Modern humans, taxonomically known as Homo sapiens sapiens, emerged in Africa 200,000 years ago and began the migration out-of-Africa to colonize the globe between 50,000 and 70,000 years ago (1, 2). Studies on human evolutionary history relate that most of the world’s populations have descended from 19 ancestral human ethnic groups (Figures 1A,B) (2, 4). However, the human genome, which is constantly evolving, is a melting pot of past, present, and even future genetic signs of adaptations to diverse environmental niches, and it appears that they are not always meant to create life-threatening disorders (5, 6). These differences are explained by genetic variants including single nucleotide polymorphisms (SNPs), copy number variations (CNVs), and deletion or insertion (Del/Ins) polymorphisms (7). Other non-genetic mechanisms, such as transgenerational plasticity and cultural evolution, were undoubtedly additional powerful forces that contributed to human adaptation (8). However, discrete changes in the nature and frequency of specific genetic variants might influence health triggered by environmental factors (9). Such variants have been revealed with the completion of the Human Genome Project’s mapping of the human haploid reference genome (10) and the incorporation of other worldwide genomic databases (11) so that the understanding of the genetic basis of human disease and, ultimately, the prevention of many diseases may be achieved (12).

Currently, the paradigm shift in medicine from reactive to predictive is focused in providing models of prevention strategies based on the population’s genetic makeup and the risk factors that contribute to the emergence of chronic diseases, whether infectious or non-communicable (13). Clinicians need to reconsider their traditional approach to managing major diseases (such as hypertension, heart disease, type 2 diabetes, cancer, renal, and liver disease) from a bench to bedside/translational perspective, combining novel omics data with pathological clinical phenotypes in search of an individualized therapy (14). This has resulted in a multitude of terms, including Predictive Medicine, Individualized Medicine, Personalized Medicine, and Precision Medicine (15, 16), all of which acknowledge that each person is unique but still shares ancestral genetic variants based on ethnicity and environmental circumstances. These characteristics may explain why certain people are susceptible or prone to diseases when exposed to risky conditions or behaviors, but others in similar circumstances (i.e., family members) are unaffected (17). Personalized Medicine “omics” techniques have been proposed for nearly all medical fields including Nutrition, where Genomic Nutrition, Personalized Nutrition, and Precision Nutrition are becoming increasingly important (18).

The Personalized Medicine and Nutrition (PerMed-Nut) approach in Hepatology will inevitably include managing the main etiologies that cause chronic liver disease worldwide (19), such as alcohol persistence, chronic viral hepatitis B and C infections, metabolic-associated steatotic liver disease, hepatotoxicity (drugs or toxins), and auto-immune conditions. However, the prevalence of these etiologies varies greatly between countries due to genetic, environmental, and cultural differences in the host populations (20). As a result, the extent of liver damage might be immediate and self-limiting, or it can progress to chronic phases in which the inflammatory process of injury causes fibrosis, cirrhosis, and, in rare cases, hepatocellular carcinoma (HCC).

How can we begin using the PerMed-Nut approach as a strategy to prevent chronic liver diseases? Firstly, it is essential to understand the impact of genes and the environment at a regional level to develop measures to prevent liver damage. Hence, this work aims to define these factors for the prevention and management of liver illnesses using a PerMed-Nut model and the need for training in genomic education. We will address some polymorphic genes associated with the clinical outcomes of liver diseases as well as sociocultural features of the Mexican population in the sections that follow.

Studies examining the genetic ancestry of the Latin American (LATAM) populations including Mexico have revealed heterogeneous proportions of three main ancestral lineages: Amerindian, European, and African. As shown in Table 1, most LATAM countries contain all three with some having a higher degree of African (21, 28) and Native American (22, 27, 29, 30) ancestry than European (3, 23–26, 29). The indigenous people of Mexico are part of the third Native American migration wave that crossed the Bering Strait to the American continent around 20,000 years ago (2) (Figure 1B, blue arrow). These Native Americans settled primarily in Mexico (Tenochtitlan) and Peru (Cuzco) followed by Brazil, the United States, Bolivia, Columbia, and in lesser proportions Argentina, Venezuela, Ecuador, Canada, and Alaska (31). The current 68 ethnic groups of Mexican Amerindians are descendants of the original First Nations who followed either a nomadic or agricultural lifestyle, primarily in Aridoamerica and Mesoamerica, respectively (3, 32). During the Spanish colony (from 1521 to 1826), a genetic and cultural admixture occurred among Mexican Amerindians, Spaniards, and enslaved Africans (21). The Spanish Catholic Church recognized new births using a caste system, with Amerindian and Black heritage overlooked that has marked the social distribution of the ancestral lineages since colonial up until modern times.

Most Mexicans are admixed containing practically half of the main lineages (24, 25). However, as illustrated in Table 2, the degree of admixture varies across the country. Northern Mexico has a higher rate of European trait carriers (33, 34) and intermediate rates in the Central Region (35–37), contrasting with Southern Mexico, who are more likely to be carriers of Amerindian traits (35, 39) including the true Native Americans per se (38). African ancestry is present in varying quantities among the admixed general population and Afro-Mexicans who reside along the South Pacific and the Gulf of Mexico coastal communities (40). Further genetic studies show indigenous mitochondrial DNA as the maternal source of inheritance, while Y-STR analysis tracks European paternal lineage (37, 41).

Among the Genome-Wide Association Study (GWAS) database catalog, a total of 284 studies related to liver diseases have been conducted, identifying 1,546 associations in over 606 genes (42, 43). They are mainly reported in European, Asian, and African populations and scarcely in Native American ancestry (Figure 2A). However, one GWAS using the Mexican Biobank have shown 25 associations in 15 genes involved in lipid metabolism and transportation, vitamin A metabolism, protein folding, regulation of gene expression, cellular signaling, embryonic development, and heart development (Figure 2B). Among the most important clinical associations are hypercholesterolemia, hyper triglyceridemia, body weight, creatinine levels, hypertension, and arthritis. Furthermore, this study confirmed earlier findings of the north–south gradient of European-Amerindian ancestry (44).

Overall, the underlying genetic heterogeneity of most LATAM populations including Mexico constitutes a key aspect that makes sub-structure analysis and GWAS combined important tools to reveal which lineage is carrying the disease-related genetic polymorphisms and, consequently, the genetic foundation of disease vulnerability (17, 45). As shown in Figure 3A, regional variations in the ancestral component carrying the genetic variants as well the interactions with environmental and lifestyle factors support the need of regional PerMed-Nut strategies to address these differences (46).

One important factor in the gene–environment interaction equation is diet. The domestication of endemic wild plants and animals by the prehispanic groups of ancient Mexico, approximately 6,000 years ago, is a historic milestone for the peopling and development of the Aztec civilization and other ethnic groups because it provided the primary source of nutrients for the indigenous communities (47). Mexico is noted for three staple plants: maize, beans, and chili, along with squash, tomato, amaranth, and chia growing in an eco-agricultural style known as “milpa” using the “chinampas” system (48). The inverted Mesoamerican food pyramid contains edible leafy green vegetables and wild fruits at the top, cereals/grains at the middle, and animal meat at the bottom, implying that it was consumed in smaller quantities because animal rearing was uncommon. The exposure to this diet over millennia may have exerted positive selective pressure on the Mexican genome, favoring the dominance of diet-related adaptive gene (DRAG) polymorphisms that regulate essential energy, immunological, and nutritional pathways (47). Based on the earlier environmental conditions, the adaptive allele, which was selected over the wild allele, is a risk allele for disease in unfavorable conditions such as the occurring globalized nutrition transition (48–50). Different allelic frequencies of these DRAGs may influence the risk of complex diseases among populations based on interactions with dietary contexts, such as the current obesity endemic. For example, the cholesterol transporter ATP-binding cassette transporter A1 (ABCA1) gene variant (R230C, rs9282541) is unique to Native American individuals and has been associated with low high-density lipoprotein cholesterol (HDL-C) levels, obesity and type 2 diabetes in admixed Mexicans (51, 52). The positive selection of the C allele among the Native American population may be related to energy-saving processes among the ancient Mesoamericans. Overall, the current frequency of the ABCA1 230RC + CC genotypes ranges from 6 to 20% (46) and studies performed in central west Mexico have shown that up to 41% of Native American individuals who are carriers of the ABCA1 C allele have low HDL-c levels compared to admixed Mexicans in 7% (53), suggesting the need of targeted strategies among the population.

In this sense, populations that maintain their historical staple foods are less likely to develop nutrition-related disorders (54). However, when combined with imbalanced modern diets, these adaptive genes may generate pathological processes. In Mexico, globalization and urbanization have driven the nutrition transition, leading to a shift toward a hepatopathogenic diet containing ultra-processed foods, unhealthy dietary habits, and an imbalance in essential fatty acids, vitamins, and minerals (48, 55) (Figure 3B). Notably, a recent study analyzing data from the National Health and Nutrition Survey (2018–2019) revealed that 68% of the Mexican population consumes a western dietary pattern high in processed foods compared to only 7% of those following a traditional Mexican diet (56). Currently, 72.1% of the Mexican population is overweight or obese; this risk factor, in combination with genetic vulnerability, has increased the incidence of cardiovascular disease, type 2 diabetes, cerebrovascular events, hepatopathologies, and cancer (breast and prostate) (57). Thus, understanding the ancestral and historical transitions is the foundation for developing a regionalized PerMed-Nut approach to address the dynamic interplay between genetic and environmental features that could affect the outcome of liver diseases in this region.

Medical specialties and subspecialties, in their first stage of scientific medicine focused more on the complications of chronic disease, prolonging the patients’ life and improving their quality of life, but do not prevent in all cases disease remission (136). Faced with this situation, PerMed-Nut approaches based on genomic medicine/nutrition need to integrate medical, nutritional, sociocultural, and emotional/spiritual aspects of health (137). However, new medical education and training for medical professionals are required (138, 139). In LATAM and Mexico, updating the medical and other health sciences education curriculum both at the undergraduate and graduate levels must be considered a priority. This curriculum needs to integrate the so-called basic subjects: Biochemistry, Cell Biology, Genetics/Genomics, and Molecular Biology at different levels with bioinformatics, technological/digital strategies (Telemedicine) and novel clinical approaches focused on preventing chronic diseases and long-term complications (140). These basic subjects can be integrated sequentially during the first years of schooling, not independently, as in the past. In the last century, most medical specialties and careers in Nutrition were created separately. However, with this new understanding, physicians/clinicians need to integrate nutrition, while the nutritionist should handle the knowledge of disease the same way as the doctors work (141).

Likewise, hepatology was not born when most medical specialties were created (142). Although some hepatology postgraduate courses have been sponsored by the associations for the study of the liver to update medical specialists, pre-graduate doctors and nutritionists need to understand the molecular physiology of the liver, while more postgraduate courses in MedPer-Nut are required to advance in Genomic Hepatology (143). Furthermore, the capability to analyze hundreds or thousands of these genes simultaneously leads us to large-scale data management (Big Data) and specialized bioinformatics (machine learning and other artificial intelligence methods), together with advanced omics biotechnologies (epigenetics, metagenomics, proteomics, lipidomics, and metabolomics), digital media, and electronic medical records (144). These applications are not the Medicine of the future, they are the present Medicine that will require training and re-constructing health career curriculums.

Lastly, the major benefit of re-engineering the educational curriculum is to promote the formation of researchers in LATAM and Mexico, thus creating novel knowledge in the field of MedPer-Nut in this region (145). In this sense, transforming the present clinical practice guidelines is an ongoing challenge because most recommendations are based on studies carried out in foreign populations (146). As illustrated in Figure 4, the genetic profile interacting with the environmental factors that concur in Mexico, may not replicate in other regions and vice versa. Thus, the vision is to prevent the onset and progression of chronic liver disease using MedPer-Nut approaches concordant with the genetic and environmental characteristics of the population (147).

In the field of Medicine, we are now moving toward a new landscape of what exactly health means and how the pathological process begins. A primary goal is to avoid the onset of chronic diseases such as obesity, type 2 diabetes, and cardiovascular and liver diseases with their associated complications in the advanced stages. Reaching this goal will require detecting the genetic susceptibility to such diseases at young ages or at early stages, avoiding the pathology’s development as is the case of liver cirrhosis due to alcohol, viral hepatitis, or MASLD. Such studies are the beginning of the pathway toward the new age of PerMed-Nut in liver diseases.

In perspective, 20 years ago, it was commonly said that genes and environment interact with each other, but it was not clear how such interactions took place, nor which were the main environmental factors. Currently, it is recognized that at least three environmental factors constantly interact with our genes: diet (micro and macronutrients), physical activity (exercise), and emotions (stressors) (137). Human adaptability to these elements lies in the genetic variations gained through evolution that mark the differences between individuals or populations at the genomic and cultural levels (47, 148, 149). As shown in this review, within LATAM, despite having a common social history of the peopling of the continent, a wide spectrum of ancestral inter-variability is notable as well a distinct environmental conditions (24, 25, 28, 33). In the case of Mexico, it has been shown that the North–South gradient of the European-Amerindian ancestry impacts importantly in the distribution of the several genes with biomedical implications for the risk of chronic liver diseases (Tables 2, 3; Figure 3) (32, 44, 45, 153). More so, this pattern of distribution could also be replicated intra-regionally in light of the social-demographic movements that occurred over time as in the case of the ABCA1 polymorphism (46). This feature is the reason for further studies regarding the plausible association of certain genetic alleles with the clinical outcomes to tailor preventive strategies.

The diet-related alleles that have been studied to date among the Mexican population are key elements in the development of chronic illnesses including liver disease. As shown in Table 3, some polymorphisms are related to high food preferences for carbohydrates or lipids, altered food behaviors (excessive alcohol consumption), and dyslipidemias that can partly explain the increasing onset of MAFLD among the Mexican population. Interestingly, several genomic studies in Mexican Amerindian and admixed cohorts have identified the signature of positive selection of some serum lipid-modulating gene traits involved in cardiovascular diseases (150–152) that plausibly could overlap with the natural history of MAFLD. Overall, these genes can be useful for the development and validation of polygenic risk scores testing for the susceptibility in liver diseases among the Mexican population in the context of the tripartite ancestry (154–156). On the other hand, the impact of nutrition in patients with chronic viral hepatitis, specifically hepatitis B and C is an opportunity of exploration since patients with these pathologies have unmet needs in terms of their nutrition care to prevent further liver damage due to genetic susceptibility and harmful eating habits. Ultimately, understanding the molecular basis of these pathologies and the interactions that take place with the environment will derive in the making of a PerMed-Nut strategy appropriate for the Mexican population focused on the implementation of preventive strategies based on nutrition, exercise, and mental health instead of treating advanced diseases (157).

LATAM including Mexico shares a common ancestry in terms of genetics and culture that have an impact on health. However, further research regarding the distribution of genetic risk alleles and the interaction with environmental factors is required in this region. PerMed-Nut strategies based on these factors are the forthcoming trend in the field of Genomic Hepatology and other fields of medical specialties for preventing and managing chronic liver diseases. Knowledge of the genetic and lifestyle factors involved in the onset and progression of the major etiologies of chronic liver diseases needs to be generated by local researchers to provide regional clinical practice guidelines concordant with the features of the population. Achieving this PerMed-Nut approach is not without challenges since updated Medicine and Nutrition education curriculums are required. Training and preparing future health professionals and researchers with new clinical and investigative skills focused on preventing liver diseases in the field of Genomic Hepatology globally is a vision that clinicians and nutritionists should be concerned about.

AP: Conceptualization, Investigation, Visualization, Writing – original draft, Writing – review & editing. SR: Conceptualization, Investigation, Visualization, Writing – original draft, Writing – review & editing. IM-M: Investigation, Visualization, Writing – review & editing. AJ-A: Investigation, Visualization, Writing – review & editing. KG-A: Investigation, Visualization, Writing – review & editing. CO-G: Investigation, Visualization, Writing – review & editing. OR-L: Investigation, Visualization, Writing – review & editing. LT-R: Investigation, Visualization, Writing – review & editing.