To understand the interaction between the evolutionary and genetic changes associated with specific environments, it is necessary to know when and how these events occurred among the different populations. In the case of Mexico, the establishment of a sedentary lifestyle required approximately 5000 years[14,15]. During this period, the Mesoamericans began the domestication of the well-known staple foods of Mexico, such as maize (Zea mays L.), beans (Phaseolus spp), squash and pumpkin (Curcubita spp) and chili (Capsicum spp). This process was accompanied by the discovery and consumption of fermented alcoholic beverages made from a number of endemic agave plants (Agave spp). The origin of alcoholic beverages, as described by the Aztecs, was a mythical love story between two deities, “Mayahuel” and “Quetzalcóatl” (Figure 2)[16-18].

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Figure 2 The tale of Mayahuel. The ancient gods gathered in the heavens understood that their people got bored eating only maize and chili; thus, they sent Quetzalcóatl, the god of the winds, to bring the young and beautiful goddess Mayahuel, granddaughter of a “tzintzimitl, a star who attempted to prevent the sun from rising". Quetzalcóatl and Mayahuel fell in love and together promised that they would give their people a magic plant to recover their happiness. Meanwhile, the evil grandmother noticed that Mayahuel had disappeared; thus, she and other “tzintzimitl” went down to the earth to find her. Mayahuel and Quetzalcóatl were hidden in the form of a tree with two arms (branches); one arm was Mayahuel, and the other was Quetzalcóatl. When the grandmother found them, she cut Mayahuel´s arm into many small pieces, but not Quetzalcóatl’s, who was then transformed into a human again. Nothing could be done for Mayahuel, so Quetzalcóatl buried the leftover pieces in the ground and wept for his loss deeply. Finally, from these parts, the maguey was born. The mature maguey “cries” the honey-water, or “aguamiel”, that emerges from the center of the plant, representing the tears of Quetzalcóatl. “Octli poliuhqui” is the fermented nectar of the maguey that brings happiness. Thus, Mayahuel in the Nahuatl language stands for all that surrounds the maguey[16,17]. Mayahuel may be considered a dual deity. On the one hand, she represented a woman with many breasts who nourished many children, the 400 rabbits (“Centzon Totochtin”); thus, she was associated with the earth and fertility. On the other hand, she was associated with drunkenness and adultery. This mythological symbol had such great influence that one day of the month was devoted to the rabbit, and those born on that specific date were destined to either be a drunk or commit adultery[17,18].

The core of the mature agave plant produces a honey water, or “aguamiel”, rich in amino acids and proteins[19], which once fermented, produces the traditional alcoholic beverage. The Nahuas in their native language named the former “iztac octli” and the latter “octli poliuhqui”[20]. However, when the Spaniards arrived on the continent, “octli poliuhqui” was phonetically derived as the term “pulque”[20,21].

The “octli” but not “octli poliuhqui” served as nourishment for the elderly and sick and for women after childbirth[22]. The “octli” and perhaps the “octli poliuhqui” were given to all family members, including babies and children, in public ceremonies[17]. The “octli poliuhqui” was also used for medicinal purposes as an antidepressant or as an anesthetic before human sacrifice[16,18].

Additionally, the early Mexicans were familiar with the effects of the abuse of “octli poliuhqui”; thus, excessive drinking was strictly prohibited by law primarily during the religious holidays, and a death penalty was implemented[17]. The Aztec rulers often declared that the abuse of “octli poliuhqui” was the source and beginning of all evil and all ruin[17]. Unfortunately, these laws were not reinforced after the 15^th century, granting a tolerance of the abusive consumption of alcoholic beverages during the colonial period[4,23].

The rich history of the consumption of “pulque” by the Mexicans over many centuries is an essential component of the framework that is required to understand the relationship among the Mexican genome, alcoholism and liver disease at present.

Mexico is one of the leading countries with a high mortality rate due to liver diseases in the world[10]. The National Health Secretariat reported an average of 25000 cases of cirrhosis per year from 2000 to 2010[24]. The primary etiologies of cirrhosis are alcohol, followed by hepatitis C infection and non-alcoholic steatohepatitis[25-27].

For Mexico, the WHO reported that the amount of alcohol consumed is 8.4 L of pure alcohol per capita among individuals older than 15 years of age, which corresponds to an intermediate category as previously described[10]. However, if this parameter is applied only to drinkers, alcohol consumption increases to 27.1 L, which is similar to what had been reported in countries with the highest levels of alcohol consumption per capita[10].

However, the pattern of drinking score shows a better scope of alcoholism among the Mexican population. By examining the amount of alcohol consumed by occasion, we observed that alcohol consumption occurs primarily during the weekends[28], unlike in Europe where they drink wine almost daily, at lunch or dinner.

Hepatologists may advise their patients not to drink any alcoholic beverage to maintain a healthy liver. However, a large proportion of adults around the world drink alcoholic beverages[1,5,6]. Thus, the recommendation to avoid liver damage is that the amount of alcohol consumed should be equal or less than 2 drinks per occasion (20-40 g ethanol), not more than 4 drinks per day and not more than 10 to 12 drinks per week, allowing the liver to rest at least 1 or 2 d[1,5,6]. Furthermore, it has been suggested that the number of alcoholic drinks should be less in women than in men because women have a higher risk for developing ALD[1,5,6].

However, each weekend, approximately 30 million Mexicans have been estimated to consume more than five drinks per occasion (more than 80 g of ethanol), with another 10 million consuming at least one alcoholic drink daily. However, alcohol abuse has been detected in 5 million people with a strong dependence on alcohol[28].

The average Mexican begins consuming alcohol before the age of 18 years perhaps because of a strong cultural influence. Studies conducted in the western region of Mexico have shown that 61.4% of the 12- to 17-year-old have already begun to drink alcohol[27]. The primary types of alcoholic beverages consumed in Mexico are beer, tequila and “pulque”, and other distilled beverages are consumed in a lower proportion[27-30]. However, the distribution of alcoholic beverage preferences is heterogeneous. Thus, in central Mexico, “pulque” is preferred, in contrast to tequila in the west or beer in the northern and southern parts of the country (Figure 3). These preferences are associated with the historical cultural background of each region and may be related to the mortality caused by cirrhosis. The mortality rate in central Mexico is greater than 30/100000, followed by the north at less than 10/100000 and the west at less than 5/100000[30,31].

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Figure 3 Main types of alcoholic beverages consumed by geographical region in Mexico.

In western Mexico, young people begin to drink beer either during the weekend or at any social or religious event, such as weddings, coming-of-age parties and christenings. After the initiation of alcohol use, the number of beers consumed per occasion over the weekend ranges from 4 to 6 (80-100 g); this number gradually increases to 20-24 beers/355 mL each (300-360 g of alcohol)/occasion per person over a period of approximately 10 years. The second stage involves the combination of beer with tequila or any other distilled beverage during a period of 8 to 10 years. During this stage, the amount of alcohol consumed ranges from 380 to 640 g daily. In the third stage, alcohol dependence is severe, and patients may or may not present with cirrhosis. By this time, they drink an average of 510 g of alcohol per day (450-720 g)[26,32-34].

The time between the initiation of alcohol use and the diagnosis of cirrhosis is 23 to 30 years[26,35]. However, we have identified two distinct age peaks of clinical cirrhosis. In the first group, patients are young, approximately 30 years old, and a plausible genetic predisposition to liver cirrhosis has been proposed to be involved. In the second group, the average age is approximately 45 years[33]. Compared to other countries, Mexico, according to our findings, may have the youngest people with alcoholic cirrhosis in the world. Apparently, the Apo E2[33] and FABP2[36] gene polymorphisms may be involved in the early onset of ALD among the Mexican population.

The majority of patients with ALD seek medical attention in the advanced stages of the disease with a Child-Pugh score of C and multiple complications, such as encephalopathy, variceal bleeding, infections and ascites[25,27,35]. These clinical characteristics are present in the two primary age groups of patients with alcoholic cirrhosis[33]. Furthermore, the patients with alcoholic cirrhosis continue to drink high amounts of alcohol after diagnosis and may die earlier in life due to clinical complications[25]. This observation may be one of the foremost reasons why hepatocellular carcinoma is rare in Mexico compared with other regions of the world[37,38], in conjunction with other environmental factors[39].

ALD has been associated with nutritional deficiencies and malnutrition worldwide[40]. However, preliminary data from a reference center in western Mexico have shown that obesity is also present. Among 90 patients, 17% of the alcoholic cirrhotic patients were malnourished, whereas overweight and obesity were detected in 33% of the patients, with another 50% of normal weight[35]. These data are consistent with the fact that Mexico has the highest prevalence of obesity[41], thus adding a new risk factor for liver disease. Furthermore, in this group of patients, 34% of the patients had drug addictions, which is an increasing social and health problem[35].

Thus, the combination of alcoholism, obesity, drugs and, in several cases, viral hepatitis B or C, leads us to explore specific strategies for treatments and prevention programs to detect cirrhosis at early stages of the disease.

Alcohol has a stimulatory effect on the dopaminergic neurons of the ventral tegmental area. Dopamine is captured by DRD2 in these neurons in the nucleus accumbens, causing a pleasant effect that is integrated into the mesolimbic system[48,67,68].

The DRD2 Taq I A1 polymorphism consists of a T/C nucleotide substitution (rs1800497) that alters the Taq I restriction site located 10541 bp downstream of the termination codon. Several studies have investigated the association of this gene polymorphism with alcohol dependence. Taq I A1 allele carriers reportedly have lower amounts of DRD2 receptors than the Taq I A2 carriers[73]. Thus, A1 allele patients require higher amounts of alcohol to achieve the desired effect[66-68,74-76]. In additional studies, the association between the A1 allele Taq I and alcohol use disorders has been corroborated in some but not in others. However, in several meta-analyses, a significant association between Caucasian A1 allele carriers and alcohol addiction has been found[48,77].

The allelic distribution of DRD2 displays a wide range of frequencies worldwide[74-79], but the highest prevalence of the A1 allele is found among the Amerindian Pima (83%) and Mayas (71%) from Mexico[80,81] (Figure 4).

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Figure 4 Frequency of Taq I A dopamine receptor D2 polymorphisms in different countries. ¹HapMap.

The ADH1B gene has a polymorphic site, resulting in the Arg47His substitution (rs1229984). The A2 allele (ADH1B His47) confers a 100-fold higher catalytic activity to the ADH1B enzyme than the A1 allele (ADH1B Arg47). The A2 allele carriers have a higher ethanol oxidation capacity than the A1 carriers. However, the A2 carriers have a higher acetaldehyde production that leads to an alcohol-flushing response that has been considered to be protective.

The protective effect of the A2 allele against alcohol dependence is well known in the East Asian population[82]. A study conducted in a cohort of pregnant women from England demonstrated that the A2 carriers consumed less alcohol before pregnancy, had less incidents of binge drinking during pregnancy and were abstainers during the first trimester of gestation[83]. However, although this allele apparently reduces the risk of alcohol dependence, it may confer a substantial risk of chronic liver disease, especially among heavy drinkers[84].

In contrast, A1 allele carriers do not present with the rapid production of acetaldehyde, which eliminates the alcohol-flushing response. A study conducted in a large cohort of individuals from Copenhagen revealed that A1 allele homozygotes drank more alcohol and had a higher risk for developing alcohol dependence[85]. The A1 allele has also been associated with alcohol dependence in several other studies[86-88].

The CYP2E1 gene, which encodes the enzyme that oxidizes ethanol in the microsomal oxidation system, is essential in the pathophysiology of ALD. Alcohol consumption induces the expression of CYP2E1, which is directly involved in the primary oxidation pathway of this substrate, displacing the enzymatic activity of ADH1B (K_m: 8-10 mmol/L for CYP2E1 vs 0.2-2.0 mmol/L for ADH1B)[69,89].

The C2 allele, which is less common, has a C/T transition at nucleotide position -1019 within the 5’ terminal regulatory region. The C2 allele is associated with a 100-fold higher transcription activity, higher protein concentration and increased enzyme activity, which lead to a faster rate of alcohol oxidation[90,91].

The C2 allele carriers have been demonstrated to consume excessive amounts of alcohol, which may be caused by the high transcriptional activity of CYP2E1. C2 allele carriers metabolize ethanol (alcohol) to acetaldehyde at a higher rate. Acetaldehyde is a highly toxic and mutagenic metabolite that increases oxidative stress by producing reactive oxygen species and lipid peroxides, such as 4-hydroxy-2,3-nonenal, 4-hydroxy-2,3-alkenals and malondialdehyde[92]. An association between an increased risk for ALD and alcoholic cirrhosis has been reported among the carriers of the C2 allele[93-95], several of whom belong to the mestizo population of western Mexico[96].

The ALDH2 gene encodes the primary mitochondrial isoform enzyme that oxidizes acetaldehyde to acetate in the liver[70,97]. The C/G transition in exon 12 of ALDH2 causes an amino acid substitution of glutamic acid for lysine at position 487 (ALDH2 Glu487Lys, rs671). The A2 allele (ALDH2 Lys487) has little or null enzymatic activity. This deficiency leads to the accumulation of acetaldehyde and consequently provokes a flushing response, which discourages alcohol drinking[97]. Because flushing is an undesirable symptom, it confers relative protection against abusive alcohol consumption. An association between A2 allele carriers and a lower risk for alcohol dependence and reduced alcohol use has been reported[98].

With regard to the distribution of the polymorphisms of the liver alcohol-metabolizing genes, all present contrasting frequencies among different population groups (Figure 5A-C). Among Asians, the ADH1B gene displays the highest frequency of the A2 protective allele, with 78% in Japan and 69% in China. In contrast, the lowest frequency for the A2 allele was detected in Germany and Mexico, at 4% and 3%, respectively (Figure 5A)[91,99-105], wherein the frequency of the A1 allele associated with alcohol dependence was much higher.

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Figure 5 Frequency of polymorphisms of enzymes that metabolize alcohol. A: Alcohol dehydrogenase 2 (ADH2); B: Aldehyde dehydrogenase class 2 (ALDH2); C: Cytochrome P450 2E1 (CYP2E1) in different countries. A-B: Mexico 1: Western Mexico; Mexico 2: Native from Mexico “Otomi”; Mexico 3: Native from Mexico “Huicholes”; Japan 1: Rural country; Japan 2: Mestizos from Japan; C: Mexico 1: Western Mexico; Mexico 2: North an central Mexico; Mexico 3: Native from Mexico “Huicholes”; Chile 1: Mestizos; Chile 2: Native from Chile “Mapuches”.

The C2 allele for the CYP2E1 gene has a frequency of approximately 30% in Japan and China and 2% in the United States. In Chile and Mexico, the frequency is 16% among the mestizo population (Figure 5B)[91,93,94,105-108]. Interestingly, among the Amerindians of western Mexico, such as the “Huichol” people, this gene polymorphism shows a prevalence of 50%, which is the highest rate reported to date[91].

The highest frequency of the A2 allele for the ALDH gene has been reported in China (29%) and Japan (26%). In Germany, Sweden and Mexico, its frequency is extremely low or absent[91,99-105], which could explain, to some extent, the high amount of alcohol consumption that has been reported in those countries.

We could speculate that the selective evolution of both the brain and liver genes was not necessarily directed only by the exposure to alcohol. For example, liver cytochrome genes metabolize a large variety of xenobiotics, whereas those expressed in the brain fulfill the addiction criteria. However, an alternative point of view is to consider these genes as part of a general survival mechanism. Thus, the basic biological necessities of life, such as food (sugars, e.g., glucose) or sexual reproduction, are ensured and rewarded by pleasure; however, these necessities may not be driven by pleasure exclusively.