Genes and Alcoholism: Taste, Addiction, and Metabolism

C H A P T E R

50 Genes and Alcoholism: Taste, Addiction, and Metabolism Arturo Panduro1,2, Ingrid Rivera-In˜iguez1,2, Omar Ramos-Lopez1,2 and Sonia Roman1,2 1

Department of Molecular Biology in Medicine, Civil Hospital of Guadalajara “Fray Antonio Alcalde”, Guadalajara, Mexico 2Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico

LIST OF ABBREVIATIONS ACSS ADH ALDH ANKK1 BRS CO2 CYP2E1 DRD2 FFA MEOS NAD 1 NADH NA PROP PTC RDS SNPs TCA TRPV1 VS VTA VLDL-C

These SNPs provide protective and risk alleles which, combined with environmental factors, have been related to the susceptibility towards alcoholism. Furthermore, these genes also influence food choices in susceptible individuals, increasing the risk for obesity and nutrition-related chronic diseases in alcoholics. Sociocultural factors may also interact with genes influencing alcohol addiction.

acyl-CoA synthetase short chain family member alcohol dehydrogenase aldehyde dehydrogenase ankyrin kinase domain containing 1 brain reward system carbon dioxide cytochrome P4502E1 dopamine D2 receptor free fatty acids microsomal ethanol oxidizing system nicotinamide adenine dinucleotide oxidized nicotinamide adenine dinucleotide reduced nucleus accumbens 6-n-propylthiouracil phenylthiocarbamide reward deficiency syndrome single nucleotide polymorphisms tricarboxylic acid cycle transient receptor potential cation channel subfamily V member 1 ventral striatum ventral tegmental area very- low density cholesterol

TASTE AND ALCOHOLISM

INTRODUCTION Alcohol consumption and addiction in humans involve the interaction between several biological functions including taste, flavor perception, brain reward systems, and alcohol detoxification pathways. This chapter focuses on several genes encoding single nucleotide polymorphisms (SNPs) that show a differential distribution among populations worldwide. Neuroscience of Alcohol. DOI: https://doi.org/10.1016/B978-0-12-813125-1.00050-7

Bitter taste is a sensory factor that influences drinking patterns (Tepper et al., 2009). Ethanol elicits bitterness, burning, and stinging sensations in the oral cavity (Nolden, McGeary, & Hayes, 2016). Hence, variations in the perception of ethanol intensity account for differences in alcohol consumption. Synthetic compounds such as 6-n-propylthiouracil (PROP) and phenylthiocarbamide (PTC) are used to phenotypically classify individuals in nontasters and tasters (Tepper et al., 2009). Tasters are classified as medium tasters and supertasters. Nontasters have a higher preference and more frequent consumption of alcoholic beverages than tasters (Duffy et al., 2004b), as well as an association with a history of alcoholism (DiCarlo & Powers, 1998). Conversely, supertasters consume less beer than nontasters when they first started drinking beer on a regular basis, suggesting that supertasters are protected against alcoholism (Intranuovo & Powers, 1998). The TAS2R proteins expressed by the taste receptor cells of the tongue and palate epithelia mediates bitter-

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taste perception. These bitter-taste receptors are seventransmembrane, G-protein-coupled, receptor proteins encoded by intronless genes (Feeney, O’Brien, Scannell, Markey, & Gibney, 2011). One example is the TAS2R38 gene related to the perception of glucosinolates, bitter-tasting compounds found in the Brassica sp. (Kim et al., 2003) and PTC/PROP compounds. Three functional TAS2R38 polymorphisms (A49P, V262A, and I296V) may explain up to 85% of the variance in PTC taste sensitivity (Drayna, 2005; Kim et al., 2003) which, in turn, correlate with ethanol bitterness (Allen, McGeary, & Hayes, 2014; Hayes, Feeney, & Allen, 2013). Moreover, PAV and AVI are two of the most common TAS2R38 haplotypes which have been related to the greatest (tasters) and lowest (nontasters) sensitivity to PTC/PROP bitterness, respectively (Bufe et al., 2005; Kim & Drayna, 2005). PAV homozygotes perceive greater bitterness from ethanol on circumvallate papillae than heterozygotes and AVI homozygotes (Nolden et al., 2016). PAV homozygotes consume lower amounts of alcohol compared with PAV/AVI heterozygotes and AVI homozygotes (Duffy, Peterson, & Bartoshuk, 2004a; Hayes et al., 2011; Wang et al., 2007). Additionally, two novel TAS2R38 haplotypes were recently reported in the Mexican population (PAI and AVV) (Ramos-Lopez et al., 2015) which confer a taster and nontaster phenotype, respectively, as demonstrated by functional expression analyses (Bufe et al., 2005). AVV nontaster haplotype was the most prevalent among Mexicans and was associated with alcohol intake (Ramos-Lopez et al., 2015). Other TAS2R bitter-taste genes are implicated in alcoholism (Edenberg & Foroud, 2006). A missense mutation in the TAS2R16 gene (K172N) was associated with risk for alcohol dependence and alcohol-drinking scores in African-Americans (Hinrichs et al., 2006; Wang et al., 2007). This variant is located in the ligand-binding domain altering receptor sensitivity to the bitter compounds, beta-glucopyranosides (Hinrichs et al., 2006). Moreover, the N259S polymorphism located within the TAS2R13 gene showed significant association with overall intensity for an ethanol whole-mouth solution (Allen et al.) and with measures of alcohol consumption (Dotson, Wallace, Bartoshuk, & Logan, 2012). Additionally, three SNPs within the transient potential cation channel subfamily V member 1 (TRPV1) gene, which encodes a polymodal nociceptor (also denoted as vanilloid receptor 1) were associated with higher ratings of ethanol sensations, such as burning and stinging (Allen et al., 2014) (Table 50.1, upper section).

ALCOHOL ADDICTION The brain reward system (BRS) modulates survival behaviors such as food intake and sexual activity.

Several psychoactive substances, such as alcohol (Ma & Zhu, 2014), also target the BRS. The brain reward circuitry is constituted by the ventral tegmental area (VTA), nucleus accumbens (NA), ventral striatum (VS), bed nucleus of the stria terminalis, hippocampus, and amygdala. In the BRS, dopamine is the main neurotransmitter involved in motivation and reinforcement (Tupala & Tiihonen, 2012). Alcohol intake stimulates the release of dopamine, mainly in the NA (Boileau et al., 2003). Consequently, increases in dopamine regulate the rewarding effects of alcohol and may promote drinking (Di Chiara, 1997). Alterations in dopaminergic neurotransmission associated with dysfunctional reward processing, impaired reinforcement learning, and increased sensitivity to alcoholassociated stimuli lead to addictive behaviors, such as alcohol seeking and excessive consumption (Charlet, Beck, & Heinz, 2013). Changes in striatal dopamine levels in response to alcohol intake may be neurobiological markers of vulnerability to alcohol use disorders (AUD) (Setiawan et al., 2014). Five different receptor subtypes that belong to the large G-protein-coupled, receptor superfamily mediate dopamine activity. Nevertheless, dopamine D2 receptor (DRD2) encoded by the DRD2 gene is a key regulator of dopamine actions (Mi et al., 2011). Thus, differences in the relative amount or functional capacity of DRD2 affect the subjective pleasure associated with positive rewards (Wise, 2006). One of the most widely researched polymorphisms is the DRD2/ ANKK1 Taq1A restriction fragment length polymorphism, which resides in exon 8 of a neighboring gene, ankyrin repeat, and kinase domain containing 1 (ANKK1), located 10 kb downstream from the DRD2 gene (Neville, Johnstone, & Walton, 2004). This functional variant causes a Glu713Lys substitution within the 11th ankyrin repeat of the ANKK1 gene (Table 50.1, middle section). In vivo human studies have found an altered DRD2-binding capacity and density in the striatum of TaqA1 allele carriers (Jo¨nsson et al., 1999; Ritchie & Noble, 2003). Interestingly, some studies have supported the putative association of the TaqA1 polymorphism with alcoholism (Munafo`, Johnstone, Welsh, & Walton, 2005) and risk for alcohol dependence (Wang, Simen, Arias, Lu, & Zhang, 2013). Additionally, the TaqA1A1 genotype was recently associated with heavy alcohol-drinking patterns in a Mexican-Mestizo population (Panduro et al., 2017a). Furthermore, the TaqA1 allele was associated with increased mortality over a 10-year period in alcohol-dependent individuals (Berggren et al., 2010). The frequency of the TaqA1 allele shows variations among populations which, in turn, may help to partially explain some of the differences in alcohol-drinking habits reported worldwide. The highest frequencies of

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ALCOHOL ADDICTION

TABLE 50.1

Genomic Data of Gene Polymorphisms Involved in Alcoholism

Gene Name

Locus

Gen size (base pair)

Polymorphism

Reference sequence (rs)

Risk variant

7q34

1143

A49P

rs713598

AVI haplotype

V262A

rs1726866

I296V

rs10246939

BITTER TASTE RECEPTOR PROTEINS Gen ID: 5726 Taste 2 receptor member 38, TAS2R38

Gen ID: 50833

7q31.32

996

K172N

rs846664

K allele

12p13.2

1637

N259S

rs1015443

S allele

17p13.2

43,996

A/G intron variant

rs224547

A allele

Taste 2 receptor member 16, TAS2R16 GEN ID: 50838 Taste 2 receptor member 13, TAS2R13 Gen ID: 7442 Transient potential cation channel subfamily V member 1, TRPV1

A/C intron variant rs4780521

C allele

C/T intron variant rs161364

C allele

Glu713Lys (TaqA1/A2)

rs1800497

TaqA1 allele

C957T

rs6277

C allele

2 141C Ins/Del

rs1799732

2 141C/Del allele

A1385G

rs6276

G allele

Arg48His ( 1/ 2)

rs1229984



1 allele

12q24.12 43,099

Glu487Lys ( 1/ 2)

rs671



1 allele

10q26.3

2 1053 C/T ( C1/ C2)

rs2031920



C2 allele

DOPAMINE RECEPTORS Gen ID: 1813

11q23.2

65,685

Dopamine receptor D2, DRD2

ALCOHOL-METABOLIZING ENZYMES Gen ID: 125

4q23

15,056

Alcohol dehydrogenase 1B (class I), beta polypeptide, ADH1B GEN ID: 217 Aldehyde dehydrogenase 2 family (mitochondrial), ALDH2 GEN ID: 1571

11,754

Cytochrome P450 family 2 subfamily E member 1 CYP2E1

Data obtained at NCBI GenBank: Accessed August 2017. Bp: base pairs; Rs: Reference sequence.

this risk allele documented to date have been found in indigenous populations from Mexico, including Mayas (70%), Nahuas, and Huicholes (65% and 67%, respectively) and Pima Indians (63%) (Panduro et al., 2017a). In contrast, Asian (Chinese, Japanese, Vietnamese) and African (Nigerian, Gambian, Kenyan) populations present a 40% frequency of this allele. In contrast, certain European populations have some of the lowest frequencies (about 20%) described across the globe including Britain and Italy (1000 Genomes Project Consortium, 2015).

Other polymorphisms within the DRD2 gene have been implicated in alcohol-related phenotypes. The Callele and C/C genotype of the synonymous C957T polymorphism showed a decreased DRD2-binding and strong association with alcohol dependence (Swagell et al., 2012). A significant association between a deletion polymorphism 141C Ins/Del in the promoter region of the DRD2 gene and early onset of alcohol dependence was found (Grzywacz et al., 2012). Another SNP located in exon 8 of the DRD2 gene (A1385G) correlated with the presence of alcohol withdrawal syndrome with

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50. GENES AND ALCOHOLISM: TASTE, ADDICTION, AND METABOLISM

Genetic Susceptibility Profiles Associated With Alcoholism Phenotypic outcome

Genes

Risk profile

Protective profile

Alcohol bitterness perception

Nontaster

Taster

TAS2R38

AVI or AVV haplotype carriers do not perceive greater ethanol bitterness

PAV or PAI haplotype carriers perceive greater ethanol bitterness

Alcohol addiction

Addictive behavior

Nonaddictive behavior

DRD2/ANKK1

DRD2/ANKK1 Taq A1 have a higher consumption of alcohol and unhealthy foods

DRD2/ANKK1 Taq A2 have a moderate consumption of alcohol and unhealthy foods

Alcohol metabolism Lower acetaldehyde levels

Higher acetaldehyde levels

Alcohol dehydrogenase (ADH) ADH1B

ADH1B 1

ADH1B 2

Lower enzymatic activity

Higher enzymatic activity Unpleasant alcohol consumption related symptoms and signs

Aldehyde dehydrogenase (ALDH) ALDH2

ALDH2 1

ALDH2 2

Active form

Inactive form

Higher acetaldehyde turnover to acetate

Lower acetaldehyde turnover to acetate Unpleasant alcohol consumption related symptoms and signs

Cytochrome P450 (CYP2E1) CYP2E1

CYP2E1 C2

CYP2E1 C1

Higher acetaldehyde turnover to acetate

Lower acetaldehyde turnover to acetate

seizures (Grzywacz et al., 2012). Furthermore, DRD2 haplotypes have been associated with some alcoholrelated phenotypes in distinct populations (Kraschewski et al., 2009) (Table 50.1, middle section).

Influence of Alcoholism-Related Taste and Addiction Genes With Food Choice Taste and addiction genetic signatures that confer high risk for alcoholism also affect food choices. This scenario may predispose people with these genetic factors to obesity and chronic diseases due to the high consumption of unhealthy foods and alcohol abuse. The bitter taste related to alcohol consumption also influences the intake of cruciferous vegetables (Bartoshuk, Duffy, & Miller, 1994). Studies in children show that PROP tasters do not prefer bitter, cruciferous vegetables. In contrast, children with TAS2R38 nontaster genotypes consume more energy from sugary foods and beverages (Joseph, Reed, & Mennella, 2016). Moreover, PROP nontasters seem to have a greater body composition and higher

preference for fatty foods (Keller, 2012). Other genes such as CD36 could predispose to increased fat consumption in African populations (Keller, 2012). It is not clear whether TAS2R38 directly affects body composition (Ortega et al., 2016). Gender, age, ethnicity, and social, emotional, and cognitive factors could be interacting with genetics. Furthermore, disturbances in BRS trigger unhealthy food consumption. Lack of self-control is common in people with addiction disorders (MacKillop, 2013), who could also be at high risk for being overweight or obese. Similarly, emotional alterations influence addictive behaviors. A western type of diet provides small, short-term rewarding feelings to a greater degree than healthy eating, thus, promoting an imbalance of gut bacteria that exacerbate negative emotions (Panduro, Rivera-In˜iguez, Sepulveda-Villegas, & Roman, 2017b). Furthermore, overeating is often an attempt to reduce negative emotions (Gianini, White, & Masheb, 2013; Gibson, 2012). Consumption of high-energy, palatable foods stimulate dopamine release in the BRS and influence motivated behaviors as much as alcohol

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ALCOHOL METABOLISM GENES

and drug use (Russo & Nestler, 2013; Urban & Martinez, 2012). However, it has been shown that people with addictive behavior experience reward deficiency syndrome (RDS) (Blum et al., 1996). Hence, food could reinforce the repetitive behavior among alcoholics by affecting appetite control (Spoelder, Tsutsui, Lesscher, Vanderschuren, & Clark, 2015). DRD2/ANKK1 TaqA1/A2 polymorphism is associated with addictive behaviors, psychiatric and personalities disorders, and cognitive impairments (Gelernter et al., 2006; Noble, 2000; Richter et al., 2015). Emerging research has pointed out that eating disorders are related to DRD2 expression (Genis-Mendoza, Nicolini, Tovilla-Zarate, Lopez-Narvaez, & Gonzalez-Castro, 2016). Moreover, carriers of A1 allele consume more energy-dense foods (carbohydrates and fast food), present overconsumption episodes, and loss of food control when compared with TaqA2 carriers (Epstein et al., 2007). In contrast, in some populations the A1/A1 genotype is not frequent and binge episodes are more influenced by emotional feelings, especially in females (Davis et al., 2012). Nonetheless, these rewarding food behaviors appear to promote weight gain, and the presence of the A1 allele is related to weight gain and body fat percentage (Chen et al., 2012). Notably, the presence of A1 allele interferes with the body’s ability to lose weight. A1 carriers present lower reductions in body composition and lower adherence while dieting when compared with A2 carriers (Roth, Hinney, Schur, Elfers, & Reinehr, 2013).

ALCOHOL METABOLISM GENES Excessive alcohol consumption is associated with chronic diseases such as cancer, diabetes, cardiovascular, liver, and neuropsychiatric diseases (Rehm & Shield, 2013). Physiologically, alcohol abuse is influenced by impairments in alcohol metabolism. Less than 10% of alcohol is excreted in breath, sweat, and urine. The rest is oxidized mainly in the liver (B 90%) and in other organs, such as stomach, muscle, kidneys and brain. The first-pass metabolism occurs by action of alcohol dehydrogenase (ADHσ) in the small intestine. Alcohol enters the hepatocytes by passive diffusion, which depends on blood alcohol concentration (Cederbaum, 2012). Alcohol is oxidized in the cytosol by ADH1B forming a toxic by-product, acetaldehyde. This reaction requires NAD 1 as a cofactor that is reduced to NADH. NAD 1 availability limits this reaction. Acetaldehyde is converted to acetate by ALDH2, and again NAD 1 is reduced to NADH. Acetate can be further oxidized to carbon dioxide (CO2) in the heart, skeletal muscle, and brain, or converted to Acetyl-CoA by Acyl-CoA synthetase short chain family member (ACSS) consuming ATP. Acetyl-

487

CoA can be used for the synthesis of free fatty acids, very low-density cholesterol (VLDL-C), and ketone bodies, or enter the Krebs cycle (Cederbaum, 2012). An illustrative summary of the main metabolic pathways involved in alcohol oxidation is shown in Fig. 50.1 (Zakhari, 2006). However, alcohol metabolism differs according to enzymatic isoforms (Edenberg, 2007). Polymorphic variations among alcohol metabolizing-enzyme genes ADH, ALDH, and CYP2E1 influence alcohol rate metabolism (Table 50.1, lower section). As shown in Figs. 50.1A and B, two metabolic profiles are described which confer a risk or protective profile, respectively. Furthermore, these isoenzymes are present in distinct proportions according to ethnicity (Zuo et al., 2013). For example, the Arg48His polymorphism in the ADH1B gene generates two allelic functional variants referred as ADH1B 1 (Arg48) and ADH1B 2 (His48). ADH1B 1 is more prevalent among Caucasians (Eng, Luczak, & Wall, 2007) than in other populations. In contrast, ADH1B 2 carriers show a higher enzymatic activity (40 100-fold increase), resulting in higher conversion to acetaldehyde, which confers unpleasant symptoms such as flushing, rhinitis, and vomiting, thus reducing the desire to drink (Cook et al., 2005). Therefore, ADH1B 2 is considered a protector allele against alcohol consumption. This variant is predominant among north Asian populations (Japanese, Chinese and Koreans), followed by middle Easters, and is rare among native Mexicans (Roman, ZepedaCarrillo, Morena-Luna, & Panduro, 2013). This polymorphism has recently been associated with high risk of mortality in men (Almeida et al., 2017). Furthermore, the mitochondrial enzyme ALDH2 also presents functional polymorphisms that affect drinking behavior. Glu487Lys in exon 12 has been studied worldwide, showing two variants, ALDH2 1 and ALDH2 2 (Ehlers, Liang, & Gizer, 2012). ALDH2 2 has been referred to as a protective variant against alcoholism in Asian populations due to its low or null activity, which promotes lower acetaldehyde turnover to acetate. Therefore, manifestations of unpleasant alcohol consumption appear, and alcohol consumption ceases. In contrast, in populations with Mexican-Amerindian ancestry, the protective allele is absent (GordilloBastidas et al., 2010; Roman et al., 2013). An alternative microsomal pathway is activated at high alcohol blood concentrations by the CYP2E1 enzyme producing ROS, toxic, and carcinogenic compounds. The -1053 C/T polymorphism encoded in the CYP2E1 gene generates CYP2E1 C1 and CYP2E1 C2 allelic variants. Carriers of C2 allele show an increased enzymatic activity that rapidly converts ethanol into acetaldehyde. The highest prevalence in the world of the C2 allele has been reported in native Mexican Huicholes (Gordillo-Bastidas et al., 2010).

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1A: Genetic protection Portal vein

Ethanol Peroxisomes

MEOS

Catalase

CYP2E1*C1

Ethanol

Acetaldehyde

H2O2

H2O

Acetaldehyde NADP+ + 2H2O

NADPH + H+ + O2

NAD + ADH1B*2 NADH Acetaldehyde Mitochondria

Acetaldehyde NAD+ ALDH2*2 NADH Acetate

Circulation ATP

ACSS AMP Acetyl-CoA

CO2 TCA

Energy required tissues

FFA

VLDL

Ketone bodies

1B: Genetic risk

FIGURE 50.1 Genetic variants of alcohol metabolizing-enzymes. ADH1B and ALDH2 enzymes metabolize alcohol in the liver into acetaldehyde, and then to acetate. The enzyme CYP2E1 (Km 5 8 10 mM) metabolizes alcohol at high blood concentrations. The peroxisomal catalase is an alternate pathway. A, genetic protection variants include: ADH1B 2 (Km 5 1.9 mM, Vmax 5 4.8 U/mg) carriers, which have a higher enzymatic activity, resulting in higher conversion to acetaldehyde; ALDH2 2 (Km 5 0.0046 mM, Vmax 5 0.017 U/mg) carriers have lower acetaldehyde turnover to acetate, and CYP2E1 C1 carriers have lower enzymatic activity. B, genetic risk variants include: ADH1B 1 (Km 5 0.016 mM, Vmax 5 0.18 U/mg) carriers have a lower enzymatic activity; ALDH2 1 (Km 5 0.00020 mM, Vmax 5 0.60 U/mg) carriers have higher acetaldehyde turnover to acetate, and CYP2E1 C2 carriers show an increased enzymatic activity that rapidly converts ethanol into acetaldehyde. MEOS, microsomal ethanol oxidizing system, ACSS, Acyl-CoA synthetase short chain family member, CO2, carbon dioxide, FFA, Free fatty acids, very low-density cholesterol, TCA, tricarboxylic acid cycle.

Portal vein

Ethanol

MEOS

Peroxisomes CYP2E1*C2

Catalase Acetaldehyde

Acetaldehyde

Ethanol NADPH + H+ + O2

H2O2

H2O

NADP ++ 2H2O

NAD+ ADH1B*1 NADH

Acetaldehyde

Mitochondria Acetaldehyde NAD+

ALDH2*1

NADH Acetate

Circulation ATP

Energy required tissues

ACSS

AMP

CO2 TCA

Ketone bodies

Acetyl-CoA

FFA VLDL

SOCIOCULTURAL FACTORS Alcohol drinking is a human practice in which the biological and social tolerance towards ethanol are entwined. Genetic polymorphisms derived from coevolutionary processes may have enabled humans to use the additional calories of alcohol without harm. However, allele distribution and cultural differences may influence the prevalence of a risk or protective genetic profile towards alcohol addiction combined

with a modern-day lifestyle (Table 50.2). For example, in Mexico, the production of low-degree alcoholic beverages such as tejuino and pulque obtained by the fermentation of the endemic maize and agave plants, respectively, were part of a traditional Mesoamerican lifestyle (Roman et al., 2013). On the other hand, drinking was prohibited for most of the native population and was reserved only for the sick and warriors, or during certain religious festivities. Interestingly, Mexican-Amerindians have a higher prevalence of the

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REFERENCES

risk alleles than modern Mexicans (Mestizos). Nonetheless, after Spanish colonization, not only a genetic admixture of the native population was initiated, other drinks such as wine, beer, mezcal, and tequila became available, and the pattern of drinking was modified. Currently, the heterogeneticallyadmixed population is exposed to high-caloric foods and alcohol and are at higher risk for chronic diseases. More so, the high-risk score of drinking patterns in Mexico is typified by three stages of drinking (Panduro et al, 2017a; Roman et al., 2013). Regional alcoholic beverages are consumed in family festivities at early ages and those who continue to drink excessively during adulthood may provoke an early onset of liver disease, especially in Mestizo individuals with genetic susceptibility. In contrast, native populations that maintain their traditional lifestyle despite their risky genetic background are less prone to liver damage even when consuming large quantities of alcohol (Panduro et al., 2017a).

MINI-DICTIONARY OF TERMS Taster People that perceive more intensively bitter flavor. Medium tasters People that perceive PROP as a moderately bitter flavor. Supertasters People that perceive PROP as extremely bitter. Nontaster People that less intensively perceive bitter flavor. Reward deficiency syndrome A dopamine deprivation that affects emotions and cognition among people with addictions. Tejuino Alcoholic beverage obtained by fermented maize. Pulque Alcoholic beverage obtained by fermented agave sap.

KEY FACTS Genetic Marks for Alcoholism • Alcohol consumption and addiction are mediated by taste, flavor perception, brain reward systems, and alcohol detoxification pathways. • TAS2R38 polymorphisms modulate the nontaster phenotype, affecting alcohol perception and food intake. • DRD2/ANKK1 Taq1A polymorphism is associated with addictive behaviors, such as alcohol intake and unhealthy eating patterns. • Genetic variations in detoxification liver enzymes (ADH1B, ADH1C, ALDH2, and CYP2E1) mediate the metabolic rate of alcohol. • Key gene polymorphisms have a heterogeneous allele frequency among different populations that influence the pattern of drinking.

SUMMARY POINTS • This chapter describes some important key genes involved in alcohol addiction. • These genes include the bitter taste receptors, (TASR238), dopaminergic transmission pathways (DRD2), and alcohol-metabolizing enzymes (ADH, ALDH, CYP2E1). • The risk of addiction is associated with an alcohol nontaster, low D2 receptor density, and lower acetaldehyde accumulation profile. • Protection against addiction is associated with an alcohol taster, higher D2 receptor density, and higher acetaldehyde accumulation profile. • Additionally, the risk genetic profile of excessive alcohol consumption seems to predispose alcoholics to become overweight or obese by inducing the intake of unhealthy foods. • Social and cultural factors influence the availability of alcohol and patterns of drinking.

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