Background

The extensive growth and development that occurs in utero and childhood marks a sensitive period during which external factors can elicit biological changes which programme an individual’s ability to maintain health or increase risk of later life disease [1,2,3]. Body size, nutrition and socioeconomic position (SEP) at birth and during childhood are commonly studied characteristics which have been strongly linked with later life health [4,5,6,7,8,9].

There are a variety of mechanisms through which these early life factors may impact later life health [2, 4, 7, 10]. Epigenetic regulation is one such mechanism [2, 11]. Epigenetics refers to alterations in gene expression. Epigenetic modifications do not alter the sequence of DNA, but can regulate how that DNA is expressed and ultimately, how the gene functions. Epigenetic modifications include histone modifications and DNA methylation amongst others [12]. These malleable epigenetic signals are essential for development and cell proliferation but can also occur in response to environmental stimuli [13]. Evidence from animal studies and a limited number of human studies suggests that early life exposures can modify several epigenetic signatures in a multitude of genes [11, 14].

Understanding which early life exposures evoke changes in the epigenome, and identifying the genomic regions in which these changes are occurring will support efforts to maintain health and prevent disease in later life. Furthermore, since epigenetic changes are potentially modifiable, a greater understanding of the specific changes induced by early life factors can elucidate potential targets for intervention strategies.

Since this is a relatively new area of research, most evidence examining the epigenetic effect of early life factors have come from animal and exploratory studies incorporating a variety of early life exposures and applying different analytical methods. Although there has been some review of the role of early life factors on the epigenome in humans [15], to the best of our knowledge, there has been no systematic review of the existing literature examining body size, nutrition and social exposures in relation to epigenetic signals. This review will collate human studies examining the impact of these early life exposures on epigenetics measured at the same time or any age subsequent to the exposure.

Aim

The overall aim of the review is to examine the epigenetic effect of the following factors:

  1. i.

    Body size and growth in early life

  2. ii.

    Nutrition during pregnancy and early life

  3. iii.

    Markers of socioeconomic position in early life

Methods/design protocol registration

This study protocol is registered with the PROSPERO database (registration number: CRD42016050193) and has been reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) checklist, included as Additional file 1.

Key terms

For the purposes of this review, early life is defined as the period including prenatal, infancy, early and middle childhood, up to 12 years to capture the pre-adolescence period. Full definitions of each of each key variable used in the review can be found in Table 1.

Table 1 Definitions of key variables included in review
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Eligibility criteria

Papers will be included if they meet the following criteria:

  • Original studies published in peer-reviewed journals

  • Epigenetic markers measured either at the same time or any age subsequent to the early life exposure (i.e. epigenetics can be measures in infancy, childhood, adolescence or adulthood)

  • Current, prospective report or retrospective recall of indicators of body size (see Table 1)

  • Current, prospective report or retrospective recall of nutrition and/or diet (see Table 1)

  • Current, prospective report or retrospective recall SEP (see Table 1)

  • English language

  • Non-clinical samples

We will not include:

  • Studies not meeting inclusion criteria

  • Reviews

  • Studies based on animals

  • Studies only assessing the effect of adulthood exposures on epigenetic markers

  • Studies assessing the effect of epigenetic markers before early life exposures

  • Samples with a specific clinical condition

Search strategy

Using OvidSP as the database interface, a joint electronic search on MEDLINE and Embase will be conducted. The BIOSIS database will be searched using ISI Web of Science. The search will use free-text search terms (Table 2) with truncations to allow for different spellings, proximity operators (‘adj’ in OvidSP, ‘NEAR’ in ISI Web of Science) and joined using Boolean logic (“AND”, “OR”). The reference lists’ of relevant reviews, all included papers and their ISI citation index (via Web of Science) will be searched for studies meeting inclusion criteria. Eligible studies identified will be combined with the electronic search results.

Table 2 Search terms
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Study selection

Results of the searches will be merged and stored in the reference manager, EndNote. All duplicate citations will be removed. All abstracts will be screened for eligibility by two independent researchers (from JM, WW and RH). The full text of all potentially eligible papers will then also be double screened and reasons for their exclusion will be documented. Disagreements about the paper’s eligibility will be resolved through discussion and if necessary, a third reviewer.

Data extraction

Each reviewer will extract the relevant information using the data extraction form (Additional file 2).The following information will be extracted from selected papers: citation details, study details including design, country/region and sample size; participant details including age and sex; and exposure and outcome details, including details on methods used. A free-text box for recording main findings will be used because of the expected heterogeneous methods that will have been used.

Quality assessment

Various tools for assessing the quality of observational studies such as the Downs and Black checklist [16] and Newcastle-Ottawa Scale [17] are available. However, these are not suitable for assessing the quality of epigenetic studies. The following aspects of the paper which may relate to the quality of each study will be extracted and discussed; study design, methods used to measure epigenetics, statistical analysis including adjustment of relevant confounders, recall bias, i.e. prospective or retrospective measures of early life factors and generalisability [18].

Synthesis

Descriptive tables will be used to outline the included studies in the systematic review. Results will be grouped under the following thematic groups: (1) body size in early life; (2) nutrition in early life; 3) SEP in early life. If there is more than one exposure assessed in an individual study, they will be discussed separately where practical. If feasible, the effects of similar epigenetic analyses methods, e.g. epigenome-wide association studies/locus-specific studies and the age at which epigenetic markers were identified will also be grouped within each theme.

Due to the expected diversity in eligible studies, in terms of methods used, a meta-analysis will not be conducted [18]. Therefore, a narrative synthesis will be undertaken. The structure of the narrative synthesis will be based on guidance from Economic and Social Research Council Methods Programme [19]. This will involve preliminary synthesis, exploring relationships between and within studies, with particular focus on sources of heterogeneity in study design and characteristics between studies, and assessing the robustness of the synthesis, i.e. assessing the strength of the evidence given the methodological quality and generalisability of included papers [18, 19].

Reporting

The findings of this systematic review will be reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) guidelines [20].

Discussion

This study will systematically review the literature examining the effect of body size and growth, nutrition and socioeconomic position in early life on the epigenome. The relationship between different early life exposures and epigenetics as well as other sources of between-study heterogeneity will be explored. The strengths and limitations, and therefore potential for bias, of individual studies will be considered. Since this is a relatively new field, we anticipate that there will be a small number of studies and considerable between-study heterogeneity in terms of study design and characteristics. In addition to collating existing evidence of the effects of early life on the epigenome, this review will form a significant component of a wider research study examining epigenetic responses to exposures in early life and over the life course and its impact on healthy ageing.