Inflammatory Cytokine Polymorphisms, Air Pollution, and Very Preterm Birth

描述（由申请人提供）：我们建议研究以下假设：孕妇在怀孕期间暴露于空气污染物与极早产（VPTB，妊娠<32周）风险增加相关，以及炎症基因多态性改变空气污染对VPTB风险的影响。基于已有的VPTB病例对照研究，结合我们在空气污染暴露评估和基因-环境相互作用分析方面的专业知识和资源，我们建议开展基因-环境相互作用与VPTB的首次流行病学研究。VPTB是美国婴儿死亡的最常见原因，也是导致低胎龄婴儿神经和肺部疾病的主要原因[1-7]。在美国，约12%的活产婴儿患有PTB，而VPTB的患病率约为2%。专家一致认为PTB的病因是多因素的，包括遗传、母体行为和环境因素[10,11]。尽管越来越多的证据表明PTB与环境空气污染有关，但所报道的关联背后的生物学机制仍然未知。炎症被认为是空气污染对健康影响的主要途径之一[19-21]。迄今为止，还没有研究涉及空气污染与PTB病因中炎症性遗传变异之间的基因-环境相互作用。我们建议使用来自加州非常早产研究（CVPTB）的数据，这是一项来自加州南部5个县的非常早产病例对照研究，这些县以高颗粒物、臭氧和交通暴露而闻名。研究人员对母婴对进行了基因分型，研究了先前在26个炎症/免疫反应途径基因中发现的50个与PTB相关的单核苷酸多态性（snp），以研究它们对VPTB的影响。我们将结合广泛的空气监测数据和空气污染建模方法（土地利用回归（LUR）， CALINE4, kriging）来估计CVPTB研究对象怀孕期间的空气污染暴露。除了出生证明记录外，我们还将从产前筛查记录中获得VPTB病例的病历审查数据和妊娠中期的居住史，与以往仅依赖出生证明中的分娩地址的研究相比，这些数据将加强暴露评估。我们还将从产前筛查记录中获得人口统计和产妇用药数据。因此，CVPTB数据集，结合我们在空气污染评估和评估基因-环境相互作用方面的卓越专业知识和资源，提供了一个新颖而独特的机会，首次探索基因-环境相互作用作为VPTB风险的贡献因素，特别是空气污染与炎症途径中涉及的特定snp之间的相互作用。拟议的研究将提供宝贵的信息，以更好地了解空气污染与早产，特别是VPTB之间的联系机制，为将发育中的胎儿视为需要更多保护的敏感亚群的空气污染监管政策提供科学数据和支持。

DESCRIPTION (provided by applicant): We proposes to examine the hypotheses that maternal exposure to air pollutants during pregnancy is associated with an increased risk of very preterm birth (VPTB, <32 weeks gestation), and that polymorphisms in inflammatory genes modify the influence of air pollution on the risk of VPTB. Relying on an existing, well- conducted case-control study of VPTB and combining it with our expertise and resources in air pollution exposure assessment and in analyzing gene-environment interactions, we propose to conduct the first epidemiologic study of gene-environment interactions and VPTB. VPTB is the most frequent cause of infant mortality in the US, and a main contributor to neurological and pulmonary disorders in children with infants born at lower gestational age at highest risk [1-7]. PTB occurs in ~12% of live births in the US [5], with VPTB at a prevalence of ~2% [9]. Experts agree that the cause of PTB is multifactorial, including genetics, maternal behaviors, and environmental factors [10, 11]. Although growing evidence is linking PTB to ambient air pollution, the biological mechanisms underlying the reported associations are still unknown. Inflammation is one primary pathway believed to be involved in air pollution-induced health effects [19-21]. To date, no study has addressed gene-environmental interaction between air pollution and inflammatory genetic variants in the etiology of PTB. We propose to use data from the CA Very Preterm Birth (CVPTB) Study, a nested case-control study of VPTB from 5 counties in Southern CA known for high particulate matter, ozone, and traffic exposures. Fifty single nucleotide-polymorphisms (SNPs) previously shown to be related to PTB in 26 inflammatory/immune response pathway genes were genotyped in mother-infant pairs to examine their contributions to VPTB. We will utilize a combination of extensive air monitoring data and air pollution modeling approaches (land use regression (LUR), CALINE4, kriging) to estimate air pollution exposures in pregnancy for CVPTB Study subjects. In addition to birth certificates records, we will have available to us data from medical chart reviews for VPTB cases and residential history during mid-pregnancy from prenatal screening records which will strengthen the exposure assessment compared to previous studies relying solely on delivery addresses from birth certificates. We will also have available to us demographic and maternal medication data from prenatal screening records. Thus, the CVPTB dataset, combined with our exceptional expertise and resources in air pollution assessment and in assessing gene-environment interaction, provides a novel and unique opportunity to - for the very first time - explore gene-environment interactions as contributors to the risk of VPTB, specifically the interactions between air pollution and specific SNPs involved in inflammatory pathways. The proposed study will provide invaluable information to better understand the mechanisms linking air pollution to premature birth, especially VPTB, providing scientific data and support for air pollution regulatory policies which consider the developing fetus as a sensitive sub-population that needs greater protection.