Disease load at conception predicts survival in later epidemics in a historical French-Canadian cohort, suggesting functional epigenetic imprinting

Background: Epigenetic inheritance is a potentially important determinant of health in several mammals. For humans, the existing evidence is weak. We investigate whether disease exposure triggers functional epigenetic inheritance among humans by analyzing siblings who were conceived under different disease loads, and comparing their mortality in later epidemics. Under functional epigenetic inheritance, we expect that those who were conceived under high pathogenic stress load will have relatively low mortality during a later epidemic. Methods: We use data from the Registre de la Population du Québec Ancien, which covers the historical population living in St. Lawrence Valley, Québec, Canada. Children born in 1705-1724 were grouped according to their exposure during conception to the measles 1714-15 epidemic. The 1714-15 epidemic was followed by two mortality crises in 1729-1734 which were caused by measles and smallpox. Using proportional hazard Cox regression models with multivariate adjustment and with fixed-effects approach that compare siblings, we analyze whether mortality in 1729-1734 is affected by exposure to the 1714-15 epidemic. Results: hildren who were conceived during the peak of the measles epidemic of 1714-15 exhibited significantly lower mortality during the 1729-1734 crisis than those who were born before the 1714-15 epidemic (mortality hazard ratio 0.106, p<.05 in multivariate adjusted models; 0.142 p<.1 in sibling comparison models). Conclusion: The results are consistent with the functional epigenetic inheritance mechanism that responds to pathogen stress and suggest that early disease exposure may be protective later in life. Alternative explanations for the mortality patterns are discussed and shown to be problematic.