Despite years of intense efforts to reduce the rates of preterm birth (PTB), our understanding of the underlying mechanisms of PTB and racial disparity is limited. Recent data suggests that infection/inflammation has an important, complex role in early PTB. However, the mechanisms that modulate its clinical expression remain poorly understood. There is compelling evidence that PTB is a heterogenous complex entity determined by multiple genetic and environmental factors. Studies by our team have demonstrated a strong evidence of gene-environment interactionson PTB in both Chinese and U.S.populations. This proposed study is to investigate the role of infection/inflammation, genetic susceptibility, and gene-environment interactions in determiningpreterm disparities among three racial groups (Black, White, and Hispanic) in the U.S. We hypothesize that the risk of PTB associated with infection/inflammation is elevated in individuals with the relevant variants of candidate genes: 1) those involved in the initiation and regulation of infectious/inflammatory process: Interleukin 1 (IL-1), IL-6, IL-10, and tumor necrosis factor (TNF);2) those involved more distally in the cascade of inflammatory process that lead to PTB: corticotropin releasing hormone (CRH);3) those that may modify infectious/inflammatory process: C-reactive protein (CRP) and protein C. We further hypothesize that the significant racial disparity in PTB may be partially explained by: 1) differences in allele frequencies of the above candidate genes;2) differences in the prevalence of intrauterine infection/inflammation;and 3) differences in gene- infection and gene-environment interactions. We will utilize the existent epidemiologic and clinical data and biospecimens from a total of 1,000 preterm mother-infant pairs (cases) and 2,000 term controls being collected at the Boston Medical Center. This proposal seeks support to accomplish two new specific aims: (1) to genotype the above proposed candidate genes for all the mothers and their infants in the study;and (2) to perform statistical analyses to test the above hypotheses. We have assembled a multi-disciplinary team that possesses technical and intellectualcapability and relevant experience to carry out the study. Another important strength of this proposal is the existent large multi- racial U.S. samples. The findings from this proposed study will expand our understanding of the role of infection/inflammation, genetic susceptibility, and gene-environment interactions in the pathogenesis of PTB and in determining racial disparitiesin PTB. PERFORMANCE SITE(S) (organization, city, state) Boston Medical Center/Boston University School of Medicine, Boston, Massachusetts Harvard School of Public Health, Program for PopulationGenetics, Boston, Massachusetts KEY PERSONNEL. See instructions on Page Name Xiaobin Wang, MD, ScD Jerome O. Klein, MD Milton Kotelchuck, PhD Gary Kaufman, MD John Kasznica, MD Paul Wise, MD, MPH 11. Use continuation pages as needed to provide the required information in the format shown below. ? Organization Role on Project Boston Medical Center/Boston University Principal Investigator School of Medicine Boston Medical Center/Boston University Co-Investigator School of Medicine Boston University School of Public Health Co-Investigator Boston Medical Center/Boston University Co-Investigator School of Medicine Boston Medical Center/Boston University Co-Investigator School of Medicine Boston Medical Center/Boston University Co-Investigator School of Medicine PHS 398 (Rev. 4/98) Page 2. BB Number pages consecutively at the bottom throughout the application. Do not use suffixes such as 3a, 3b. BB Name Barry Zuckerman, MD Gerald Coffman, MS Xiping Xu, MD, PhD Louise Ryan, PhD Tainhua Niu,ScD Pierre Zalloua, PhD Poul Thorsen, MD, PhD b Principal Investigator/Program lbtor (Last, first, middle): Wang, Xiaobin Organization Role on Project Boston Medical Center/Boston University School ofMedicine Boston University School of Public Health Harvard School of Public Health Harvard School of Public Health Harvard School of Public Health Harvard School of Public Health University of Aarhus, Denmark Co-investigator Senior Data Analyst Co-Investigator Co-Investigator Genetic Epidemiologist Molecular Geneticist Consultant PHS 398 (Rev. 4/98) Page 3_ BB Number pages consecutively at the bottom throughout the application. Do not use suffixes such as 3a, 3b. CC Principal investigator/Program Director (Lasf, First, Middle): Wang, Xiaobin RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page Description, Performance Sites, and Personnel Table of Contents Budget Justification Consortium Agreement Biographical Sketch-Principal Investigator/Program Director (Not to exceed three Other Biographical Sketches (Not to exceed two pages for each) 13-4R Other Support NA Resources 47-49 Research Plan Introduction to Revised Application (Not to exceed 3 pages) NA Introduction to Supplemental Application (Not to exceed 1page) NA a.
Specific Aims b. Background and Significance c. Preliminary Studies/Progress Report ...(Items a-d: not to exceed 25 pages*) d. Research Design and Methods e. Human Subjects f. Vertebrate Animals g. Literature Cited h. Consortium/Contractual Arrangements i. Consultants - Support Letters Checklist Type density and type size of the entire application must conform to limits provided in instructions on page 6. APPENDIX: I. Wang W, Zuckerman B, Coffman G, Corwin M. Familial aggregation of low birth weight among whites and blacks in the United States. New England Journal of Medicine. 1995(Dec. 28);333:1744-1749. II. WangW, Chen D, Niu T, Wang Z, Wang L, Ryan L, Smith T, Christiani DC, Zuckerman B, Xu X. Genetic susceptibility to benzeneand shortenedgestation: Evidence of gene-environment interaction. American Journal of Epidemiology. 2000(Oct. 15);152(8):693-703. III. Wang X, Zuckerman B, Kaufman G, Wise P, Hill M, Niu T, Ryan L, Wu D, Xu X. Molecular epidemiology of preterm delivery: Methodology and Challenges. Pediatric and Perinatal Epidemiology. (Inpress). IV. Wang X, Zuckerman B, Pearson C, Kaufman G, Chen C, Wang G, Niu T, Wise P, Bauchner H, Xu X. Maternal cigarette smoking, metabolic gene polymorphism, and infant birth weight. JAMA. (Submitted). V. Niu T, RabbeeN, Ryan L, Chen D, Xu X, Wang X. Maternal and fetal CYP1Al gene polymorphism, benzene exposure, and shortened gestation: Application of 1-TDT. Pediatric and Perinatal Epidemiology. (Submitted). VI. Maternal Questionnaire VII. Medical Record Abstraction Sheet PHS 398 (Rev. 4/98) (Form Page 3} Page 4 Number pages consecutively at the bottom throughout the application. Do not use suffixes such as 3a, 3b.
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