Gender Specific Differences in Disease Susceptibility: The Role of Epigenetics

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.

Immunochromatographic and microscopic detection of Plasmodium falciparum in recipients of P. falciparum-infected donor blood

“…Though, post-transfusion parasitemia did not statistically associate with these variables. In contrast to the findings in this study, males have been reported to be more susceptible to infectious diseases than females (Klein 2000 ; Altamimi et al 2020 ; Bunders and Altfeld 2020 ; Migliore et al 2021 ). The only attributable reason to this observation of the high incidence of P. falciparum infection in female blood recipients was that disproportionately more female blood recipients than male blood recipients were encountered during the study.…”

Sex Dimorphic Responses of the Hypothalamus-Pituitary-Thyroid Axis to Energy Demands and Stress

“…These pathologies are part of the autoimmune thyroid disorders that show changes in methylation of several genes, gene polymorphisms and also miRNAs identified either specific for each disease or common to both ( 89 ). However, the high preponderance in women of this diseases and in many other autoimmune ones, as well as in experimental animal models, support that the sexual dimorphism in normal and abnormal immune responses could be due to epigenetic alterations in X chromosome ( Box 1 ) which codes for many genes of in the immune system ( 83 , 98 , 99 ). Common features among several autoimmune diseases involve incomplete inactivation of some genes in the X chromosome (XCI), or asymmetric inactivation of X chromosome (skewed XCI) where 75-80 or over 95% of one parent’s chromosome is inactivated ( 98 , 99 ).…”

“…However, the high preponderance in women of this diseases and in many other autoimmune ones, as well as in experimental animal models, support that the sexual dimorphism in normal and abnormal immune responses could be due to epigenetic alterations in X chromosome ( Box 1 ) which codes for many genes of in the immune system ( 83 , 98 , 99 ). Common features among several autoimmune diseases involve incomplete inactivation of some genes in the X chromosome (XCI), or asymmetric inactivation of X chromosome (skewed XCI) where 75-80 or over 95% of one parent’s chromosome is inactivated ( 98 , 99 ). Analyses of 309 GD and 490 HT female subjects together with meta-analyses of previous reports confirm the increased XCI skewing and extreme skewing in female subjects with GD and HT respectively ( 100 ).…”

Sex, Allergic Diseases and Omalizumab

“…Scleroderma, multiple sclerosis, rheumatoid arthritis and asthma, in particular, reflect these gender differences [ 25 , 26 , 27 , 28 , 29 , 30 ]. The incidence and course of systemic lupus erythematosus (SLE) differ between the sexes, with a nine-fold higher incidence in women linked to the influence of estrogen on epigenetic, immune and genetic factors (X-linked genes such as Foxp3, TNF and Tlr7) [ 31 , 32 ]. Hashimoto’s thyroiditis, Graves’ disease, myasthenia gravis, multiple sclerosis and Sjögren’s syndrome are also prevalent in women compared to men [ 33 , 34 , 35 , 36 , 37 ].…”