Dataset Information

Causal effects of maternal circulating amino acids on offspring birthweight: a Mendelian randomisation study.

ABSTRACT:

Background

Amino acids are key to protein synthesis, energy metabolism, cell signaling and gene expression; however, the contribution of specific maternal amino acids to fetal growth is unclear.

Methods

We explored the effect of maternal circulating amino acids on fetal growth, proxied by birthweight, using two-sample Mendelian randomisation (MR) and summary data from a genome-wide association study (GWAS) of serum amino acids levels (sample 1, n = 86,507) and a maternal GWAS of offspring birthweight in UK Biobank and Early Growth Genetics Consortium, adjusting for fetal genotype effects (sample 2, n = 406,063 with maternal and/or fetal genotype effect estimates). A total of 106 independent single nucleotide polymorphisms robustly associated with 19 amino acids (p < 4.9 × 10^-10) were used as genetic instrumental variables (IV). Wald ratio and inverse variance weighted methods were used in MR main analysis. A series of sensitivity analyses were performed to explore IV assumption violations.

Findings

Our results provide evidence that maternal circulating glutamine (59 g offspring birthweight increase per standard deviation increase in maternal amino acid level, 95% CI: 7, 110) and serine (27 g, 95% CI: 9, 46) raise, while leucine (-59 g, 95% CI: -106, -11) and phenylalanine (-25 g, 95% CI: -47, -4) lower offspring birthweight. These findings are supported by sensitivity analyses.

Interpretation

Our findings strengthen evidence for key roles of maternal circulating amino acids during pregnancy in healthy fetal growth.

Funding

A full list of funding bodies that contributed to this study can be found under Acknowledgments.

SUBMITTER: Zhao J

PROVIDER: S-EPMC9879767 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Publications

Causal effects of maternal circulating amino acids on offspring birthweight: a Mendelian randomisation study.

Zhao Jian J Stewart Isobel D ID Baird Denis D Mason Dan D Wright John J Zheng Jie J Gaunt Tom R TR Evans David M DM Freathy Rachel M RM Langenberg Claudia C Warrington Nicole M NM Lawlor Deborah A DA Borges Maria Carolina MC

EBioMedicine 20230123

<h4>Background</h4>Amino acids are key to protein synthesis, energy metabolism, cell signaling and gene expression; however, the contribution of specific maternal amino acids to fetal growth is unclear.<h4>Methods</h4>We explored the effect of maternal circulating amino acids on fetal growth, proxied by birthweight, using two-sample Mendelian randomisation (MR) and summary data from a genome-wide association study (GWAS) of serum amino acids levels (sample 1, n = 86,507) and a maternal GWAS of o ...[more]

PMID: 36696816

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Project description:BackgroundCirculating levels of amino acids were associated with blood pressure (BP) in observational studies. However, the causation of such associations has been hypothesized but is difficult to prove in human studies. Here, we aimed to use two-sample Mendelian randomization analyses to evaluate the potential causal associations of circulating levels of amino acids with BP and risk of hypertension.MethodsWe generated genetic instruments for circulating levels of nine amino acids by conducting meta-analyses of genome-wide association study (GWAS) in UK Biobank participants with metabolomic data (n = 98,317) and another published metabolomics GWAS (n = 24,925). Data on the associations of the genetic variants with BP and hypertension were obtained in the UK Biobank participants without metabolomic data (n = 286,390). The causal effects were estimated using inverse-variance weighted method.ResultsSignificant evidence consistently supported the causal effects of increased branched-chain amino acids (BCAAs, i.e., leucine, isoleucine, and valine) levels on higher BP and risk of hypertension (all P < 0.006 after Bonferroni correction except for Pleucine-on-diastolicBP = 0.008). For example, per standard deviation higher of genetically predicted isoleucine levels were associated with 2.71 ± 0.78 mmHg higher systolic BP and 1.24 ± 0.34 mmHg higher diastolic BP, as well as with 7% higher risk of hypertension (odds ratio: 1.07, [95% CI: 1.04-1.10]). In addition, per standard deviation higher of genetically predicted glycine level was associated with lower systolic BP (- 0.70 ± 0.17 mmHg, P = 4.04 × 10-5) and a lower risk of hypertension (0.99 [0.98-0.99], P = 6.46 × 10-5). In the reverse direction, genetically predicted higher systolic BP was associated with lower circulating levels of glycine (- 0.025±0.008, P = 0.001).ConclusionsThis study provides evidence for causal impacts of genetically predicted circulating BCAAs and glycine levels on BP. Meanwhile, genetically predicted higher BP was associated with lower glycine levels. Further investigations are warranted to clarify the underlying mechanisms.

Project description:Backgrounds: There is growing evidence linking glutamine levels to the risk of gastrointestinal diseases, yet the presence of a causal relationship remains uncertain. In this study, we employed a Mendelian randomization (MR) approach to investigate potential causal associations between glutamine and colitis, inflammatory bowel disease (IBD), and digestive tumors. Methods: Genetic instrumental variables for glutamine exposure were identified from a genome-wide association study (GWAS) involving 114,751 participants. We pooled statistics from GWAS of gastrointestinal diseases in European populations, encompassing colitis (cases=1193, controls=461,740), IBD (cases=31,665, controls=33,977), Crohn's disease (cases=17,897, controls=33,977), ulcerative colitis (cases=1,239, controls=990), oesophageal cancer (cases=740, controls=372,016), gastric cancer (cases=6,563, controls=195,745), liver cell carcinoma (cases=168, controls=372,016), hepatic bile duct cancer (cases=418, controls=159,201), pancreatic cancer (cases=1,196, controls=475,049), and colon cancer (cases=1,494, controls=461,439). To ensure the validity of our findings, we utilized several analytical approaches including inverse variance weighted, weighted median, weighted mode, MR-Egger, and simple mode method. Results: Using the IVW method, we found that glutamine levels were inversely associated with colon cancer (OR = 0.998; 95% CI: 0.997-1.000; P = 0.027), colitis (OR = 0.998; 95% CI: 0.997-1.000; P = 0.020), and IBD (OR = 0.551; 95% CI: 0.343-0.886; P = 0.014). Subgroup analysis revealed a negative association between glutamine and Crohn's disease (OR = 0.375; 95% CI: 0.253-0.557; P = 1.11E-06), but not with ulcerative colitis (OR = 0.508; 95% CI: 0.163-1.586; P = 0.244). Glutamine levels showed no significant correlation with oesophageal cancer (OR = 1.000; 95% CI: 0.999-1.001; P = 0.566), gastric cancer (OR = 0.966; 95% CI: 0.832-1.121; P = 0.648), liver cell carcinoma (OR = 1.000; 95% CI: 0.999-1.000; P = 0.397), hepatic bile duct cancer (OR = 0.819; 95% CI: 0.499-1.344; P = 0.430), and pancreatic cancer (OR = 1.130; 95% CI: 0.897-1.423; P = 0.301). Sensitivity analyses also supports this finding, affirming the reliability and robustness of our study. Conclusions: This study suggests that blood glutamine levels in European populations may lower the risk of colon cancer, colitis, and IBD, particularly Crohn's disease. Nevertheless, additional research involving a diverse range of ancestries is imperative to corroborate this causal relationship.

Project description:BackgroundIt has been suggested that greater maternal adiposity during pregnancy affects lifelong risk of offspring fatness via intrauterine mechanisms. Our aim was to use Mendelian randomisation (MR) to investigate the causal effect of intrauterine exposure to greater maternal body mass index (BMI) on offspring BMI and fat mass from childhood to early adulthood.Methods and findingsWe used maternal genetic variants as instrumental variables (IVs) to test the causal effect of maternal BMI in pregnancy on offspring fatness (BMI and dual-energy X-ray absorptiometry [DXA] determined fat mass index [FMI]) in a MR approach. This was investigated, with repeat measurements, from ages 7 to 18 in the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 2,521 to 3,720 for different ages). We then sought to replicate findings with results for BMI at age 6 in Generation R (n = 2,337 for replication sample; n = 6,057 for total pooled sample). In confounder-adjusted multivariable regression in ALSPAC, a 1 standard deviation (SD, equivalent of 3.7 kg/m2) increase in maternal BMI was associated with a 0.25 SD (95% CI 0.21-0.29) increase in offspring BMI at age 7, with similar results at later ages and when FMI was used as the outcome. A weighted genetic risk score was generated from 32 genetic variants robustly associated with BMI (minimum F-statistic = 45 in ALSPAC). The MR results using this genetic risk score as an IV in ALSPAC were close to the null at all ages (e.g., 0.04 SD (95% CI -0.21-0.30) at age 7 and 0.03 SD (95% CI -0.26-0.32) at age 18 per SD increase in maternal BMI), which was similar when a 97 variant generic risk score was used in ALSPAC. When findings from age 7 in ALSPAC were meta-analysed with those from age 6 in Generation R, the pooled confounder-adjusted multivariable regression association was 0.22 SD (95% CI 0.19-0.25) per SD increase in maternal BMI and the pooled MR effect (pooling the 97 variant score results from ALSPAC with the 32 variant score results from Generation R) was 0.05 SD (95%CI -0.11-0.21) per SD increase in maternal BMI (p-value for difference between the two results = 0.05). A number of sensitivity analyses exploring violation of the MR results supported our main findings. However, power was limited for some of the sensitivity tests and further studies with relevant data on maternal, offspring, and paternal genotype are required to obtain more precise (and unbiased) causal estimates.ConclusionsOur findings provide little evidence to support a strong causal intrauterine effect of incrementally greater maternal BMI resulting in greater offspring adiposity.

Dataset Information

Causal effects of maternal circulating amino acids on offspring birthweight: a Mendelian randomisation study.

Background

Methods

Findings

Interpretation

Funding

Publications

Causal effects of maternal circulating amino acids on offspring birthweight: a Mendelian randomisation study.

Similar Datasets

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