Joint effects of maternal metabolic conditions and plasma branched-chain amino acids on child risk of autism spectrum disorders (ASD): Evidence of sex difference
Embargo until
2020-08-01
Date
2019-06-26
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Johns Hopkins University
Abstract
Background: Maternal obesity and diabetes are known risk factors for the development of child autism spectrum disorder (ASD). The association of other maternal metabolic disorders with ASD have been much less studied. Elevated branched-chain amino acids (BCAAs) are also associated with metabolic disorders and lower BCAAs have been linked to ASD. This dissertation sought to explore the role of maternal plasma BCAAs in the pathway from maternal metabolic disorders to child ASD and whether the associations differed by child’s.
Methods: This study leveraged the Boston Birth Cohort (BBC), an ongoing prospective cohort study in the Boston area representing a predominantly urban, low-income, minority population. Of over 3,000 mother-infant pairs from the BBC prospectively from birth since 2004, this dissertation analyzed 864 with pertinent data. Maternal lipids were measured using standard clinical methods, and targeted BCAA metabolites were quantitatively profiled using liquid chromatography-tandem mass spectrometry (LC-MS/MS), using plasma samples collected 24-72 hours postpartum. A composite BCAA score was created using factor analysis and dichotomized at the median. Maternal obesity and diabetes were combined into one binary variable (ob/DM), and cholesterol subtypes were dichotomized using clinical cut-points. A multiple maternal metabolic disorders score was developed and dichotomized into (MMD<3 vs. 3). Logistic regression was used to explore the association between maternal BCAAs and child ASD risk and the potential role of BCAAs as mediators. Joint effects between BCAAs and maternal metabolic conditions (ob/DM (n=864), low high-density lipoprotein cholesterol (HDL-C) (n=829), and multiple metabolic disorders (MMD) (n=829)) as well as child’s sex were also explored for both ASD and other developmental disorders. Lastly, joint associations between all three risk factors – BCAAs, maternal metabolic conditions, and child’s sex – were examined.
Results: While maternal BCAAs alone were not associated with child risk of ASD and did not mediate the association between maternal metabolic disorders and ASD, they were jointly associated with maternal ob/DM on child ASD risk (adjusted BCAA score OR 2.35, 95% CI 1.21, 4.55). While maternal HDL-C alone was not associated with child ASD risk, HDL-C and child’s sex had a joint effect on this risk. Among mothers with low HDL-C, elevated BCAA score was associated with higher risk of child ASD (OR 4.67, 95% CI 1.33, 16.36; pinteraction=0.006). Maternal MMD and above median BCAA score synergistically increased the risk of ASD (adjusted OR: 3.20, 95% CI: 1.65-6.18; pinteraction= 0.019). Finally, the risk of ASD was the greatest among male children with mothers with elevated BCAAs and metabolic disorder(s) compared to other groups.
Conclusions: Maternal metabolic disorders had joint effects with elevated maternal plasma BCAAs and with male sex on child risk of ASD, and the risk was greatest among children with all three risk factors. These findings, raise the prospect of early risk assessment and primary prevention of ASD.
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Keywords
autism spectrum disorder, obesity, diabetes mellitus, dyslipidemia, metabolic syndrome, pre- and perinatal risk factors, sex differences, branched-chain amino acids, metabolomics