Effects of prenatal DHA supplementation and maternal and offspring FADS polymorphisms in relation to cardiometabolic health of Mexican children Restricted; Files Only

Abstract

Risk factors for cardiometabolic disease are emerging earlier in the life course, including among children and adolescents. Polyunsaturated fatty acids (PUFAs) have a cardioprotective role as precursors to the n-3 and n-6 long-chain PUFAs (LC-PUFAs), which modulate inflammation. However, gaps remain in our understanding of the role of LC-PUFAs for cardiometabolic health (CMH) during critical periods of growth and development, such as gestation and early adolescence. Currently, the long-term effects of prenatal n-3 docosahexaenoic acid (DHA) supplementation are unclear, which may be partially attributable to population heterogeneity in variants of the fatty acid desaturase (FADS) genes that regulate LC-PUFA metabolism. The objective of this dissertation was to examine the relationship between prenatal DHA supplementation, maternal and offspring FADS polymorphisms, and cardiometabolic health in a population of Mexican children. To accomplish this, we used data from a double-blind randomized controlled trial of prenatal DHA supplementation (POSGRAD) in Mexico, in which the offspring have been followed from birth (n=973) through age 11 years (n = 566).

First, we examined clustering of cardiometabolic markers in 413 children and compared a metabolic syndrome (MetS) score to an exploratory CMH score, which additionally included adipokines and inflammatory markers. We found that measures of adiposity and lipids explained the most variation for both scores, and the MetS score captured nearly as much variation as the exploratory CMH score. Next, we evaluated the effect of prenatal DHA supplementation on offspring MetS scores and examined the role of variations in maternal FADS single nucleotide polymorphisms (SNPs) in 314 children. There was no main effect of prenatal DHA supplementation; however, we observed effect modification by variants of maternal SNP rs174602. Offspring of maternal TT genotype who received prenatal DHA had lower MetS scores relative to the placebo group, while offspring of maternal CC genotype who received DHA had higher MetS scores relative to offspring whose mothers received placebo. Finally, we examined the role of variants in both maternal and offspring FADS genes on MetS scores and assessed interactions with prenatal DHA supplementation and offspring diet quality (n=203). Offspring SNP rs174602 did not modify the association of prenatal DHA supplementation with MetS score. Although associations between examined FADS haplotypes and MetS score were null, there was evidence of interaction between SNP rs174602 and current dietary PUFA intake; children with TT or TC genotype and high dietary n-6:n-3 ratios had higher MetS scores relative to those with low n-6:n-3 ratios, while children with CC genotype and high n-6:n-3 ratios had lower MetS scores relative to those with low n-6:n-3 ratios.

The findings from this dissertation provide valuable insights by improving our understanding of cardiometabolic risk early in the life course and demonstrating the importance of examining gene-nutrient interactions, especially for interpreting results from nutrition supplementation trials. While further research is needed to validate our findings in larger, ethnically diverse populations, this work has the potential to guide and inform the development of targeted nutrition recommendations early in the life course to improve CMH.

Table of Contents

Chapter 1 : Introduction. 1

1.1 Objective & Specific Aims. 2

1.2 References. 6

Chapter 2 : Literature Review.. 11

2.1 Cardiometabolic disease in pediatric populations. 11

2.1.1 Health of school-age children, obesity epidemic, and tracking of risk factors across life course 11

2.1.2 Epidemiology of cardiometabolic disease: distribution and determinants. 12

2.1.3 Physiology of metabolic syndrome and cardiometabolic disease. 13

2.1.4 Defining CM risk in pediatric populations. 16

2.2 Overview of LC-PUFAs. 18

2.2.1 Structure, function, and metabolism of PUFAs and LC-PUFAs. 18

2.2.2 Role of LC-PUFAs in inflammation. 20

2.2.3 Role of LC-PUFAs in lipid and glucose metabolism.. 21

2.2.4 Dietary sources and recommended dietary intakes. 21

2.2.5 Changes in the food supply. 23

2.3 Prenatal DHA supplementation and cardiometabolic health. 23

2.3.1 Potential biological mechanisms. 24

2.3.2 Evidence from animal models. 25

2.3.3 Evidence from human populations. 25

2.4 Role of gene-nutrient interactions in CMH.. 28

2.4.1 Overview of gene-nutrient interactions. 28

2.4.2 FADS variants and PUFA metabolism.. 29

2.4.3 FADS variants and CMH: evidence in adult populations. 30

2.4.4 FADS variants and CMH: evidence in pediatric populations. 31

2.4.5 Genetic variability in FADS SNPs across populations. 32

2.4.6 Relative contribution of maternal and offspring genotype. 33

2.5 Summary and Overall Significance. 34

2.6 References. 35

Chapter 3 : Expanded Methods. 54

3.1 Study setting and participants. 54

3.2 Trial design. 55

3.2.1 Recruitment and eligibility criteria. 55

3.2.2 Enrollment and randomization. 55

3.2.3 Intervention. 56

3.3 Follow-up study at age 11 years. 57

3.4 Statistical Methods. 58

3.4.1 Evaluation of selection bias. 58

3.4.2 Imputation of missing data. 60

3.4.3 Principal component analysis. 62

3.4.4 Processing of genetic data. 64

3.4.5 Haplotype estimation. 65

3.4.6 Energy adjustment for dietary intake. 66

3.5 References. 68

Chapter 4 : Clustering of Cardiometabolic Risk Factors in Mexican Pre-Adolescents. 70

4.1 Abstract 71

4.2 Introduction. 72

4.3 Methods. 74

4.4 Results. 79

4.5 Discussion. 82

4.6 References. 88

4.7 Tables and Figures. 96

4.8 Supplementary Tables and Figures. 101

Chapter 5 : Maternal single nucleotide polymorphism rs174602 modified the effect of prenatal DHA supplementation on offspring cardiometabolic health at 11 years: follow-up of a randomized controlled trial in Mexico. 107

5.1 Abstract 108

5.2 Introduction. 110

5.3 Methods. 111

5.4 Results. 116

5.5 Discussion. 118

5.6 References. 125

5.7 Tables and Figures. 135

5.8 Supplementary Tables and Figures. 141

Chapter 6 : Maternal and offspring fatty acid desaturase variants, prenatal DHA supplementation, and dietary n-6:n-3 fatty acid ratio in relation to cardiometabolic health in Mexican children. 145

6.1 Abstract 146

6.2 Introduction. 147

6.3 Methods. 149

6.4 Results. 154

6.5 Discussion. 157

6.6 References. 162

6.7 Tables and Figures. 169

6.8 Supplementary Tables and Figures. 174

Chapter 7 : Discussion and Conclusions. 182

7.1 Key Findings. 182

7.2 Strengths and Limitations. 185

7.3 Clinical and Public Health Implications. 188

7.4 Recommendations for Future Research. 189

7.5 References. 193

About this Dissertation

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School	Laney Graduate School
Department	Nutrition and Health Sciences
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Health Sciences, Nutrition
Palavra-chave	Docosahexaenoic Acid Mexican children Cardiometabolic Health Gene-nutrient interactions Prenatal supplementation LC-PUFAs
Committee Chair / Thesis Advisor	Usha Ramakrishnan, Emory University
Committee Members	Yan V. Sun, Emory University Jessica A. Alvarez, Emory University Aryeh D. Stein, Emory University Erin P. Ferranti, Emory University

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