Maternal and offspring FADS polymorphisms, dietary LC-PUFAs, and adolescent cardiometabolic health

通过这个博士前奖学金，我将获得生命课程的深入培训 改善心脏代谢健康（CMH）的方法，营养干预和纵向队列分析， 遗传分析的生物信息学方法和科学交流。心血管疾病的危险因素 疾病是全球主要的死亡原因，在生命过程的早期出现，在幼儿和 青少年。因此，确定早期和有效的干预战略至关重要。多不饱和脂肪 多不饱和脂肪酸（PUFAs）作为长链PUFAs（LC-PUFAs）的前体具有心脏保护作用。 酸（AA）、n-3二十碳五烯酸（EPA）和n-3二十二碳六烯酸（DHA），其调节 炎症然而，我们对LC-PUFA在关键时期的作用的理解仍然存在差距。 生长和发育，如妊娠和青春期早期，为以后的CMH。目前，长期 产前补充DHA的效果仍未得到充分研究。研究之间的不一致结果可能是 这归因于调节脂肪酸去饱和酶（FADS）基因的变异体的群体异质性。 n-3和n-6前体转化成它们的LC-PUFA形式。大多数研究将遗传 已经在欧洲人群中进行了信息，但基因型分布的种族/民族差异 FADS变体的数量值得进一步研究。为了解决这些差距，我们将使用产前DHA的数据， 与Instituto Nacional de Salud合作进行的补充试验（POSGRAD，NCT 00646360） Pública（INSP）在墨西哥。从出生起就对母子进行跟踪;最近， 在11岁时收集后代的遗传学、饮食、身体组成和生物学标记 年在导师们的支持下，我将使用这个独特的数据集来实现以下具体目标： 确定产前补充DHA对青春期早期后代CMH谱的影响 （n=485）和研究母体FADS基因中的变体的效应修饰（n = 396）和2）检查 在低摄入量的研究人群中，后代FADS基因的变异是否与CMH谱相关 n-3脂肪酸（n = 285）。我将使用血脂、血压、肥胖、胰岛素抵抗和 炎症以评估CMH谱。我假设FADS基因的变异改变了饮食LC的作用- 墨西哥青少年妊娠期和青春期早期对CMH的PUFA。通过解决这些 互补的目标，我们将大大推进关键时期基因营养相互作用的理解， 在一个人口的增长和发展时期，通常是研究不足。通过完成 这项工作，我将开发创新方法的专业知识，包括降维技术， 描述CMH、单倍型估计以及解决缺失数据和由于损失导致的选择偏倚的方法 跟进拟议的工作补充了2020-2030年NIH营养研究战略计划， 强调使用精确的健康方法来确定营养在整个生命过程中的作用。

PROJECT SUMMARY Through this predoctoral fellowship, I will obtain in-depth training in life course approaches to improve cardiometabolic health (CMH), analysis of nutrition interventions and longitudinal cohorts, bioinformatics approaches for genetic analysis, and scientific communication. Risk factors for cardiometabolic disease, the leading global cause of mortality, are emerging earlier in the life course, among young children and adolescents. It is therefore critical to identify early and effective intervention strategies. Polyunsaturated fatty acids (PUFAs) have a cardioprotective role as precursors to the long-chain PUFAs (LC-PUFAs) n-6 Arachidonic Acid (AA), n-3 Eicosapentaenoic Acid (EPA) and n-3 Docosahexaenoic Acid (DHA), which modulate inflammation. However, gaps remain in our understanding of the role of LC-PUFAs during critical periods of growth and development, such as gestation and early adolescence, for later CMH. Currently, the long-term effects of prenatal DHA supplementation remain understudied. Inconsistent results across studies may be attributable to population heterogeneity in variants of the fatty acid desaturase (FADS) genes that regulate the conversion of n-3 and n-6 precursors into their LC-PUFA forms. The majority of studies incorporating genetic information have been conducted in European populations, but racial/ethnic variation in the genotype distribution of FADS variants warrants further research. To address these gaps, we will use data from a prenatal DHA supplementation trial (POSGRAD, NCT00646360) conducted in collaboration with Instituto Nacional de Salud Pública (INSP) in Mexico. Mother-child pairs have been followed since birth; most recently, data on maternal and offspring genetics, diet, body composition, and biological markers were collected from offspring at age 11 years. With the support of my mentors, I will use this unique dataset to address the following specific aims: 1) Determine the effect of prenatal DHA supplementation on offspring CMH profiles during early adolescence (n=485) and investigate effect modification by variants in maternal FADS genes (n = 396) and 2) Examine whether variants in offspring FADS genes are associated with CMH profiles in a study population with low intake of n-3 fatty acids (n = 285). I will use measures of lipids, blood pressure, adiposity, insulin resistance, and inflammation to assess CMH profiles. I hypothesize that variants in FADS genes modify the role of dietary LC- PUFAs during gestation and early adolescence on CMH among Mexican adolescents. By addressing these complementary aims, we will significantly advance understanding of gene-nutrient interactions during critical periods of growth and development in a population that has typically been understudied. Through completion of this work, I will develop expertise in innovative approaches including dimensionality reduction techniques to characterize CMH, haplotype estimation, and approaches to address missing data and selection bias due to loss to follow-up. The proposed work complements the 2020-2030 NIH Nutrition Research Strategic Plan, which emphasizes use of precision health approaches to define the role of nutrition across the life course.