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The Childhood Plasma Proteome: Discovering Its Applications in Public Health Advisor: Dr

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The Childhood Plasma Proteome: Discovering Its Applications in Public Health Advisor: Dr THE CHILDHOOD PLASMA PROTEOME: DISCOVERING ITS APPLICATIONS IN PUBLIC HEALTH By Sun Eun Lee, M.S. A dissertation submitted to Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland March, 2015 © 2015 Sun Eun Lee All Rights Reserved ABSTRACT Background: Child health is shaped by cumulative interactions with environments even before birth. However, our understanding of the underlying biological mechanisms remains far from complete. Plasma proteomics may offer unique opportunities to understand underpinning biological processes that respond to early nutritional exposure, reflect ongoing health conditions, or mediate health consequences. The overall goal of this thesis is to evaluate applications of plasma proteomics in discovering new bio- signatures or generating hypotheses with regard to prenatal micronutrient (MN) supplementation and childhood inflammation and cognitive function. Methods: In 1999-2001, a double-blind randomized trial of antenatal micronutrient supplementation was conducted in the rural District of Sarlahi, Nepal. Pregnant women received either vitamin A alone as the control, or with folic acid, iron-folic acid, iron- folic acid-zinc, or a multiple micronutrient supplement containing all three plus 11 other vitamins and minerals from early pregnancy to 3 months postpartum. From 2006-2007, children born during this trial were followed up at the age of 6-8 years for plasma specimen collection and a year later for the assessment of cognitive function by psychological tests. We applied quantitative proteomics to identify proteins in plasma of 500 Nepalese children that co-vary with a plasma inflammation biomarker, alpha-1-acid glycoprotein (AGP) and general intellectual function, measured by an immunoradial diffusion assay and the Universal Nonverbal Intelligence Test (UNIT), respectively. We evaluated the effects of antenatal micronutrient supplementation by examining differentially abundant proteins and enriched gene sets by maternal MN intervention (each compared to the control group). A subset of children (n=249) who had both ii proteomics and psychological test outcomes were included for the analysis of child cognitive outcome. Results: Among 982 proteins quantified in >10% of total samples, 99 were strongly associated with AGP at a family-wise error rate of 0.1%. Positively associated proteins include known positive acute phase proteins and numerous unexpected intracellular signaling proteins. Negatively associated proteins were secretory hepatic proteins involved in transporting lipids, micronutrients, growth factors and sex hormones, and extra-hepatic proteins regulating extracellular matrix metabolism. Among 751 proteins quantified in >10% of the sub-samples, 9 and 13 proteins were positively and negatively associated with the UNIT score, passing a false discovery rate (FDR) threshold of 5%, respectively. In fully adjusted models, associations of 7 proteins involved in subclinical inflammation remained significant, explaining an additional 5~9 % of variance in the UNIT score. Lastly, there were no overall effects of antenatal micronutrient supplementation on plasma protein profiles of children. In sex-stratified analyses, maternal folic acid supplementation increased the relative abundance of nesprin-1 by 50.9 (95% CI: 24.7, 82.8) % among boys and positively enriched 4 gene sets related to cytoskeleton and organ development among girls (all passing FDR threshold of 5%). Conclusions: Our findings suggest that a vast plasma proteome reflects homeostatic control of inflammation, low-degree chronic inflammation is an important risk factor for child development, and there was no prominent long-term effects of prenatal micronutrient supplementation on childhood plasma proteome. Further studies should be followed to evaluate future public health use of plasma biomarkers of chronic iii inflammation and potential health consequences of subtle but enduring gene-specific and functional changes by maternal folic acid supplementation in undernourished populations. Advisor: Dr. Keith West Thesis Readers: Dr. Pierre Coulombe, Dr. Parul Christian, and Dr. Ingo Ruczinski, and Dr. Yiwu He iv ACKNOWLEDGEMENTS From 2009 fall to 2015 spring, all my doctoral work at Hopkins would have been impossible without countless help and support by many people. First and foremost, I would like to offer my sincere thanks to all study participants, community field workers, and the Nepal Nutrition Intervention Project Sarlahi (NNIPS) team in the field. I had the privilege to conduct a secondary data analysis using high quality data of NNIPS-3 and its two child follow-up studies. When I visited Sarlahi District in Nepal in 2013 summer, I realized that the high quality of NNIPS data could not be achieved without incredible amount of field work, training, and efforts made by the field workers and NNIPS team. Without their dedication to community work and participation of community people, this study could not exist and I would not have this wonderful research opportunity. I would like to express special thank to Steven LeClerq who made me feel like I am part of the NNIPS family during my visiting period. Also, I give thanks to all the other NNIPS team members who showed great hospitality to me. This NNIPS study site visit will remain unforgettable to me. My thesis work was embedded in the Nutriproteomics project and I cannot thank each member of Nutriproteomics team enough. They actually did all the critical and outstanding work from designing the study, performing laboratory experiments, developing methods and analytic tools, and managing the whole project. I joined this team in 2012. Whenever I was lost in the complexity of this project, Lee Shu-Fune Wu was always supportive of me. She helped me not only with my work, but also gave me a big smile, comfort, and sincere encouragement. Dr. John Groopman served on my school-wide oral exam committee. I appreciate his intellectual guidance on this project v and thoughtful feedback on my thesis. Dr. Robert Cole and his laboratory at the School of Medicine performed all proteomics analysis and it was such a nice opportunity for me to learn the state-of-art high throughput-technologies he brought to public health nutrition. I am also thankful for his responsiveness to my requests and keen questions that made me think through my methodology and interpretation of findings. Dr. Kerry Schulze and her laboratory analyzed all micronutrients and inflammatory indicators, which were essential parts of my thesis. When I was stuck with some issues and no one seemed to solve my questions, she steered me in the right direction and gave me good alternative solutions. I sincerely appreciate all of their invaluable contributions to this project and always being supportive to my research. There are three people who gave me invaluable guidance and provided me opportunities to learn and grow. I would like to express my great appreciation to Dr. Ingo Ruczinski. Because of the nature of a large-scale data analysis, I had to apply different analytic skills from what I had learned from regular Biostatistics classes. Because I was new to a large-scale data analysis, I faced many statistic and analytic challenges. Whenever I requested a meeting, Dr. Ruczinski made time for me and put effort to address my questions. Also, I am thankful that he taught me the true attitude a researcher should have; I challenged the results until I could not think of any other ways to reject the findings. It was a great lesson to me and this attitude will ground me in my future research. I am thankful for Dr. Parul Christian who was my supervisor for CHERG work and is a committee member of my departmental, school-wide oral exam, and final defense exam. CHERG study with meta-analysis was a great research experience as a vi student and she always gave me clear ideas and instructions to follow. As a main principal investigator of NNIPS-3 and child follow-up studies, she provided me critical feedback and fair and reliable support on my thesis research. I will never forget how she did not mind spending extra hours to help me to prepare my defense seminar. I feel truly grateful to my advisor, Dr. Keith West for his endless generosity and patience, and financial and mental support. He guided the big picture of my study beyond what literature says or what other people conventionally believe. His pioneering spirit and enthusiasm for proteomics inspired me throughout my research. The countless meetings with him kept motivating me to have creative and innovative thinking. Due to his support, I could truly enjoy my thrilling and exciting research. Most of all, I would like to thank him for sending me to Bangladesh and Nepal to learn community-based cohort study. This experience became the foundation of my research and will help me to power through other public health nutrition research in the future. This study would not have been possible without enormous financial support from the Bill and Melinda Gates Foundation and it actually supported me beyond. Dr. Yiwe He who is a program officer of the Foundation willingly agreed to serve on my external committee member and flew from Seattle to Baltimore to attend my defense seminar and final oral exam. He provided invaluable feedback on my research as funder’s perspective and it was unforgettable experience to have him in my committee. I am truly thankful for his support for my research as well as steady financial support for this project. Lastly, I would like to thank to Dr. Pierre Coulombe who served as a chair of my thesis committee. I am thankful for his time and effort to review my thesis and invaluable biologic feedback on my research. vii Special thanks to essential people in the Human Nutrition and the department of International Health who made my Hopkins life possible - Peggy Bremer, Rhonda Skinner, Tom Durkin, Carol Buckley, and Cristina Salazar. Thank you for your willingness to help me. I would like to thank my dear friends, Rachel Dlugash and Tatenda Mupfuze who were always there for me and listened my story.
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