1. Introduction

Metabolism is made up of a complex set of chemical processes that are essential to every aspect of human life. Our genetic makeup closely regulates these metabolic activities, which are essential for breaking down food into energy, building cellular structures, and getting rid of waste. The importance of studying the role of genetics in metabolism is growing due to the significant influence metabolism has on human health. Studies have shown that genetic variations resulting from evolution, migration patterns and environmental adaptation are associated with changes in metabolic processes [1]. These variants may also influence differences in population adaptation to environmental stress and evolutionary metabolic characteristics. Humans have various genetic diversity, migratory patterns, and environmental adaptations. Population genetics studies have shown that natural selection, gene flow, and genetic drift have significantly affected the development of population-specific metabolic adaptations, such as those seen in high-altitude populations such as Tibetans and Andean peoples [2]. By examining the genetic underpinnings of metabolism in many groups, researchers have acquired important knowledge for treating some metabolic illnesses. For example, certain genetic variants are associated with metabolic disorders, and Pro12Ala variants of the PPARγ gene are associated with a reduced risk of T2D in some populations but are less common in others, such as East Asian populations [3]. This paper aims to address this gap by exploring genetic factors that influence metabolism, focussing on how these factors differ across human populations. Through comparative analysis, the paper will examine key genetic variants associated with metabolic traits and examine the role of population genetics in shaping these traits. Understanding the genetic characteristics and metabolic changes of different populations can help develop more effective disease prevention and treatment programs. These studies shed light on evolutionary strategies for adapting to the environment and responding to metabolic stress in humans and contribute to understanding the prevalence of metabolic diseases in the population.

2. Genetic Basis of Metabolism

2.1. Metabolic pathways and genes

2.1.1. Overview of metabolic pathways

The web of interconnected biochemical processes known as metabolic pathways is what keeps organisms alive and enables them to develop, procreate, and react to their surroundings. Generally, these pathways can be classified into two classes: catabolic pathways and anabolic pathways. While the latter uses energy to transform simpler molecules into more complex ones, the former breaks down molecules to create energy.

One of these catabolic processes is glycolysis, in which the cytoplasmic forms of glucose are broken down into pyruvate, adenosine triphosphate (ATP), and NADH. The citric acid cycle, which produces the majority of the ATP in a cell, depends on this pathway for its essential substrate, which is provided at the beginning of cellular respiration [4]. Beta-oxidation is another important route. This mechanism breaks down the fatty acids in the mitochondria to produce acetyl-CoA, which can then enter the citric acid cycle [5]. Gluconeogenesis, as used in the anabolic pathway, is the process by which glucose is produced in the liver from non-carbohydrate precursors like glycerol and lactic acid. This pathway plays an important role during fasting or strenuous exercise when individuals have low glucose levels in the body [6]. In addition, the pentose phosphate pathway is another important anabolic pathway. It provides reducibility for biosynthesis in the form of NADPH and for nucleotide synthesis in the form of ribose 5-phosphate [7].

2.1.2. Key genes and their roles in metabolism

Metabolism is controlled by a complex network of genes that encode enzymes, transporters, and regulatory proteins necessary for the different metabolic processes. These genes are responsible for strictly and precisely controlled metabolic pathways, ensuring that energy production, biosynthesis, and catabolism occur efficiently in response to our body’s needs. Consequently, it is essential to comprehend the function of these important genes in order to unravel the hereditary foundation of metabolic features and the variances in them across various populations.

One of the most extensively studied genes in the field of human metabolism is the peroxisome proliferator-activated receptor γ (PPARγ), which plays a key role in lipid metabolism and glucose homeostasis. PPARγ is a nuclear receptor that regulates the expression of genes involved in adipogenesis, fatty acid storage, and insulin sensitivity. A variant of PPARγ, Pro12Ala, has been found to reduce the risk of T2D and improve insulin sensitivity, particularly in European populations [1, 3]. The Pro12Ala variant was discovered through genetic association studies in large cohorts of these populations. These studies revealed that the Ala allele was associated with improved metabolic outcomes. Another key gene is glucokinase (GCK). GCK acts as a glucose sensor in the pancreas, regulating insulin secretion based on blood glucose levels. Mutations in GCK can cause hyperglycemia or hypoglycemia, depending on whether the mutation increases or decreases the activity of the enzyme [8]. Because of its strong correlation with obesity and metabolic syndrome, the FTO gene — also referred to as the fat mass and obesity-associated gene — has garnered a lot of interest.An enzyme that controls fat storage and energy balance is encoded by FTO. Studies have shown that common FTO variants affect body mass index (BMI), making individuals more susceptible to obesity, but the effects vary among different ethnic groups [9].

2.2. Genetic variants and metabolic traits

The genetic variant is the difference in DNA sequence between an individual and a population. These variants can affect the way a gene is expressed or the function of the protein it codes for, which can significantly impact metabolic traits.

Single nucleotide polymorphisms, or SNPs, are common genetic variations in humans. These changes can occur in the coding region of a gene and then affect human gene expression by altering the structure and function of the protein. A well-known SNP in the PPARy gene is rs1801282, which causes a substitution of Pro12Ala in the protein. This variant is associated with a reduced risk of type 2 diabetes and improved insulin sensitivity and is highly present in European populations [6]. Other genetic variants are strongly associated with an increased risk of metabolic diseases such as obesity and CVD .For example, it has been previously shown that there is a strong correlation between obesity and metabolic syndrome and changes in the FTO gene. The rs9939609 SNP in the FTO gene has been found to affect appetite and food intake, which changes energy balance and raises the risk of obesity and a higher body mass index, especially in individuals from Europe and South Asia [10]. Different genetic variants are also evident in the evolutionary histories of various populations and the effects of environmental adaptation. Colder climate residents were more likely to have mutations in the UCP1 gene, which codes for the uncoupling protein 1 involved in heat production. These polymorphisms improve one's capacity to produce heat in cold climates, indicating a direct connection between metabolic traits, environmental adaptation, and genetic variation [11].

3. Population Genetics and Metabolism

3.1. Definition and significance of population genetics

The genetic composition of a population is the core of focus groups, not individuals. In this context, a population is a group of hybrid individuals of the same species who share a common gene pool, which is often described in terms of allele frequency. It is a quantitative group of specific genes in different variants of the relative abundance. A fundamental concept in population genetics is the Hardy-Weinberg equilibrium; it provides a mathematical model under the assumption that the absence of evolutionary forces acting on the population affects the prediction of genotype distribution in the population. According to this principle, in the absence of factors such as mutation, selection, or migration, allele and genotype frequencies in large random mating populations will remain constant over several generations [12].

To ascertain genetic diversity and look at population dynamics, population genetics must be used. These dynamics are clarified by population genetics, which also helps us comprehend the adaptive relationships between genetic diversity, population history, and complex traits like those related to disease and metabolism. The ability to trace the evolutionary history of human populations is an important function of population genetics. By analyzing genetic components, researchers have been able to piece together human migration patterns, population movements, and mixing events over thousands of years. [13] The famous "out of Africa" theory that modern humans originated in Africa and later spread to other parts of the world is strongly supported by studies of mitochondrial DNA and Y-chromosome markers [14]. As a result, populations undergo different genetic changes as they adapt to new environments. Population genetics also plays a key role in understanding the genetic basis of adaptation. By identifying genetic variants under positive selection, researchers can infer how populations have adapted to specific environmental challenges, including diet, climate, and disease. Adapting the Tibetan population to a high-altitude environment is related to the genetic variation of the EPAS1 gene, which regulates human response to hypoxia [15]. These studies illustrate how population genetics can reveal the mechanisms by which natural selection forms genetic variation and promotes population-specific adaptation.

3.2. Evolutionary perspective on genetic diversity

Genetic diversity within and between the human population is the result of millions of years of evolution influenced by mutation, natural selection, genetic drift and gene flow. The influence of various factors. Mutations are the ultimate source of genetic diversity. Mutations introduce new alleles into the population gene pool, providing raw materials for evolutionary force. Most mutations are neutral or harmful, but occasionally, mutations can provide a selective advantage in the specific environment, increasing the likelihood of being passed on to offspring. This process is known as natural selection, in which favorable alleles become more prevalent in the population over time, while unfavorable alleles are eliminated. A typical example is the mutation leading to the formation of the sickle cell allele in the HBB gene, which is retained in certain populations because it confers a protective advantage against malaria. In malaria-endemic areas, such as parts of Africa, individuals heterozygous for the sickle cell allele have a selective advantage because they are less likely to develop severe malaria, leading to a higher prevalence of this allele in these populations [16]. Genetic drift is a random change in allele frequency that occurs in a small population, usually resulting in a loss of genetic diversity over time. Unlike natural selection, genetic drift is a random process, which means that its effects are more pronounced in small populations because chance events can significantly alter the genetic composition.

4. Comparative Analysis of Findings

4.1. Genetic diversity and metabolism

Differences in how distinct populations digest and use different macronutrients, such as proteins, lipids, and carbohydrates, can be caused by variations in genetic composition. These genetic variations are frequently the consequence of long-term adjustments to certain food and environmental patterns. One example is the fluctuation in adult lactase persistence, or the capacity to digest lactose. The LCT-13910C/T mutation governs this characteristic, which varies significantly amongst populations [17]. Nonetheless, in certain groups, the genetic mutation sustains lactase production well into adulthood, enabling individuals to digest lactose and partake of dairy products without experiencing any negative consequences.

A study by Hubacek et al. examined the frequency of the RCT-13910C /T genotype in Czech Roma/Gypsy and Czech/Slavic populations [17]. Their results showed a substantial difference in the two groups' proportions of the lactose tolerance allele T allele. The T allele that permits lactose tolerance was found in about 27% of the Czech Roma/Gypsy population, whereas it was present in 76% of the Slavic and Czech populations. The reduced incidence among Roma/Gypsies is consistent with findings in other Indian populations and shows that lactase persistence is less common in populations that have historically relied less on dairy products [17].

4.2. Metabolic diseases and genetic predispositions

To create successful preventative and treatment plans, it is critical to comprehend the genetic predispositions that lead to these illnesses. It has been determined that certain genetic variations, which typically differ between populations, have a substantial impact on an individual's vulnerability to various diseases. This section of the study will examine several genetic characteristics linked to metabolic illnesses, focussing on T2D and insulin resistance. Additionally, we will describe how these genetic predispositions interact with environmental factors to affect the risk.

PPARγ Pro12Ala is one of the better-researched genetic variations linked to T2D. Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor essential for controlling glucose metabolism, lipid storage, and adipocyte development. The PPARγ gene encodes it. Reduced receptor activity results from the Pro12Ala mutation, resulting in the substitution of alanine for proline at position 12 of the PPARγ protein. According to one study, people with the Pro12Ala variant are less likely to develop T2D than non-carriers [1]. The protective effect on insulin sensitivity was attributed to the effect of this mutation. Less active PPARγ of the Pro12Ala variant is associated with better insulin sensitivity and control of adipocyte differentiation and fatty acid storage. Carriers of this variation are, therefore, unlikely to be involved in the development of insulin resistance. Different populations have different Pro12Ala variant prevalences. In particular, this variant is linked to a slight decrease in the incidence of type 2 diabetes and is more prevalent in European populations (such as Swedes, Finns, and French Canadians). For instance, research indicates that the Ala allele is present in about 20% of Finnish populations and 12–25% of other European groups [3]. Though this mutation is less common in East Asian populations — roughly 4% of the population — it's possible that other genetic factors have a greater impact on the risk of diabetes [3].

Insulin signalling pathway involves a protein that is expressed by the insulin receptor Substrate 1 (IRS1) gene. Mutations close to the IRS1 gene alter insulin signalling, raising the risk of insulin resistance and type 2 diabetes in the body. Rung et al. examined the relationship between insulin resistance and mutations in the IRS1 gene in a study involving French, Danish, and Finnish Europeans. In these populations, specific polymorphisms similar to the IRS1 gene were associated with insulin resistance and a high prevalence of T2D [18]. The influence of IRS1 polymorphisms on insulin resistance implies that genetic screening is essential in groups at high risk for type 2 diabetes.

4.3. Diet and genetic adaptations

Tibetans who live at high altitudes have evolved genetic defenses against harsh surroundings. Their ability to adapt influences their eating patterns and metabolism by enhancing oxygen utilization in low-oxygen situations. The Tibetan Plateau, sometimes called the "roof of the world," has been home to the Tibetan people for many generations. Only roughly 60% of oxygen levels are at sea level [2]. Researchers identified an alteration in the EPAS1 gene as one of the major genetic adaptations present in Tibetans. A transcription factor involved in the body's reaction to low oxygen levels is encoded by the EPAS1 gene. Tibetans can ensure that their tissues get enough oxygen while avoiding the negative effects of high hemoglobin levels. People carrying this particular EPAS1 gene have lower hemoglobin and red blood cell counts than those living at lower altitudes. This adaptation reduces the chance of developing chronic mountain diseases.

5. Implications for Health and Disease

For the early diagnosis and treatment of metabolic illnesses in some populations, genetic screening is crucial. Identification of those who are susceptible to metabolic problems can significantly lower the occurrence of linked diseases including diabetes and cardiovascular disease. Srikanthan et al. successfully predicted the likelihood of metabolic syndrome incidence in a West Virginia community using a collection of biomarkers they discovered through a systematic review [19]. To illustrate this point, the study team includes markers that are closely associated with the genetic and environmental background of a given community. This highlights the significance of customizing genetic screening methods to the features of diverse populations.

Incorporating genetic data particular to a population into risk prediction models may also make it easier to apply better disease control techniques. European Americans, African Americans, and Hispanics are the three racial/ethnic groups in whom one study showed the validity of various metabolic genetic risk scores in predicting T2D risk [20]. The results indicated that the genetic risk score significantly predicted T2D risk in each group, despite the prediction ability revealing slight variability in the population due to genetic variety. Greater waist-to-hip ratios are found in African Americans compared to European Americans, and a higher body mass index is associated with a higher risk of T2D in Hispanics. Using these models to include specific genetic differences associated with metabolic disorders across different ethnic groups will help researchers create more targeted medicines. For example, to prevent the emergence of some metabolic illnesses in areas where specific risk alleles are more prevalent, improved surveillance and early lifestyle adjustments may be required.

6. Conclusion

This paper explores the complex relationship between heredity and metabolism. By studying the genetic variation of different dietary patterns, metabolic traits and their genetic diversity, we can gain a deeper understanding of how these factors contribute to metabolic differences between different populations. This understanding is critical to guiding a personalized approach to healthcare, especially when tackling metabolic diseases such as obesity, T2D, and CVD. The genetic diversity present in human populations testifies to the evolutionary processes that have shaped our species for thousands of years. From an evolutionary perspective, we can better understand the formation of adaptations in specific populations and their impact on modern health challenges. However, we must admit that this paper has some limitations. Although this paper summarizes the key points and conclusions, it does not cover all the complex details because the field of genetic and metabolic research is quite challenging. The use of previously published work, which might not represent the most recent developments in genetic research, is one drawback. Since this study focuses on known genetic variants and their impact on metabolism, it's also possible that it missed any less well-known or recently found novel variants.