Aims: Compare methylome in normal white blood cells before and after puberty.

Hypothesis: Puberty is accompanied by characteristic changes in the epigenome that mediate greater leukocyte inflammatory responses in the post-pubertal age.

Variables: Normal males and females sampled and tested for DNA methylation at pre- (e.g. ~age 7) and post- pubertal ages (e.g. ~15 +).

The question: Why do children survive when adults do not? One aspect of the puberty transition is extraordinary but neglected: pre-pubertal children show a remarkable resistance to mortality from the same severe infections, sepsis and trauma that are otherwise commonly fatal in post-pubertal individuals (adults). Studying the biology behind resistance and how it is lost in the puberty transition could provide a treasure trove of insights into basic mechanisms and new leads for drugs.

The rationale: Blood leukocytes of children consistently produce less pro-inflammatory, and more anti-inflammatory cytokines than their adult counterparts. The natural resistance of children to mortality from influenza and other infections is lost at puberty, implying a hormonally-mediated (and deleterious) 'reprogramming' of the host response. Our central hypothesis is that a specific epigenetic program in leukocytes mediates the superior resistance of children to mortality.

Analysis plan: Given the overlap with longitudinal modelling of the HM450 ARIES data set, it is proposed that data for this project will be analysed in Bristol under the supervision of Caroline Relton by a visiting researcher from HSPH.