Table 1.

Epigenetic mechanisms and sex bias in various diseases

Disease	Epigenetic mechanism	Affected gene	References
Respiratory diseases
LRTIs	Increased susceptibility and mortality of males, since estrogens regulate lncRNAs, which interact with NOS-3 that enhances macrophage-mediated killing of bacteria		[32]
COVID-19	Increased susceptibility and mortality of males, due to estrogen contribution to viral defense and decreased gene methylation in males	ACE2	[44]
Asthma	Increased incidence in pre-adolescent males and post-adolescent females, due to sex and age-related changes in gene methylation	SIRPD, IFRD1	[55, 56]
COPD	Decreased gene methylation in males	KRT77	[59]
PAH	Increased susceptibility in females, due to estrogen-mediated increase in gene methylation	Ephx2	[60]
Autoimmune diseases
IBD, MS, RA, SLE	Increased susceptibility in females, due to estrogen-mediated control of immune responses, abnormal silencing of X-linked genes and X-linked miRNA expression (miR106A, miR-17-92, miR-18b, miR-223)	IL-1R/2R/3R, IL-13, TLR7, IRAK1, FOXP3, GATA1, CD40L, IL-10, CXCR3	[61]
Gastrointestinal diseases
HCC and liver fibrosis	Increased susceptibility in males due to increased histone methylation in males, causing gene silencing	Cyp, Sult, H19, Igf2, miR675	[91]
Neuropsychiatric diseases
ASD	Increased incidence in males due to: Decreased ASD-related gene methylation and thus increased expression		[93]
	Expression of Y-linked genes escaping inactivation	KDM5C, NLGN4	[94]
MDD	Increased incidence in females, due to increased gene methylation and thus decreased gene expression of anti-MDD genes		[93]
AD	Increased incidence in males due to: Decreased gene inactivation in females	KDM6A, PCDH11X	[98]
	Hypomethylation of genes in males	Aurora kinase C	[103]
	Reduced HDAC2 levels in females		[103]
Cancer
43 cancer types including glioblastoma	Decreased incidence and mortality of some cancer types, e.g., glioblastoma in females due to tumor suppressor genes escaping XCI	CNKSR2, ATRX, DDX3X, KDM6A, KDM5C, MAGEC3	[105]
Breast and ovarian cancer	Increased susceptibility in females due to dysregulation of the Xist RNA expression and repressive marks, causing gene expression imbalances	ATRX	[111]
Stomach and esophageal cancer	Increased susceptibility in females due to gene mutations, hindering interaction with ATM protein kinase to ensure efficient DNA damage response and repair	EP400	[112]