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

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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.