Determinants of placental leptin receptor gene expression and association with measures at birth
Introduction
Obesity is a major global health issue, and a key modifiable risk factor for cardiovascular and metabolic (cardiometabolic) diseases [1,2]. It is now clear that pathways to obesity and associated disease begin very early in life [3,4] and understanding their determinants is imperative to inform intervention strategies; which are more likely to be effective earlier in the life course [5].
The Developmental Origins of Health and Disease paradigm proposes that pregnancy is a critical period of developmental plasticity, and that adverse exposures during this period can induce long term changes in health [6,7]. The placenta plays a vital role in development as it regulates maternal-fetal exchanges [8]. Indeed, epidemiological studies have linked dysregulation of placental function to adverse later life health [9,10].
Leptin is a pro-inflammatory adipokine that functions as a hormone regulating energy homeostasis and fat storage [11]. It is also important in pregnancy across different species, where leptin levels increase in the maternal circulations [12]. This is primarily due to increased leptin production by the placenta, although the amount of placental leptin expressed is species-specific [[12], [13], [14]]. Leptin binds to the leptin receptor [12]. Previous studies have identified single nucleotide polymorphisms (SNPs) in the leptin receptor gene, LEPR, associated with obesity [[15], [16], [17], [18]] and inflammation in adults [[19], [20], [21], [22]]. Several recent studies have also identified expression quantitative trait loci (eQTLs) in the placenta [23,24], including one in LEPR [23]. However, previous studies have used a relatively small number of placental samples and as such this eQTL is yet to be validated. Additionally, few studies have examined the link between placental LEPR expression and early life phenotypes [25,26].
We therefore investigated the associations between genotype at SNPs in LEPR, maternal in utero factors and placental LEPR expression in healthy infants from the Barwon Infant Study (BIS). We then examined whether placental LEPR expression was associated with anthropometric and inflammatory measures at birth.
Section snippets
Study population and ethics
We analyzed data and samples from participants in the Barwon Infant Study (BIS), a population-derived, longitudinal pregnancy cohort study of 1074 mother and infant pairs established in Victoria, Australia. A detailed description of the cohort has been published previously [27]. Briefly, pregnant women were recruited during antenatal appointments at approximately 15 weeks of pregnancy between 2010 and 2013. Women were invited to participate if they resided within the Barwon region, were
Study population characteristics and placental LEPR expression
Of the 1074 BIS participants, 1022 had placenta RNA available. Following data cleaning, expression data was obtained for 854 infants; which were included in subsequent analyses. Characteristics of this study population are summarised in Table 1. Log10 placental LEPR expression in the study population ranged from −0.70 to 0.97 fold change compared to the median expression in the cohort. There was modest evidence that this expression was sex-specific, with lower levels in females (−0.035 [95% CI:
Main findings
Genotype at two intronic LEPR SNPs was associated with LEPR expression levels. However, there was no convincing evidence for an association of the investigated maternal pregnancy factors and expression. Placental LEPR expression was negatively associated with hsCRP in umbilical cord blood but was not associated with birth weight z-score or infant adiposity.
Genetic variation is associated with placental LEPR expression
To date, no previous studies have specifically explored the association between fetal genotype in LEPR and placental LEPR expression.
Conclusion
Overall, our findings indicate that genetic variation in LEPR plays a key role in regulating LEPR expression in the placenta, with potential consequences on leptin signalling and function in early development. These findings should be confirmed in further studies. Future studies should also extend on these findings to elucidate the causal nature of these relationships and potential underlying mechanisms, including examining both expression and epigenetic regulation of LEPR and LEP as well as
Data Availability
The datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.
Contribution to authorship
A.V, R.S and T.M designed the study. A.V performed all experiments and statistical analyses, and wrote the manuscript. T.M extracted RNA from samples, provided assistance with the statistical analyses, performed GWAS analyses, and contributed to the interpretation of the results. B.N contributed to the planning of the experiments and interpretation of the results. D.B, F.C and R.S contributed to the interpretation of the results and manuscript writing. All authors discussed the results and
Declaration of competing interest
The authors have no conflict of interest to disclose.
Acknowledgements
We thank the Barwon Infant Study participants and their families for taking part in the study, as well as the staff who helped recruit and gather data. We also thank QIMR Berghofer Medical Research Institute and the Erasmus MC University Medical Centre for their role in coordinating and performing the genotyping of BIS samples. The establishment work and infrastructure for the BIS was provided by the Murdoch Children's Research Institute, Deakin University and Barwon Health. Subsequent funding
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