In a recent study published within the eBioMedicine, researchers examined the effect of serum levels of 20 amino acids in a mother while pregnant on offspring birthweight in a two-sample summary data Mendelian randomization (MR) framework.

Study: Causal effects of maternal circulating amino acids on offspring birthweight: a Mendelian randomisation study. Image Credit: SciePro/Shutterstock

Background

Studies have estimated that adequate fetal growth requires between 10 and 60 grams (g)/day per kilogram (kg) fetus weight of amino acids. In vivo studies in humans have shown that amino acids are essential for protein synthesis and the modulation of multiple cell signaling pathways.

For the reason that interactions between maternal, placental, and fetal mechanisms are complex, there isn’t any insight into how the fetus receives different amino acids from the mother. Furthermore, data are scarce from human studies on how maternal amino acids influence fetal growth and development. All previous studies have fetched inconsistent results of amino acid supplementation in high-risk pregnancies.

It’s also noteworthy that previous studies have found that branched-chain amino acids (BCCAs), including valine, leucine, and isoleucine, cross the placenta more rapidly using sodium-independent L system, and their high concentrations in maternal serum result in the next risk of intrauterine growth-restricted pregnancies. Previous studies have used the MR approach to substantiate the causal effect of maternal smoking while pregnant on slower fetal growth.

Concerning the study

In the current MR study, researchers used maternal single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) to infer the cause-and-effect relationship between genetically influenced intrauterine exposures (on this case, maternal circulating amino acids) and offspring birthweight.

They used data from recent metabolites and offspring birthweight genome-wide association studies (GWAS) encompassing as much as 86,507 and 406,063 participants, respectively. Further, the study dataset comprised 20 amino acids that make proteins within the human body. Examples include glutamate, glutamine, leucine, and serine.

The team used the weighted linear model adjusted (WLM-adjusted) analyses, an approximation of the structural equation modeling (SEM) approach developed by Warrington et al., to regulate for offspring genetic effects within the summary data used to guage the association of maternal genetic variants on offspring birthweight. Likewise, they estimated associations between genetic variants and amino acids.

The researchers chosen maternal SNPs strongly correlated with 20 different circulating amino acids from these GWASs validated in 2966 pregnant women enrolled within the Born in Bradford (BiB) study and 4407 women within the Fenland study.

Within the BiB study, they measured amino acids as a part of a nuclear magnetic resonance (NMR) metabolomics evaluation at 24 to twenty-eight weeks of gestation. It yielded data for nine amino acids in 2966 European women. Further, they chose SNPs from one other GWAS conducted amongst ladies and men.

Next, the team natural log-transformed amino acid levels, winsorized at five standard deviations (SDs) and transformed to Z scores, then adjusted for maternal age and top 10 principal components (PCs) from genomic data, e.g., minor allele frequency (MAF). Then, they regressed each resulting residual against the corresponding SNP utilized in the first MR evaluation. This exercise yielded 89 SNP-amino acid associations.

Results

The study results suggested that while maternal serum glutamine and serine levels positively affected offspring birthweight, leucine, and phenylalanine had a negative effect. Several sensitivity analyses accounting for bias because of violation of MR assumptions also supported these findings, although, for some amino acids, these estimates is likely to be imprecise.

Further, MR analyses suggested that the positive effect of maternal glutamine, a non-essential amino acid that becomes conditionally essential as fetal demand surpasses maternal synthesis, on offspring birthweight is likely to be liver-type isoenzyme dependent, specifically, when instrumented by the missense variant rs2657879 in glutaminase 2 (GLS2).

While the genetic variant rs2657879 had a powerful positive effect, the effect instrumented by rs7587672, an expression quantitative trait loci (eQTL) for GLS, this effect turned inverse. Note that GLS2 encodes the catalyst that helps convert glutamine to ammonia and glutamate within the liver, whereas GLS encodes the kidney-type isozyme.

Throughout the late phase of pregnancy, glycine amino acid supplements one carbon for the synthesis and methylation of deoxyribonucleic acid (DNA) needed for fetal growth. Nonetheless, there’s evidence that glycine supply stays lower than fetal demand due to its inadequate transportation across the human placenta. Thankfully, maternal circulating serine, not transported to the fetal circulation, is then used throughout the uteroplacental tissues to synthesize glycine, thus, contributing to the fetal glycine supply.

The present study findings support the above hypothesis that maternal circulating serine has a causal effect on offspring birthweight while glycine doesn’t. Nonetheless, results based on two SNPs, rs561931 of phosphoglycerate dehydrogenase (PHGDH) and rs4947534 of phosphoserine phosphatase (PSPH), suggested positive effects. Note these two gene loci encode enzymes involved in serine de novo biosynthesis. Further exploration of this interlinked serine and glycine metabolism using multivariable MR is likely to be invaluable if performed using large sample sizes.

Studies have proposed that leucine amino acid modulates fetal muscle protein synthesis through mammalian goal of the rapamycin (mTOR) signaling pathway. Accordingly, maternal circulating leucine had an inverse effect on offspring birthweight in the first MR evaluation. In contrast to findings of previous studies, researchers found higher maternal circulating BCAAs had a negative association with offspring birthweight.

Nonetheless, owing to the close link between BCAA metabolism and insulin resistance, there’s a necessity for more MR studies in larger sample sizes to delineate the impact of maternal fasting insulin and BCAAs circulating within the mother’s serum on offspring birthweight. Finally, the first MR evaluation demonstrated an inverse effect of phenylalanine on offspring birthweight, supported by similar though imprecise effect estimates of sensitivity analyses.

Conclusions

To summarize, the study results indicated that genetically predicted levels of glutamine and serine in maternal serum elevate offspring birthweight, while leucine and phenylalanine decrease it.

In keeping with the authors, they used the biggest GWAS available. Yet, they didn’t robustly estimate several potentially significant clinical effects, comparable to, of the alanine amino acid. Thus, they emphasized conducting larger GWAS of amino acids and offspring birthweight to duplicate their findings.

As well as, future studies should explore mechanisms underlying these effects, especially how amino acids get transferred across the placenta and the role of fetal genotypes in placental transmission. Most significantly, randomized controlled trials should establish whether supplementing maternal circulating amino acids while pregnant could help optimize fetal growth.