" 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

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

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.

Keywords: OMICs; complex diseases; gender medicine; genetics/molecular biomarkers; personalized medicine; pharmacogenetics; sex disparities; sexomics and genderomics; tailored drug therapy.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Modified from Global Health Estimated 2016 (www.who.int/healthinfo/global_burden_disease/en/). d.: disease; PD: Parkinson’s disease; Haemorr.: Haemorrhagic; CVD: Cardiovascular Disease; def.: deficiency; circ.: circulatory; neurol.: neurological; MS: Multiple Sclerosis; AD: Alzheimer’s Disease; Musculosk.: musculoskeletal.
Figure 2
Figure 2
Extreme clinical phenotypes and prognosis in male and female AMI patients. The increased AMI risk in males is balanced by a better prognosis, resulting in enhanced AMI outcome. Conversely, the reduced AMI risk in females is characterized by a worst prognosis, resulting in a poor AMI outcome.
Figure 3
Figure 3
Schematic picture showing key examples of sex and gender disparities in cancer.
Figure 4
Figure 4
Factors concurring to different MS risk in females with respect to males. Genetics (e.g., HLA-DRB1*1501 allele), epigenetics (e.g., TLR7, CD40L, FoxP3), environment (e.g., smoking and Vitamin D deficiency) and sex hormones (e.g., oestradiol, progesterone, oestradiol and testosterone).
Figure 5
Figure 5
Snapshot of key risk factors for the development of AD and other types of dementia.
Figure 6
Figure 6
Different actors and effects on bone formation/resorption balance according to different sexes. BMU: Basic Multicellular Unit; OPG: Osteoprotegerin; MHT: Menopausal Hormone Therapy; RANKL: Receptor activator of nuclear factor kappa-Β ligand; RANK: Receptor activator of nuclear factor kappa-Β.
Figure 7
Figure 7
Hypothesis of various cellular mechanisms involving pain transmission in females and males.
Figure 8
Figure 8
Proposed sex-omics/gender-omics strategy for research and clinical approach to diseases.

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