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Abstract
Gender differences in susceptibility to complex disease such as asthma, diabetes, lupus, autism and major depression, among numerous other disorders, represent one of the hallmarks of non‐Mendelian biology. It has been generally accepted that endocrinological differences are involved in the sexual dimorphism of complex disease; however, specific molecular mechanisms of such hormonal effects have not been elucidated yet. This paper will review evidence that sex hormone action may be mediated via gene‐specific epigenetic modifications of DNA and histones. The epigenetic modifications can explain sex effects at DNA sequence polymorphisms and haplotypes identified in gender‐stratified genetic linkage and association studies. Hormone‐induced DNA methylation and histone modification changes at specific gene regulatory regions may increase or reduce the risk of a disease. The epigenetic interpretation of sexual dimorphism fits well into the epigenetic theory of complex disease, which argues for the primary pathogenic role of inherited and/or acquired epigenetic misregulation rather than DNA sequence variation. The new experimental strategies, especially the high throughput microarray‐based epigenetic profiling, can be used for testing the epigenetic hypothesis of gender effects in complex diseases.
Acknowledgements
This research has been supported by the Ontario Mental Health Foundation, Canadian Institutes for Health and Research, National Institute of Mental Health (R01 MH074127‐01), as well as NARSAD and the Stanley Foundation. Zachary Kaminsky is a CIHR Doctoral Fellow. Special thanks to Sigrid Ziegler for her critical reading of the manuscript.