Cross-genetic determination of maternal and neonatal immune mediators during pregnancy

Abstract

BackgroundThe immune system plays a fundamental role in development during pregnancy and early life. Alterations in circulating maternal and neonatal immune mediators have been associated with pregnancy complications as well as susceptibility to autoimmune and neurodevelopmental conditions in later life. Evidence suggests that the immune system in adults not only responds to environmental stimulation but is also under strong genetic control.MethodsThis is the first genetic study of > 700 mother-infant pairs to analyse the circulating levels of 22 maternal mid-gestational serum-derived and 42 neonatal bloodspot-derived immune mediators (cytokines/chemokines) in the context of maternal and fetal genotype. We first estimated the maternal and fetal genome-wide SNP-based heritability (h2g) for each immune molecule and then performed genome-wide association studies (GWAS) to identify specific loci contributing to individual immune mediators. Finally, we assessed the relationship between genetic immune determinants and ASD outcome.ResultsWe show maternal and neonatal cytokines/chemokines displaying genetic regulation using independent methodologies. We demonstrate that novel fetal loci for immune function independently affect the physiological levels of maternal immune mediators and vice versa. The cross-associated loci are in distinct genomic regions compared with individual-specific immune mediator loci. Finally, we observed an interaction between increased IL-8 levels at birth, autism spectrum disorder (ASD) status, and a specific maternal genotype.ConclusionsOur results suggest that maternal and fetal genetic variation influences the immune system during pregnancy and at birth via distinct mechanisms and that a better understanding of immune factor determinants in early development may shed light on risk factors for developmental disorders.Electronic supplementary materialThe online version of this article (10.1186/s13073-018-0576-8) contains supplementary material, which is available to authorized users.

Neonatal Lead (Pb) Exposure and DNA Methylation Profiles in Dried Bloodspots

“…Bloodspots have been successfully used to determine early life exposures including Vitamin D [ 57 ], perfluorinated chemicals [ 58 ], and endocrine-disrupting chemicals [ 59 ]. Similarly, bloodspots have been used to evaluate outcome measures such as immune function [ 60 , 61 ], thyroid hormones [ 62 ] and insulin concentration [ 63 ]. Epigenome-wide and targeted patterns have also been assessed recently using bloodspots.…”

Early life immunity in the era of systems biology: understanding development and disease

“…Two recent studies describe the first steps towards understanding early life immune system development [ 5 , 6 ]. Olin et al [ 5 ] found that early immune system development followed a stereotypic pattern in pre-term and term children, while Traglia et al [ 6 ] compared maternal and fetal contributors to the early life immune system. Both studies made use of high-throughput technologies to measure multiple factors simultaneously.…”

“…For example, high levels of interleukin (IL)-6, IL-1, IL-8, and tumor necrosis factor (TNF) is predictive of pre-term birth [ 8 ] and type I interferons are essential for host resistance against fetal Zika virus infection in a mouse model [ 9 ]. Traglia et al [ 6 ] focused on the heritability of cytokine and chemokine levels between mothers and infants by conducting the first genome-wide study of immune regulators in infants and mothers simultaneously. Several cytokine and chemokine levels were measured in more than 700 mother–infant pairs and the genome-wide single nucleotide polymorphism-based heritability of each was calculated to find loci that contribute to their levels.…”

“…Seven chemokines had very high levels of heritability, which suggests that there is a strong genetic component to early chemotactic programs in the infant. Traglia et al [ 6 ] identified the PLCL2 locus as being highly associated with several inflammatory cytokines and chemokines that are implicated in the humoral response and B cell receptor signaling (interferon γ, IL-2, chemokine c-c motif ligand 7, chemokine c-x-c motif ligand 9, and chemokine c-c motif ligand 19).…”

“…Maternal genetics contributed substantially to the levels of six cytokines or chemokines in the infant [ 6 ]. Of these, the neonatal level of the cytokine IL-4 was not influenced by fetal genetics but only by maternal heritability.…”