Abstract
Many complex traits or diseases, such as infectious and autoimmune diseases, cancer, xenobiotics exposure, neurodevelopmental and neurodegenerative diseases, as well as the outcome of vaccination, show a differential susceptibility between males and females. In general, the female immune system responds more efficiently to pathogens. However, this can lead to over-reactive immune responses, which may explain the higher presence of autoimmune diseases in women, but also potentially the more adverse effects of vaccination in females compared with in males. Many clinical and epidemiological studies reported, for the SARS-CoV-2 infection, a gender-biased differential response; however, the majority of reports dealt with a comparable morbidity, with males, however, showing higher COVID-19 adverse outcomes. Although gender differences in immune responses have been studied predominantly within the context of sex hormone effects, some other mechanisms have been invoked: cellular mosaicism, skewed X chromosome inactivation, genes escaping X chromosome inactivation, and miRNAs encoded on the X chromosome. The hormonal hypothesis as well as other mechanisms will be examined and discussed in the light of the most recent epigenetic findings in the field, as the concept that epigenetics is the unifying mechanism in explaining gender-specific differences is increasingly emerging.
Highlights
In humans, many complex traits or diseases have an altered sex ratio, where, by complex trait/disease, we mean a phenotype that is typically due to the interaction between genetic and environmental factors.In determining gender, many factors are involved, such as culture, ethnicity, socio economic background, religion, and many others [1], the composition of gonosomes
One aspect that is related to the gender difference arises from the observation that, generally, women are more resistant to infections than men for several reasons, in addition to the abovementioned decrease in sex hormones and different immune response, due to their life style, as men typically smoke and drink more than women, while the latter have a greater aptitude with respect to men to take precautionary measures toward the COVID-19 pandemic, such as frequent hand washing, wearing of face mask, and stay at home orders [61]
An increasing number of literature studies have reported that epigenetic dysregulation plays an important role in complex human traits/diseases and, in a considerable part of them, gender differences have been reported
Summary
Many complex traits or diseases have an altered sex ratio, where, by complex trait/disease, we mean a phenotype that is typically due to the interaction between genetic and environmental factors. Gender can be considered an environmental factor (intrinsic) of susceptibility as well as age or environmental exposures, able to interfere with the risk of many complex diseases. It is important toperiod underline thebut effect of the on incisive the epigenome does not concern only the afterthat birth is able toenvironment influence in an way the not concern only the period after birth but is able to influence in an incisive way the development in utero. Alterations of these epigenetic mechanisms and of their molecular development utero. An increasing numnumber of studies suggest that epigenetic modifications contribute to the developber of studies suggest that epigenetic modifications contribute to the development of ment of most of the complex diseases with adult onset, including behavioral pathologies, Biomedicines 2021, 9, 652 neurodevelopmental disorders, and autoimmune, metabolic, vascular, and neurodegenerative diseases
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