Preterm birth (PTB)-related disorders are the leading cause of perinatal morbidity and mortality. Inflammation exhibits a strong association with these disorders; cytokines are markers for inflammation. Several studies have suggested that fetal genotypes may contribute to the inflammatory response at the feto-maternal interface, which may have implications for membrane rupture, spontaneous PTB, and fetal injury. Although associations have been found between maternal genotypes and PTB-related disorders, few studies have examined and identified fetal genotypes that are strongly associated with the morbidities and mortality associated with PTB, and those that have demonstrated modest association require validation/replication. Thus, the primary aims of the proposed investigation are to identify fetal genetic variation associated with higher risk of PTB-related outcomes, and to identify cytokines that explain this association. By identification of high-risk neonates, the proposed analyses will enhance understanding of the pathophysiology and biological mechanisms leading to PTB-associated outcomes and suggest intervention strategies. Using existing data from the Neonatal Research Network (NRN), the proposed plan will involve analyses on 1,030 samples with genome-wide genotype data and protein expression data at five time points for 23 cytokines.
The specific aims of this investigation are to (1) delineate relationships between inflammatory cascade genetic markers and their associated cytokine protein expression levels that may be relevant to PTB-related outcomes, and (2) investigate whether any of the genetic markers andcytokines studied suggest differential risk of PTB-related outcomes. The results of this study should allow a complete narrative of the associations among cytokine genetic markers, cytokine protein expression and outcomes, including death, neurodevelopmental impairment (NDI), bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), retinopathy of prematurity (ROP), cerebral palsy (CP), Candida positive culture, hearing impairment, and bilateral blindness. These goals will be accomplished by (1) testing genetic associations to identify variants in one gene that affect cytokine protein expression levels or are associated with PTB-related outcomes; (2) using quantitative trait loci (QTL) analysis to look for QTLs that are associated with cytokine protein expression levels or with PTB-related outcomes; (3) elucidating associations between protein levels of 23 cytokines and PTB-related outcomes through Cox Proportional Hazards (PH) survival models with time-dependent covariates (TDC); (4) testing for interaction effects between cytokines and other neonatal variables to identify effect modifiers; and (5) relating these cytokine-outcome results to genotype-cytokine results. If successful, a link from gene to cytokine to outcome will result. We plan scientific publications and presentations from this work, and, guided by the results of the analysis with additional samples to conduct detailed explorations of the gene to cytokine to outcome narrative, we will submit an NICHD R01 application.
Preterm birth (PTB)-related disorders are the leading cause of perinatal morbidity and mortality. The goal of this study is to find the fetal genetic factors that explain PTB-related disorders, and the immune system messengers (cytokines) that explain the link between genes and adverse outcomes of preterm birth. By identifying the infants that are at high risk for these ill effects, the proposed analyses will help us to understand the causes of PTB-related disorders (e.g., death, cerebral palsy, blindness) and suggest strategies for better prevention and treatment.
