Short-term health benefits of breastfeeding are clear. There is also evidence of long-term breastfeeding effects, including lower blood pressure and total cholesterol, reduced risk of obesity and type-2 diabetes, and higher performance in intelligence tests.
To have long-term effects, it is necessary that having been breastfed or not (as well as other aspects, such as quality and duration) gets “imprinted” in the body and such imprinting lasts until later life periods. In this regard, epigenetics (the study of specific regulators of where, when and how much genes – regions of the DNA that contain information to generate proteins and other products by the cell – are on or off) is of potential interest. Importantly, epigenetic modifications normally pass from one cell to another after cell division, so epigenetic modifications are not easily erased throughout cell cycles over time.
Previous studies using ALSPAC data reported that maternal smoking during pregnancy was associated with methylation (a type of epigenetic marker, consisting of a chemical modification in specific regions of the DNA) patterns in the offspring that sustained until later life stages. Regarding breastfeeding, a few studies looking at specific regions of the methylome (set of all regions of the DNA where methylation can occur) provide some evidence that epigenetic factors might be involved with breastfeeding effects. However, no study to date scanned the entire methylome in relation to breastfeeding or evaluated the maintenance of one or more breastfeeding-associated methylation patterns over time.
Regarding intelligence, an additional potential mechanism relates to breast milk being a source of long-chain polyunsaturared fatty acids (LC-PUFAs) including docosahexaenoic acid (DHA), which have been implicated in brain development. Indeed, many milk substitutes currently include DHA and other LC-PUFAs. One possibility to test this hypothesis is to evaluate if the association between breastfeeding and intelligence differs according to the individual’s capacity to synthetize DHA from metabolic precursors. Special attention has been given to genetic variation in the FADS2 gene, which encodes a protein involved in desaturation processes required for endogenous synthesis of LC-PUFAS from shorter chain fatty acids. However, two published studies (including one study using data from the Avon Longitudinal Study of Parents and Children – ALSPAC) in this regarding successfully detected a FADS2-breastfeeding interaction, but the coefficients were in inconsistent. Three additional twin studies did not detect any strong interaction. Therefore, there is no firm conclusion regarding a potential FADS2-breastfeeding interaction to date. Such potential interaction also suggests that other metabolic processes might play important roles in the health effects of breastfeeding, although a comprehensive evaluation (eg, using metabolimic data) has not been performed to date. We will also analyse the rs66698963 polymorphism, which is a 22 bp insert-deletion within FADS2. This polymorphism has recently been associated with LC-PUFA levels. Moreover, signs of positive selection have also been detected, suggesting that this SNP may be functional.
In general, genetic aspects of breastfeeding have been poorly studied. However, narrow-sense heritability estimates of breastfeeding behaviour (ever vs. never) 44%-85% that have been reported in different populations. This suggests that genetic variants account for a substantial proportion of variability in breastfeeding behaviour in these populations and are, therefore, important aspects of breastfeeding. It also raises the possibility that genetic factors underlie at least some of the association of breastfeeding with health outcomes through pleiotropic effects (either mediated by or independent on breastfeeding). Moreover, exploring breastfeeding genetics might also lead to the identification of genetic variants robustly associated with breastfeeding, which could be used as instrumental variables to strengthen causal inferences through the Mendelian randomization design.
The present project aims at investigating biological mechanisms underlying breastfeeding health effects by studying the FADS2-breastfeeding interaction and additional genetic, epigenetic and metabolic aspects of breastfeeding.