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Gender Medicine: Pharmacogenetics and Personalised Medicine

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (30 April 2020) | Viewed by 76133

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Special Issue Editors

Prof. Dr. Donato Gemmati

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Associate Professor in Medical Genetics, Section of Medical Biochemistry, Molecular Biology & Genetics, Dpt. of Biomedical and Specialty Surgical Sciences, University of Ferrara, I-44100 Ferrara, Italy
Interests: pharmacogenetics/genomics, precision medicine and gender medicine in inherited thrombophilia and cardiovascular disease; coagulation and inherited bleeding disorders; SNPs in iron homeostasis and folate pathways; genetics of wound healing; childhood haematological malignancies
Special Issues, Collections and Topics in MDPI journals

Dr. Veronica Tisato

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Department of Morphology, Surgery & Experimental Medicine and LTTA Centre, University of Ferrara, 44121 Ferrara, Italy
Interests: translational research; gender medicine; regenerative medicine; personalized and precision medicine; focus on inflammation and biomarkers in cardiovascular and complex diseases; aging; neurodegenerative/cognitive impairment diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In the era of individualized and precision medicine, where pharmacogenetics and genomics have key roles, Gender Medicine should be considered an essential step for Personalised Medicine. Patient-centered care defines the third millennium health-care goal. The role of both sex and gender in physiological and pathophysiological processes of diseases is becoming crucial in terms of efficient prevention, clinical signs identification, prognosis, therapies optimisation, as well as in terms of social-psychological and cost-effective impact. Accordingly, viewing patients through a sex and gender lens is a novel and promising approach. Personalized healthcare must be based on evidence derived from targeted research studies aimed at understanding how different sex and hormonal status influence health across the life-span. To understand the genetic, molecular and biochemical bases of the existing “gap” among patients will pave the way to discovering and identifying novel drug-targets and designing new therapeutic protocols together with personalized laboratory tests. A modern project to successfully integrate gender and sex differences and precision medicine should include gender and sex specific oriented researches.
In this Special Issue, we focus on how gender-oriented precision medicine can be translated from bench to bedside. We welcome original papers and review articles that focus on the latest advances on the molecular research of gender medicine. Gender medicine in different disciplines including cardiology, endocrinology, pharmacology, oncology, dermatology, infection disease, geriatrics and aging, gastroenterology, and neurology are welcome.

Prof. Dr. Donato Gemmati
Prof. Veronica Tisato
Guest Editor

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Keywords

Sex and Gender
Genetics, genomics, and epigenetic studies
Proteomic profiling
“RNAs” profiles to predict prognosis and outcome
Biochemistry and molecular biology
Sex-specific disease biomarkers
Methylation profiles to predict prognosis and outcome
Drug response and resistance
Regenerative medicine
Hormone profiles and inflammation
Complex/multifactorial diseases

Published Papers (12 papers)

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13 pages, 927 KiB

Open AccessArticle

Sex Differences in Proatherogenic Cytokine Levels

by Stella Bernardi, Barbara Toffoli, Federica Tonon, Morena Francica, Elena Campagnolo, Tommaso Ferretti, Sarah Comar, Fabiola Giudici, Elisabetta Stenner and Bruno Fabris

Int. J. Mol. Sci. 2020, 21(11), 3861; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21113861 - 29 May 2020

Cited by 34 | Viewed by 3330

Abstract

Background: It has been shown that sex affects immunity, including cytokine production. Given that atherosclerosis is an inflammatory disease promoted by specific cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, we aimed at evaluating whether sex could affect the levels of these proatherogenic cytokines in a group of healthy adults. In this analysis, we also included other cytokines and peptides that have been implicated in atherosclerosis development and progression. Methods: A total of 104 healthy adults were recruited; we measured circulating levels of IL-1β, IL-6, TNF-α, angiotensins and angiotensin-converting enzyme-2 (ACE2), as well as osteoprotegerin and receptor activator of nuclear factor κB ligand (RANKL). Results: IL-1β, IL-6, and TNF-α were significantly higher in men as compared to women. They were all associated with testosterone and the testosterone/estradiol ratio. They remained significantly associated with sex (but not with hormones) after being tested for potential confounders. Conclusions: Sex seems to influence the levels of proatherogenic cytokines. This is consistent not only with sex differences in vulnerability to infections but also with the higher cardiovascular risk exhibited by the male gender as compared to the female gender. Nevertheless, this association is only partly explained by hormone levels. Full article

(This article belongs to the Special Issue Gender Medicine: Pharmacogenetics and Personalised Medicine)

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17 pages, 4242 KiB

Open AccessArticle

Influence of Sex on Urinary Organic Acids: A Cross-Sectional Study in Children

by Marianna Caterino, Margherita Ruoppolo, Guglielmo Rosario Domenico Villani, Emanuela Marchese, Michele Costanzo, Giovanni Sotgiu, Simone Dore, Flavia Franconi and Ilaria Campesi

Int. J. Mol. Sci. 2020, 21(2), 582; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21020582 - 16 Jan 2020

Cited by 33 | Viewed by 3978

Abstract

The characterization of urinary metabolome, which provides a fingerprint for each individual, is an important step to reach personalized medicine. It is influenced by exogenous and endogenous factors; among them, we investigated sex influences on 72 organic acids measured through GC-MS analysis in the urine of 291 children (152 males; 139 females) aging 1–36 months and stratified in four groups of age. Among the 72 urinary metabolites, in all age groups, 4-hydroxy-butirate and homogentisate are found only in males, whereas 3-hydroxy-dodecanoate, methylcitrate, and phenylacetate are found only in females. Sex differences are still present after age stratification being more numerous during the first 6 months of life. The most relevant sex differences involve the mitochondria homeostasis. In females, citrate cycle, glyoxylate and dicarboxylate metabolism, alanine, aspartate, glutamate, and butanoate metabolism had the highest impact. In males, urinary organic acids were involved in phenylalanine metabolism, citrate cycle, alanine, aspartate and glutamate metabolism, butanoate metabolism, and glyoxylate and dicarboxylate metabolism. In addition, age specifically affected metabolic pathways, the phenylalanine metabolism pathway being affected by age only in males. Relevantly, the age-influenced ranking of metabolic pathways varied in the two sexes. In conclusion, sex deeply influences both quantitatively and qualitatively urinary organic acids levels, the effect of sex being age dependent. Importantly, the sex effects depend on the single organic acid; thus, in some cases the urinary organic acid reference values should be stratified according the sex and age. Full article

(This article belongs to the Special Issue Gender Medicine: Pharmacogenetics and Personalised Medicine)

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16 pages, 3478 KiB

Open AccessArticle

Glucocorticoids Equally Stimulate Epithelial Na⁺ Transport in Male and Female Fetal Alveolar Cells

by Mandy Laube, Diana Riedel, Benjamin Ackermann, Melanie Haase and Ulrich H. Thome

Int. J. Mol. Sci. 2020, 21(1), 57; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21010057 - 20 Dec 2019

Cited by 7 | Viewed by 2513

Abstract

Preterm infants frequently suffer from respiratory distress syndrome (RDS), possibly due to lower expression of epithelial Na⁺ channels (ENaC). RDS incidence is sex-specific, affecting males almost twice as often. Despite the use of antenatal glucocorticoids (GCs), the sex difference persists. It is still controversial whether both sexes benefit equally from GCs. We previously showed that Na⁺ transport is higher in female compared with male fetal distal lung epithelial (FDLE) cells. Since GCs increase Na⁺ transport, we hypothesized that their stimulating effect might be sex-specific. We analyzed FDLE cells with Ussing chambers and RT-qPCR in the presence or absence of fetal serum. In serum-free medium, GCs increased the ENaC activity and mRNA expression, independent of sex. In contrast, GCs did not increase the Na⁺ transport in serum-supplemented media and abolished the otherwise observed sex difference. Inhibition of the GC receptor in the presence of serum did not equalize Na⁺ transport between male and female cells. The GC-induced surfactant protein mRNA expression was concentration and sex-specific. In conclusion, female and male FDLE cells exhibit no sex difference in response to GCs with regard to Na⁺ transport, and GR activity does not contribute to the higher Na⁺ transport in females. Full article

(This article belongs to the Special Issue Gender Medicine: Pharmacogenetics and Personalised Medicine)

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11 pages, 438 KiB

Open AccessArticle

Changes in Adipose Tissue Distribution and Association between Uric Acid and Bone Health during Menopause Transition

by Gloria Bonaccorsi, Alessandro Trentini, Pantaleo Greco, Veronica Tisato, Donato Gemmati, Nicoletta Bianchi, Melchiore Giganti, Maurizio Rossini, Giuseppe Guglielmi and Carlo Cervellati

Int. J. Mol. Sci. 2019, 20(24), 6321; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20246321 - 14 Dec 2019

Cited by 8 | Viewed by 4023

Abstract

Despite convincing experimental evidence, epidemiological studies on the effects of serum uric acid (SUA) on bone health are still conflicting since factors influencing SUA bioavailability have not been adequately considered. To shed some light on this issue, we investigated the impact of adiposity and menopause status on the relationship between SUA and bone health. We examined SUA in relation to bone mineral density (BMD) at different skeletal sites and with markers of bone metabolism in 124 pre-menopausal and 234 post-menopausal women and assessed whether adiposity, evaluated by anthropometry and dual x-ray absorptiometry (DXA), might have a discriminant role. After conservative adjustment (covariates: age, hormones treatment, smoking and time since menopause), SUA showed a significant and positive association with total hip BMD (β = 0.220, p < 0.01) among postmenopausal women, maintained also after adjustment for legs adiposity. Notably, stratification for waist circumference quartiles revealed that the correlation between SUA and total hip BMD was significant (r = 0.444, p = 0.001) in the highest quartile (91–100 cm). Our results suggest that SUA might be beneficial for bone health in postmenopausal women being characterized by a more android fat distribution, ascribing to SUA a discriminant role during menopause transition, potentially relevant also for men. Full article

(This article belongs to the Special Issue Gender Medicine: Pharmacogenetics and Personalised Medicine)

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8 pages, 985 KiB

Open AccessCommunication

The Zebrafish (Danio rerio) Is a Relevant Model for Studying Sex-Specific Effects of 17β-Estradiol in the Adult Heart

by Selina Hein, David Hassel and Georgios Kararigas

Int. J. Mol. Sci. 2019, 20(24), 6287; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20246287 - 13 Dec 2019

Cited by 14 | Viewed by 2753

Abstract

Cardiovascular diseases are a major cause of morbidity and mortality, and there are significant sex differences therein. However, the underlying mechanisms are poorly understood. The steroid hormone 17β-estradiol (E2) is thought to play a major role in cardiovascular sex differences and to be protective, but this may not hold true for males. We aimed at assessing whether the zebrafish is an appropriate model for the study of E2 effects in the heart. We hypothesized that E2 regulates the cardiac contractility of adult zebrafish in a sex-specific manner. Male and female zebrafish were treated with vehicle (control) or E2 and the cardiac contractility was measured 0, 4, 7 and 14 days after treatment initiation using echocardiography. There was no significant effect on the heart rate by E2. Notably, there was a significant decrease in the ejection fraction of male zebrafish treated with E2 compared with controls. By contrast, there was no major difference in the ejection fraction between the two female groups. The dramatic effect in male zebrafish occurred as early as 4 days post treatment initiation. Although there was no significant difference in stroke volume and cardiac output between the two male groups, these were significantly higher in female zebrafish treated with E2 compared with controls. Gene expression analysis revealed that the levels of estrogen receptors were comparable among all groups. In conclusion, our data demonstrate that the adult zebrafish heart robustly responds to E2 and this occurs in a sex-specific manner. Given the benefits of using zebrafish as a model, new targets may be identified for the development of novel cardiovascular therapies for male and female patients. This would contribute towards the realization of personalized medicine. Full article

(This article belongs to the Special Issue Gender Medicine: Pharmacogenetics and Personalised Medicine)

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Review

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26 pages, 1444 KiB

Open AccessReview

Sex Specific Determinants in Osteoarthritis: A Systematic Review of Preclinical Studies

by Deyanira Contartese, Matilde Tschon, Monica De Mattei and Milena Fini

Int. J. Mol. Sci. 2020, 21(10), 3696; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103696 - 24 May 2020

Cited by 38 | Viewed by 4064

Abstract

Osteoarthritis (OA) is a highly prevalent joint disease that primarily affects about 10% of the world’s population over 60 years old. The purpose of this study is to systematically review the preclinical studies regarding sex differences in OA, with particular attention to the molecular aspect and gene expression, but also to the histopathological aspects. Three databases (PubMed, Scopus, and Web of Knowledge) were screened for eligible studies. In vitro and in vivo papers written in English, published in the last 11 years (2009–2020) were eligible. Participants were preclinical studies, including cell cultures and animal models of OA, evaluating sex differences. Independent extraction of articles and quality assessments were performed by two authors using predefined data fields and specific tools (Animals in Research Reporting In Vivo Experiments (ARRIVE) guideline and Systematic Review Centre for Laboratory animal Experimentation (SYRCLE) tool). Twenty-three studies were included in the review: 4 in vitro studies, 18 in vivo studies, and 1 both in vitro and in vivo study. From in vitro works, sex differences were found in the gene expression of inflammatory molecules, hormonal receptors, and in responsiveness to hormonal stimulation. In vivo research showed a great heterogeneity of animal models mainly focused on the histopathological aspects rather than on the analysis of sex-related molecular mechanisms. This review highlights that many gaps in knowledge still exist; improvementsin the selection and reporting of animal models, the use of advanced in vitro models, and multiomics analyses might contribute to developing a personalized gender-based medicine. Full article

(This article belongs to the Special Issue Gender Medicine: Pharmacogenetics and Personalised Medicine)

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17 pages, 727 KiB

Open AccessReview

Genetics and Sex in the Pathogenesis of Amyotrophic Lateral Sclerosis (ALS): Is There a Link?

by Francesca Trojsi, Giulia D’Alvano, Simona Bonavita and Gioacchino Tedeschi

Int. J. Mol. Sci. 2020, 21(10), 3647; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103647 - 21 May 2020

Cited by 37 | Viewed by 5956

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no known cure. Approximately 90% of ALS cases are sporadic, although multiple genetic risk factors have been recently revealed also in sporadic ALS (SALS). The pathological expansion of a hexanucleotide repeat in chromosome 9 open reading frame 72 (C9orf72) is the most common genetic mutation identified in familial ALS, detected also in 5–10% of SALS patients. C9orf72-related ALS phenotype appears to be dependent on several modifiers, including demographic factors. Sex has been reported as an independent factor influencing ALS development, with men found to be more susceptible than women. Exposure to both female and male sex hormones have been shown to influence disease risk or progression. Moreover, interplay between genetics and sex has been widely investigated in ALS preclinical models and in large populations of ALS patients carrying C9orf72 repeat expansion. In light of the current need for reclassifying ALS patients into pathologically homogenous subgroups potentially responsive to targeted personalized therapies, we aimed to review the recent literature on the role of genetics and sex as both independent and synergic factors, in the pathophysiology, clinical presentation, and prognosis of ALS. Sex-dependent outcomes may lead to optimizing clinical trials for developing patient-specific therapies for ALS. Full article

(This article belongs to the Special Issue Gender Medicine: Pharmacogenetics and Personalised Medicine)

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13 pages, 284 KiB

Open AccessReview

by Mariangela Mancini, Marialaura Righetto and Giovannella Baggio

Int. J. Mol. Sci. 2020, 21(9), 3378; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21093378 - 10 May 2020

Cited by 28 | Viewed by 3888

Abstract

Men are more frequently diagnosed with kidney cancer than women, with a more aggressive histology, larger tumors, a higher grade and stage, and worse oncological outcomes. Smoking habits and sex steroid hormones seem to have a possible role in explaining these gender disparities. Moreover, the expression of genes involved in tumor growth and immune response in kidney cancer varies between men and women, having an impact on the gender-related response to oncological therapy, such as anti-angiogenic drugs and immunotherapy. Recent advances have been made in our understanding of the molecular and genetic mechanisms involved in kidney cancer, which could partially explain the gender differences, and they are summarized in this paper. However, other key mechanisms, which fully clarify the striking clinical gender-related differences observed in kidney cancer, are not completely understood at present. We reviewed and summarized the most relevant publications about the relationship between gender and kidney cancer. Efforts should be made to progress in bench and clinical research on gender-related signatures and disparities, and their impact on the clinical management of kidney cancer. Full article

(This article belongs to the Special Issue Gender Medicine: Pharmacogenetics and Personalised Medicine)

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17 pages, 1128 KiB

Open AccessReview

Sex and Gender Aspects for Patient Stratification in Allergy Prevention and Treatment

by Massimo De Martinis, Maria Maddalena Sirufo, Mariano Suppa, Daniela Di Silvestre and Lia Ginaldi

Int. J. Mol. Sci. 2020, 21(4), 1535; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21041535 - 24 Feb 2020

Cited by 51 | Viewed by 9815

Abstract

Allergies are rapidly worsening in recent decades, representing the most common immunological diseases. The mechanism of disorders such as asthma, rhinocongiuntivitis, urticaria, atopic dermatitis, food and drug allergies, and anaphylaxis still remain unclear and consequently treatments is mostly still symptomatic and aspecific while developments of new therapies are limited. A growing amount of data in the literature shows us how the prevalence of allergic diseases is different in both sexes and its changes over the course of life. Genes, hormones, environmental and immunological factors affect sex disparities associated with the development and control of allergic diseases, while they more rarely are considered and reported regarding their differences related to social, psychological, cultural, economic, and employment aspects. This review describes the available knowledge on the role of sex and gender in allergies in an attempt to improve the indispensable gender perspective whose potential is still underestimated while it represents a significant turning point in research and the clinic. It will offer insights to stimulate exploration of the many aspects still unknown in this relationship that could ameliorate the preventive, diagnostic, and therapeutic strategies in allergic diseases. Full article

(This article belongs to the Special Issue Gender Medicine: Pharmacogenetics and Personalised Medicine)

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16 pages, 2063 KiB

Open AccessReview

Sex/Gender-Specific Imbalance in CVD: Could Physical Activity Help to Improve Clinical Outcome Targeting CVD Molecular Mechanisms in Women?

by Mauro Vaccarezza, Veronica Papa, Daniela Milani, Arianna Gonelli, Paola Secchiero, Giorgio Zauli, Donato Gemmati and Veronica Tisato

Int. J. Mol. Sci. 2020, 21(4), 1477; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21041477 - 21 Feb 2020

Cited by 24 | Viewed by 5172

Abstract

In the last two decades, new insights have been gained regarding sex/gender-related differences in cardiovascular disease (CVD). CVD represents the leading cause of death worldwide in both men and women, accounting for at least one-third of all deaths in women and half of deaths in women over 50 years in developing countries. Important sex-related differences in prevalence, presentation, management, and outcomes of different CVDs have been recently discovered, demonstrating sex/gender-specific pathophysiologic features in the presentation and prognosis of CVD in men and women. A large amount of evidence has highlighted the role of sex hormones in protecting women from CVDs, providing an advantage over men that is lost when women reach the menopause stage. This hormonal-dependent shift of sex-related CVD risk consequently affects the overall CVD epidemiology, particularly in light of the increasing trend of population aging. The benefits of physical activity have been recognized for a long time as a powerful preventive approach for both CVD prevention and aging-related morbidity control. Exercise training is indeed a potent physiological stimulus, which reduces primary and secondary cardiovascular events. However, the underlying mechanisms of these positive effects, including from a sex/gender perspective, still need to be fully elucidated. The aim of this work is to provide a review of the evidence linking sex/gender-related differences in CVD, including sex/gender-specific molecular mediators, to explore whether sex- and gender-tailored physical activity may be used as an effective tool to prevent CVD and improve clinical outcomes in women. Full article

(This article belongs to the Special Issue Gender Medicine: Pharmacogenetics and Personalised Medicine)

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36 pages, 5006 KiB

Open AccessReview

“Bridging the Gap” Everything that Could Have Been Avoided If We Had Applied Gender Medicine, Pharmacogenetics and Personalized Medicine in the Gender-Omics and Sex-Omics Era

by Donato Gemmati, Katia Varani, Barbara Bramanti, Roberta Piva, Gloria Bonaccorsi, Alessandro Trentini, Maria Cristina Manfrinato, Veronica Tisato, Alessandra Carè and Tiziana Bellini

Int. J. Mol. Sci. 2020, 21(1), 296; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21010296 - 31 Dec 2019

Cited by 67 | Viewed by 8852

Abstract

Gender medicine is the first step of personalized medicine and patient-centred care, an essential development to achieve the standard goal of a holistic approach to patients and diseases. By addressing the interrelation and integration of biological markers (i.e., sex) with indicators of psychological/cultural behaviour (i.e., gender), gender medicine represents the crucial assumption for achieving the personalized health-care required in the third millennium. However, ‘sex’ and ‘gender’ are often misused as synonyms, leading to frequent misunderstandings in those who are not deeply involved in the field. Overall, we have to face the evidence that biological, genetic, epigenetic, psycho-social, cultural, and environmental factors mutually interact in defining sex/gender differences, and at the same time in establishing potential unwanted sex/gender disparities. Prioritizing the role of sex/gender in physiological and pathological processes is crucial in terms of efficient prevention, clinical signs’ identification, prognosis definition, and therapy optimization. In this regard, the omics-approach has become a powerful tool to identify sex/gender-specific disease markers, with potential benefits also in terms of socio-psychological wellbeing for each individual, and cost-effectiveness for National Healthcare systems. “Being a male or being a female” is indeed important from a health point of view and it is no longer possible to avoid “sex and gender lens” when approaching patients. Accordingly, personalized healthcare must be based on evidence from targeted research studies aimed at understanding how sex and gender influence health across the entire life span. The rapid development of genetic tools in the molecular medicine approaches and their impact in healthcare is an example of highly specialized applications that have moved from specialists to primary care providers (e.g., pharmacogenetic and pharmacogenomic applications in routine medical practice). Gender medicine needs to follow the same path and become an established medical approach. To face the genetic, molecular and pharmacological bases of the existing sex/gender gap by means of omics approaches will pave the way to the discovery and identification of novel drug-targets/therapeutic protocols, personalized laboratory tests and diagnostic procedures (sex/gender-omics). In this scenario, the aim of the present review is not to simply resume the state-of-the-art in the field, rather an opportunity to gain insights into gender medicine, spanning from molecular up to social and psychological stances. The description and critical discussion of some key selected multidisciplinary topics considered as paradigmatic of sex/gender differences and sex/gender inequalities will allow to draft and design strategies useful to fill the existing gap and move forward. Full article

(This article belongs to the Special Issue Gender Medicine: Pharmacogenetics and Personalised Medicine)

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Other

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23 pages, 3403 KiB

Open AccessHypothesis

COVID-19 and Individual Genetic Susceptibility/Receptivity: Role of ACE1/ACE2 Genes, Immunity, Inflammation and Coagulation. Might the Double X-Chromosome in Females Be Protective against SARS-CoV-2 Compared to the Single X-Chromosome in Males?

by Donato Gemmati, Barbara Bramanti, Maria Luisa Serino, Paola Secchiero, Giorgio Zauli and Veronica Tisato

Int. J. Mol. Sci. 2020, 21(10), 3474; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103474 - 14 May 2020

Cited by 269 | Viewed by 20625

Abstract

In December 2019, a novel severe acute respiratory syndrome (SARS) from a new coronavirus (SARS-CoV-2) was recognized in the city of Wuhan, China. Rapidly, it became an epidemic in China and has now spread throughout the world reaching pandemic proportions. High mortality rates characterize SARS-CoV-2 disease (COVID-19), which mainly affects the elderly, causing unrestrained cytokines-storm and subsequent pulmonary shutdown, also suspected micro thromboembolism events. At the present time, no specific and dedicated treatments, nor approved vaccines, are available, though very promising data come from the use of anti-inflammatory, anti-malaria, and anti-coagulant drugs. In addition, it seems that males are more susceptible to SARS-CoV-2 than females, with males 65% more likely to die from the infection than females. Data from the World Health Organization (WHO) and Chinese scientists show that of all cases about 1.7% of women who contract the virus will die compared with 2.8% of men, and data from Hong Kong hospitals state that 32% of male and 15% of female COVID-19 patients required intensive care or died. On the other hand, the long-term fallout of coronavirus may be worse for women than for men due to social and psychosocial reasons. Regardless of sex- or gender-biased data obtained from WHO and those gathered from sometimes controversial scientific journals, some central points should be considered. Firstly, SARS-CoV-2 has a strong interaction with the human ACE2 receptor, which plays an essential role in cell entry together with transmembrane serine protease 2 (TMPRSS2); it is interesting to note that the ACE2 gene lays on the X-chromosome, thus allowing females to be potentially heterozygous and differently assorted compared to men who are definitely hemizygous. Secondly, the higher ACE2 expression rate in females, though controversial, might ascribe them the worst prognosis, in contrast with worldwide epidemiological data. Finally, several genes involved in inflammation are located on the X-chromosome, which also contains high number of immune-related genes responsible for innate and adaptive immune responses to infection. Other genes, out from the RAS-pathway, might directly or indirectly impact on the ACE1/ACE2 balance by influencing its main actors (e.g., ABO locus, SRY, SOX3, ADAM17). Unexpectedly, the higher levels of ACE2 or ACE1/ACE2 rebalancing might improve the outcome of COVID-19 in both sexes by reducing inflammation, thrombosis, and death. Moreover, X-heterozygous females might also activate a mosaic advantage and show more pronounced sex-related differences resulting in a sex dimorphism, further favoring them in counteracting the progression of the SARS-CoV-2 infection. Full article

(This article belongs to the Special Issue Gender Medicine: Pharmacogenetics and Personalised Medicine)

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