Role of pre-natal Vitamin D and gene interactions in Autism Spectrum Disorders; leveraging an existing case-control study

产前维生素 D 和基因相互作用在自闭症谱系障碍中的作用；

• 批准号: 9038392
• 负责人: Gayle Windham
• 金额: $ 24.88万
• 依托单位: SEQUOIA FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9038392
• 关键词: Address; Advocate; Affect; Air Pollution; Archives; Autistic Disorder; Autoantibodies; Binding; Biological; Biology; Birth; Birth Certificates; Blood; Brain; California; Candidate Disease Gene; Case-Control Studies; Child; Classification; Data; Development; Developmental Disabilities; Diagnosis; Doctor of Philosophy; Environmental Epidemiology; Environmental Exposure; Environmental Risk Factor; Estrogens; Ethnic group; Etiology; Exposure to; Family; Female; Fibrinogen; Frequencies; Gender; General Population; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genotype; Health; High Prevalence; Immune; Immunologic Markers; Individual; Inflammatory; Intellectual functioning disability; Intervention; Investigation; Laboratories; Lead; Link; Logistic Regressions; Measurement; Measures; Mediating; Methods; Modification; Mothers; Neonatal; Newborn Infant; Odds Ratio; Outcome; Participant; Pathway interactions; Perinatal; Play; Policies; Policy Maker; Population Control; Population Group; Predisposition; Pregnancy; Prevalence; Prevention strategy; Public Health; Recommendation; Records; Regulation; Research; Resources; Risk; Risk Factors; Role; SNP genotyping; Sampling; Sampling Studies; Second Pregnancy Trimester; Sex Characteristics; Sex Ratio; Skin Pigmentation; Specificity; Specimen; Spottings; Subgroup; Testing; Toxic Environmental Substances; Toxin; Translating; United States National Institutes of Health; Vitamin D; Vitamin D Deficiency; Vitamin D2; Vitamins; Work; autism spectrum disorder; base; case control; chemokine; cytokine; design; early childhood; gene environment interaction; gene interaction; genetic epidemiology; genome-wide; high risk; immune function; in utero; insight; male; maternal serum; modifiable risk; neurodevelopment; novel; persistent organic pollutants; population based; prenatal; protective effect; racial and ethnic

 DESCRIPTION (provided by applicant): Role of Prenatal Vitamin D Levels and Genetic Interactions in Autism Spectrum Disorders; Leveraging an existing case-control study Both vitamin D deficiency/insufficiency and autism spectrum disorders (ASD) have increased in prevalence over recent decades. Emerging evidence suggests vitamin D may be related to risk of ASD, particularly given recent advances in the understanding of the role of vitamin D on brain and immune function. In the proposed study, we will investigate the association between perinatal vitamin D deficiency/ insufficiency and ASD in the context of the existing Early Markers of Autism (EMA) study in order to leverage rich resources already collected. Specifically, this study aims to determine the association between maternal and neonatal vitamin D levels and risk of ASD, whether polymorphisms in genes related to vitamin D are associated with vitamin D levels and risk of ASD, and to test for interaction between vitamin D and genotype. Secondary aims are to examine whether risk differs according to subgroups, including child gender, phenotypic, and racial/ethnic groups, as well as to explore potential pathways linking vitamin D and ASD, specifically changes in immune marker levels and modification by, or interaction with, environmental toxins. The study will include ~550 children with autism, 200 with other intellectual disability (ID), and 440 unaffected children born in 2000-2003 in Southern California. ASD cases were ascertained from the California Department of Developmental Disabilities with record abstraction and confirmatory case classification based on expert clinician review. Genotyping of 2/3 of the study sample and measurement of markers of immune function and environmental exposures has already been conducted. In the proposed work, targeted genotyping of candidate genes in the remaining participants will be conducted, and vitamin D metabolites (25- hydroxyvitamin D2 and D3) will be measured using a highly sensitive laboratory methods in archived newborn blood spots and maternal serum samples. Mean levels of vitamin D will be compared across the primary study groups, and logistic regression will be used to calculate odds ratios of the association between vitamin D deficiency/insufficiency and risk of ASD, ID, and ASD+ID, adjusting for covariates from birth certificate and other EMA records. Main effects of polymorphisms and vitamin D levels will be calculated, while the interaction of these factors will be tested using logistic regression. Vitamin D levels will be compared by levels of measured toxins and immune markers, and mediating effects tested. This will be the first study with the ability to thoroughly examine the potential role of vitamin Din ASD by using quantified, in-utero and neonatal vitamin D levels, and to also consider genetic susceptibility and suspected pathways. We anticipate the results of this investigation will provide novel information about risk factors for ASD, and contribute to understanding of gene-environment interactions and underlying biology. By studying a common, modifiable exposure, this work could lead to the development of public health recommendations for prevention strategies to reduce the risk of ASD, which are currently lacking.

 描述（由申请人提供）：产前维生素D水平和遗传相互作用在自闭症谱系障碍中的作用;利用现有的病例对照研究维生素D缺乏/不足和自闭症谱系障碍（ASD）的患病率在最近几十年有所增加。新出现的证据表明，维生素D可能与ASD的风险有关，特别是考虑到维生素D对大脑和免疫功能作用的最新进展。在拟议的研究中，我们将在现有的自闭症早期标志物（EMA）研究的背景下调查围产期维生素D缺乏/不足与ASD之间的关联，以利用已经收集的丰富资源。具体而言，本研究旨在确定母亲和新生儿维生素D水平与ASD风险之间的关联，维生素D相关基因的多态性是否与维生素D水平和ASD风险相关，并测试维生素D和基因型之间的相互作用。次要目的是检查风险是否根据亚组而不同，包括儿童性别，表型和种族/民族，以及探索维生素D和ASD之间的潜在途径，特别是免疫标志物水平的变化和环境毒素的修饰或相互作用。这项研究将包括大约550名自闭症儿童，200名其他智力残疾（ID）儿童和440名出生于2000-2003年在南加州的未受影响的儿童。 ASD病例由加州发育障碍部门确定，记录摘要和确认性病例分类基于专家临床医师审查。已经对2/3的研究样本进行了基因分型，并测量了免疫功能和环境暴露的标志物。在拟议的工作中，将对其余参与者的候选基因进行有针对性的基因分型，并将使用高度灵敏的实验室方法在存档的新生儿血斑和母体血清样本中测量维生素D代谢物（25-羟基维生素D2和D3）。将比较主要研究组的维生素D平均水平，并使用逻辑回归计算维生素D缺乏/不足与ASD、ID和ASD+ID风险之间关联的比值比，调整出生证明和其他EMA记录的协变量。将计算多态性和维生素D水平的主要影响，同时使用逻辑回归测试这些因素的相互作用。维生素D水平将通过测量的毒素和免疫标志物的水平进行比较，并测试介导作用。 这将是第一项能够通过使用量化的宫内和新生儿维生素D水平来彻底检查维生素D在ASD中的潜在作用的研究，并且还考虑遗传易感性和可疑途径。我们预计这次调查的结果将提供 关于ASD风险因素的新信息，有助于理解基因-环境相互作用和潜在的生物学。通过研究一种常见的、可改变的暴露，这项工作可能会导致制定预防战略的公共卫生建议，以减少目前缺乏的ASD风险。