2))
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Podskalny, Judith M,
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Massachusetts General Hospital
United States
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Ananthakrishnan, Ashwin N; Khalili, Hamed; Song, Mingyang et al. (2017) Genetic Polymorphisms in Fatty Acid Metabolism Modify the Association Between Dietary n3: n6 Intake and Risk of Ulcerative Colitis: A Prospective Cohort Study. Inflamm Bowel Dis 23:1898-1904
Simon, Tracey G; King, Lindsay Y; Chong, Dawn Q et al. (2017) Diabetes, Metabolic Comorbidities and Risk of Hepatocellular Carcinoma: Results from Two Prospective Cohort Studies. Hepatology :
Chin, Samantha M; Sauk, Jenny; Mahabamunuge, Jasmine et al. (2017) Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection in Patients With Inflammatory Bowel Disease: A Single-Center Experience. Clin Gastroenterol Hepatol 15:597-599
Walsh, Emily; Chah, Young Wha; Chin, Samantha M et al. (2017) Clinical Predictors and Natural History of Disease Extension in Patients with Ulcerative Proctitis. Inflamm Bowel Dis 23:2035-2041
Van Der Sloot, Kimberley W J; Joshi, Amit D; Bellavance, Danielle R et al. (2017) Visceral Adiposity, Genetic Susceptibility, and Risk of Complications Among Individuals with Crohn's Disease. Inflamm Bowel Dis 23:82-88
Khalili, Hamed; de Silva, Punyanganie S; Ananthakrishnan, Ashwin N et al. (2017) Dietary Iron and Heme Iron Consumption, Genetic Susceptibility, and Risk of Crohn's Disease and Ulcerative Colitis. Inflamm Bowel Dis 23:1088-1095
Staller, Kyle; Townsend, Mary K; Khalili, Hamed et al. (2017) Menopausal Hormone Therapy Is Associated With Increased Risk of Fecal Incontinence in Women After Menopause. Gastroenterology 152:1915-1921.e1
Khalili, Hamed; Granath, Fredrik; Smedby, Karin E et al. (2016) Association Between Long-term Oral Contraceptive Use and Risk of Crohn's Disease Complications in a Nationwide Study. Gastroenterology 150:1561-1567.e1
Khalili, Hamed; Neovius, Martin; Ekbom, Anders et al. (2016) Oral Contraceptive Use and Risk of Ulcerative Colitis Progression: A Nationwide Study. Am J Gastroenterol 111:1614-1620
Lochhead, Paul; Khalili, Hamed; Ananthakrishnan, Ashwin N et al. (2016) Association Between Circulating Levels of C-Reactive Protein and Interleukin-6 and Risk of Inflammatory Bowel Disease. Clin Gastroenterol Hepatol 14:818-824.e6

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