Candidate genes linking maternal nutrient exposure to offspring health via DNA methylation: a review of existing evidence in humans with specific focus on one-carbon metabolism

Abstract

Background: Mounting evidence suggests that nutritional exposures during pregnancy influence the fetal epigenome, and that these epigenetic changes can persist postnatally, with implications for disease risk across the life course.

Methods: We review human intergenerational studies using a three-part search strategy. Search 1 investigates associations between preconceptional or pregnancy nutritional exposures, focusing on one-carbon metabolism, and offspring DNA methylation. Search 2 considers associations between offspring DNA methylation at genes found in the first search and growth-related, cardiometabolic and cognitive outcomes. Search 3 isolates those studies explicitly linking maternal nutritional exposure to offspring phenotype via DNA methylation. Finally, we compile all candidate genes and regions of interest identified in the searches and describe their genomic locations, annotations and coverage on the Illumina Infinium Methylation beadchip arrays.

Results: We summarize findings from the 34 studies found in the first search, the 31 studies found in the second search and the eight studies found in the third search. We provide details of all regions of interest within 45 genes captured by this review.

Conclusions: Many studies have investigated imprinted genes as priority loci, but with the adoption of microarray-based platforms other candidate genes and gene classes are now emerging. Despite a wealth of information, the current literature is characterized by heterogeneous exposures and outcomes, and mostly comprise observational associations that are frequently underpowered. The synthesis of current knowledge provided by this review identifies research needs on the pathway to developing possible early life interventions to optimize lifelong health.

Figure 1.

A simplified summary of one-carbon metabolism. BHMT, Betaine Homocysteine MethylTransferase; CBS, Cystathionine-Beta-Synthase; CTH, Cystathionine Gamma-Lyase; DHFR, Dihydrofolate Reductase; dTMP, Deoxythymidine Monophosphate; dTTP, Deoxythymidine Triphosphate; FAD, Flavin Adenine Dinucleotide; GNMT, Glycine N-MethylTransferase; MAT, Methionine AdenosylTransferase; MS, Methionine Synthase; MT, Methyl Transferases; MTHFD, MethyleneTetraHydroFolate Dehydrogenase; MTHF, MethyleneTetraHydroFolate Reductase; SAHH, S-Adenosyl Homocysteine Hydrolase; SHMT, Serine HydroxyMethylTransferase; TS, Thymidylate Synthase. Source: reproduced with permission from James et al. Epigenetics, nutrition and infant health. In: Karakochuk C, Whitfield K, Green T, Kraemer K (eds). The Biology of the First 1000 Days. Boca Raton, FL: CRC Press, 2017.