Exposure to antibiotics during infancy and subsequent risk of Crohn's disease: a

DESCRIPTION (provided by applicant): The candidate is a pediatric gastroenterologist with strong training in patient-oriented research methodology, and a proven commitment to applying these methods to the study of the inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC). The candidate's long-term-career goal is to be an independently funded physician scientist, combining both traditional and genetic epidemiological methods to identify modifiable risk factors in genetically susceptible populations. The candidate's short-term career goals are 1) to acquire the necessary background in genetics, genetic epidemiology, pharmacoepidemiology, and research ethics in order to conduct studies of gene-environment interactions in pediatric IBD, 2) to develop the professional skills needed to successfully lead multidisciplinary research teams, and 3) to produce the critical mass of preliminary data and publications to be credible as the PI of an R01. The proposed research plan, career development activities, mentorship team, and institutional environment are all uniquely suited to assist the applicant in achieving these goals. Our overarching hypothesis is that CD risk is determined by complex interactions between 1) early-life exposures that impact the development of gut microbiota, 2) disease-precipitating exposures that may alter the microbiota, and 3) susceptibility genes which limit bacterial killing and allow persistent stimulation of an abnormal immune response. In this proposal, the PI will test the specific hypothesis that early-life exposure to antibiotics, which may disrupt the development of the microbiota, is a risk factor for CD, particularly in genetically susceptible individuals. In Aim 1, the PI will conduct a retrospective birth cohort study including approximately 900,000 children born in Denmark between 1995 and 2007. Population-based prescription registries, patient registries, pathology databases, and other administrative data maintained by the Danish government will be used to measure the primary exposure, potential confounders, and outcomes of interest. In Aim 2, the PI will establish the feasibility of a population-based case control study that combines traditional epidemiological methods with the additional collection of genetic data in order to assess gene-environment interactions. To support the candidate's career development, he will pursue advanced coursework and independent study in the areas of genetic epidemiology, pharmacoepidemiology, biostatistics, and research ethics. The mentorship team, which includes internationally-recognized, independently-funded investigators with expertise in gastrointestinal epidemiology (Sandler), genetic epidemiology (Millikan), IBD pathogenesis (Sartor), epidemiology methods (Sorensen), and research ethics (Dressler) will guide Dr. Kappelman's research and career development. The research environment including the UNC Translational and Clinical Sciences Institute and Center for Gastrointestinal Biology and Disease at UNC and the Department of Clinical Epidemiology at the University of Aarhus will provide a productive, collegial, and collaborative atmosphere in which to pursue the above research and training goals.