Inflammatory Cytokine Polymorphisms, Air Pollution, and Very Preterm Birth

描述（由申请人提供）：我们建议检查以下假设：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。依靠现有的，进行良好的VPTB病例对照研究，并结合我们的专业知识和资源，在空气污染暴露评估和分析基因-环境相互作用，我们建议进行第一次流行病学研究的基因-环境相互作用和VPTB。VPTB是美国婴儿死亡的最常见原因，也是低胎龄婴儿中神经系统和肺部疾病的主要诱因，风险最高[1-7]。在美国，约12%的活产婴儿发生PTB [5]，VPTB的患病率约为2% [9]。专家一致认为，PTB的原因是多因素的，包括遗传学，母亲的行为和环境因素[10，11]。虽然越来越多的证据表明PTB与环境空气污染有关，但所报道的相关性背后的生物学机制仍然未知。炎症是被认为参与空气污染引起的健康影响的一个主要途径[19-21]。到目前为止，还没有研究涉及PTB病因学中空气污染和炎症遗传变异之间的基因-环境相互作用。 我们建议使用来自CA极早产（CVPTB）研究的数据，该研究是一项来自加利福尼亚州南部5个县的VPTB巢式病例对照研究，这些县以高颗粒物、臭氧和交通暴露而闻名。50个单核苷酸多态性（SNPs）以前被证明是相关的PTB在26个炎症/免疫反应途径基因进行基因分型的母亲-婴儿对检查他们的贡献VPTB。我们将利用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）、CALINE 4、克里格法）的组合来估计CVPTB研究受试者妊娠期间的空气污染暴露。除了出生证明记录外，我们还将获得来自VPTB病例的病历审查数据和来自产前筛查记录的妊娠中期居住史，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学和母亲用药数据。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风险的贡献者，特别是空气污染和炎症途径中涉及的特定SNP之间的相互作用。这项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的联系机制，为空气污染监管政策提供科学数据和支持，这些政策将发育中的胎儿视为需要更多保护的敏感亚群。

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.