Alcohol Addiction

interpretation

5.6

As per your genotype, you have a typical risk of developing Alcohol Addiction. However, a family history of addiction, regular binge drinking, stress, anxiety, mental and psychological illnesses, emotional trauma, and social and cultural factors may increase your risk of developing Alcohol Addiction.

what is Alcohol Addiction

biology

Alcohol addiction or alcoholism refers to a physical or mental dependence on alcohol. Drinking large amounts of alcohol, whether on a single occasion or over time, can affect the brain, heart, liver, pancreas, and immune system and even cause cancer. Alcohol addiction can lead to tolerance, impaired control of drinking behaviour, and continued alcohol use despite adverse consequences. The specific cause of alcohol addiction is unknown, but there is some evidence of social, cultural, environmental, psychological, and genetic links; another factor for the disorder could be the addictiveness of the substance itself.

symptoms

Overconsumption and intoxication lead to slurred speech, poor balance, temporary blackouts, and short-term memory loss. Alcohol addiction can cause anxiety, irritability, stressed-out feeling, negative thoughts, and restlessness if not drinking. Long-term withdrawal symptoms include trembling, nausea, sleeping troubles, or seizures.

GENE TABLE

Gene name	Genotype	Description
DRD2	CT	DRD2 is present as both presynaptic autoreceptors and postsynaptic receptors. Dopaminergic activation of presynaptic autoreceptors decreases both the release and synthesis of dopamine and increase dopamine reuptake. It is known that low-DRD2 binding is associated with increased drug reinforcing effects and the intensity of this reinforcement is proportional to dopamine release. Reduced density of presynaptic DRD2 may result in decreased autoreceptor activity, thereby resulting in increased dopaminergic transmission and increased drug reward. Abstinent alcohol-dependent patients have decreased DRD2 availability. Low DRD2 availability is also associated with increased craving for alcohol and increased risk of relapse. Furthermore, alcohol-dependent patients exhibit diminished dopamine release following amphetamine challenge, reflecting decreased dopaminergic neurotransmission.
FTO	TT	FTO alpha-ketoglutarate dependent dioxygenase gene is a nuclear protein of the AlkB related non-haem iron and 2-oxoglutarate-dependent oxygenase superfamily but the exact physiological function of this gene is not known. Other non-heme iron enzymes function to reverse alkylated DNA and RNA damage by oxidative demethylation. The FTO gene is expressed in hypothalamus and its effect on BMI probably occurs through modulation of food intake, with the A allele predisposing to a hyperphagic phenotype and/or a preference for energy-dense foods. The relationship between ethanol and BMI is complicated further by the possible effect of alcohol beverage type. While consumption of distilled spirits has been associated consistently with higher obesity indices, wine or beer drinking was either associated positively, inversely or not associated.
CAMKIV	TT	Calcium/calmodulin-dependent protein kinase IV (CAMKIV) is the only CREB-phosphorylating protein kinase that is found predominantly in the nuclei of neurons. It regulates the function of CREB and the transcription of CREB targets, such as neuropeptide Y, brain-derived neurotrophic factor, corticotropin-releasing factor, and activity-regulated cytoskeleton- associated protein, which might play important roles in alcohol-induced molecular changes and genetic predisposition to AD. Alteration of exploratory behavior in rats caused by chronic alcohol intake might entail the downregulation of CAMKIV in nucleus accumbens. Moreover, naloxone may reduce alcohol intake by antagonizing the downregulation of CAMKIV in the nucleus accumbens. CAMKIV is activated by increased intracellular Ca2+ concentration, which is modulated by alcohol. Acute exposure to alcohol can reduce cytoplasmic Ca2+ concentration through several pathways. On the contrary, chronic alcohol exposure elevates the intracellular Ca2+ concentration. CAMKIV is activated by Ca2+/calmodulin, a ubiquitous intracellular Ca2+ receptor involved in various signaling pathways that control the essential cellular processes. In an animal study, it was found that the inhibition of Ca2+/calmodulin will reduce both alcohol intake and its stimulatory effects. It has been proposed that cellular Ca2+ dependent pathways might play important roles in the central effect of alcohol. CREB protein is activated by phosphorylation via CAMKIV and other protein kinases. Reduced CREB phosphorylation in the central amygdala has been suggested to act as a common molecular correlate for anxiety and alcohol drinking behaviors. CAMKIV SNP polymorphisms might affect CREB phosphorylation, which could be associated with the effects of alcohol withdrawal.
ADH1B	GG	Alcohol is metabolized in the liver to acetaldehyde and acetate via the enzymes alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH). Members of this enzyme family metabolize a wide variety of substrates, including ethanol, retinol, other aliphatic alcohols, hydroxysteroids, and lipid peroxidation products. This encoded protein, consisting of several homo- and heterodimers of alpha, beta, and gamma subunits, exhibits high activity for ethanol oxidation and plays a major role in ethanol catabolism. Three genes encoding alpha, beta and gamma subunits are tandemly organized in a genomic segment as a gene cluster.
SLC6A3	GG	The solute carrier family 6 member 3 (SLC6A3) gene (also known as the dopamine transporter DAT gene) consists of 15 exons and is found on chromosome 5p15.3. Polymorphisms at the SLC6A3 locus have been implicated in gene expression, transcriptional activity, and protein availability. The 3' UTR of this gene contains a 40 bp tandem repeat, referred to as a variable number tandem repeat or VNTR, which can be present in 3 to 11 copies. Variation in the number of repeats is associated with idiopathic epilepsy, attention-deficit hyperactivity disorder, dependence on alcohol and cocaine, susceptibility to Parkinson disease and protection against nicotine dependence. The dopamine transporter (DAT1) is a 12-membrane domain Na + /Cl – dependent transporter, which functions as an important regulator of dopaminergic neurotransmission in the mesolimbic system. DAT1 is responsible for reuptake of dopamine (DA) into presynaptic terminals. The mesolimbic system plays a key role in the modulation of salience, reinforcement, reward, motivation, and substance abuse, including alcohol. Ethanolinduced activation of the ventral tegmental area DA function, by increased firing of DA neurons, is postulated as one positive reinforcement mechanism that leads to the development and maintenance of excessive alcohol consumption. After a period of chronic ethanol consumption, there is a substantial deficit in baseline mesolimbic DA function that can be compensated for by further ethanol intake and can lead to the resumption of drinking during alcohol withdrawal. Based on the function of DAT1, many groups have investigated whether DAT1 (locus SLC6A3, on chromosome 5p15.3) genetic variation that affects the level or distribution of the gene product or its function accounts for some of the differences in susceptibility to alcohol use disorders and substance abuse. The most extensively investigated DAT1 polymorphism is a 40-bp 30-untranslated region (30 -UTR) variable number tandem repeat (VNTR) in exon 15.
CPNE5	AA, AC, CT, GA	Copine V (CPNE5, also known as CPN5, COPN5) gene is located at 6p21.2. Copines are a family of calcium-dependent lipid-binding proteins comprised of 2 N-terminal C2 domains (C2Ds) and a C-terminal A domain. The C2Ds contain aspartate residues important for calcium and phospholipid binding. The CPNE5 is one of several genes that encode a calcium-dependent protein containing two N-terminal type II C2 domains and an integrin A domain-like sequence in the C-terminus. CPNE5 is expressed in both neural progenitor cells and the differentiated neurons during the neural development, suggesting that CPNE5 might play an important role in the development of the central nervous system. Although alcohol's effects on the central nervous system, including neuro-cognitive deficits, neuronal injury and neurodegeneration, are well documented, the biological and genetic mechanisms remain elusive. Hence, CPNE5 is a suitable candidate gene for study in AD. e CPNE5 gene is one of the genes in a family of calciumdependent lipid-binding proteins comprised of 2 N-terminal C2 domains (C2Ds) and a C-terminal A domain. It has been reported that the C2 domains of CPNE5 are capable of Ca2+ binding, which plays a key role in the development of the nervous system. CPNE5 is implicated in synaptic function, behavioral plasticity, or resource constraint and is moderately expressed in the adult mouse striatum. Furthermore, previous work reveals a possible association of alcohol tolerance with increased synaptic Ca2+ sensitivity, with alcohol potentially leading to calcium ion (Ca2+) overload. AD can develop at the cellular level, with changes in calcium homeostasis, while alcohol-induced apoptosis may contribute to alcohol-induced brain-vascular damage and stroke. Recent research shows that Ca2+ may play a role in pancreatic cell death and acute pancreatitis induced by alcohol metabolites.
CHRNA3	CC	CHRNA3 locus encodes a member of the nicotinic acetylcholine receptor family of proteins. Members of this family of proteins form pentameric complexes comprised of both alpha and beta subunits. This locus encodes an alpha-type subunit, as it contains characteristic adjacent cysteine residues. The encoded protein is a ligand-gated ion channel that likely plays a role in neurotransmission. Polymorphisms in this gene have been associated with an increased risk of smoking initiation and an increased susceptibility to lung cancer.
ADH1C	AA, CC	The alcohol dehydrogenase 1B and 1C genes (ADH1B and ADH1C) encode class I alcohol dehydrogenase beta and gamma subunits, respectively. These isoenzymes metabolize alcohol into acetaldehyde (among other physiological actions); acetaldehyde is then metabolized into acetate through the aldehyde dehydrogenase 2 gene (ALDH2). The gamma subunit encoded by ADH1C plays a key role in the oxidation catabolism of a wide variety of substrates, including ethanol, retinol, other aliphatic alcohols, hydroxysteroids, and lipid peroxidation products. Polymorphism in this gene is capable of altering ethanol metabolism and reducing genetic susceptibility to the alcohol dependence. Highly active ADH1C can increase the level of acetaldehyde, and then result in enhanced negative reactions to alcohol, which in turn reduces the likelihood of AD.
Near ADH1B	CC	Alcohol is metabolized in the liver to acetaldehyde and acetate via the enzymes alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH). Members of this enzyme family metabolize a wide variety of substrates, including ethanol, retinol, other aliphatic alcohols, hydroxysteroids, and lipid peroxidation products. This encoded protein, consisting of several homo- and heterodimers of alpha, beta, and gamma subunits, exhibits high activity for ethanol oxidation and plays a major role in ethanol catabolism. Three genes encoding alpha, beta and gamma subunits are tandemly organized in a genomic segment as a gene cluster. Genetic polymorphisms in the genes encoding ADH and ALDH are associated with alterations in enzyme kinetics which, in turn, determine the rates of production and removal of the toxic intermediate metabolite acetaldehyde.
HTR2A	CT	The 5-hydroxytryptamine (serotonin or 5-HT) 2A receptor is one of the subtypes of 5-HT receptors (HTR). The 5-HT 2A receptor (HTR2A or formally 5-HT2A) is a member of the G protein superfamily. Presynaptic HTR2A has been localized on dopaminergic neurons within the ventral tegmental area and nucleus accumbens, suggesting an important role within the brain reward system. Postsynaptic activation of the receptor also plays a relevant role in substance dependence. The HTR2A is related to affectivity, regulation, and pharmacologic effects of antidepressant, anti-anxiety and antipsychotic medications. It may also play a role in cellular development and differentiation, while it is the action site of certain drugs and medications. It has also been shown that HTR2A and HTR2C antagonists cause attenuation of alcohol intake in both animals and humans, and activation of HTR2A can reduce ethanol consumption.
GABRG2	CC	Gamma-aminobutyric acid type A receptor gamma2 subunit (GABRG2) gene encodes a gamma-aminobutyric acid (GABA) receptor.GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chloride channels. Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABA-A receptor. At least 16 distinct subunits of GABA-A receptors have been identified. The GABA-A receptor subunits form pentameric receptor, which is most commonly observed in the postsynaptic cell membrane of the mammalian brain, and it allows passage for chloride ions in the center of the pentamer and binding sites for GABA and modulatory drugs. Ethanol is believed to affect GABA-A receptors and their subunit composition. Alterations in the GABA-A receptor subunits are responsible for GABAergic signaling changes, which are ultimately associated with chronic alcohol use. Specifically, the mesolimbic GABAergic neurons act as inhibitory regulators of dopamine (DA) neurons in the ventral tegmental area (VTA) of the brain. However, in the presence of addictive drugs, mesolimbic dopaminergic neurons are activated.
HTR3B	GT	5-hydroxytryptamine receptor 3B (HTR3B) gene encodes subunit B of the type 3 receptor for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. This receptor causes fast, depolarizing responses in neurons after activation. Among the serotonergic receptor subtypes in the human nervous system, 5-HT3 receptors are the only known ion-channel receptors evoking fast excitation of serotonergic neurons. Acute exposure to alcohol potentiates 5-HT3 receptors at concentrations that produce intoxication, possibly through altered receptor affinity for serotonin, stabilization of open-channel state, or increased release of serotonin. Chronic heavy drinking depletes presynaptic serotonin reserves, causing a hypo-serotonergic state that may up-regulate post-synaptic 5-HT3 receptors. The 5-HT3 receptors are assembled in homo- or heteropentamers formed by 5-HT3A and 5-HT3B subunits. The 5-HT3A subunit harbors the serotonin binding site, and the 5-HT3B subunit is important for trafficking and stabilizing of the 5-HT3AB receptor complex at the cell membrane. Whilst the 5-HT3A homomers are uniformly located in various parts of the central and peripheral nervous systems, the 5-HT3AB heteromers are located predominantly in mesocorticolimbic structures implicated in alcohol and other drug addictions. The second is evidence from biochemical studies of greater conductivity with 5-HT3AB hetero-pentamers compared with 5-HT3A homo-pentamers, whereas 5-HT3B by itself appears to be non-functional. The genes encoding 5-HT3AB, namely, HTR3A and HTR3B, are located next to each other on chromosome 11q23.1 spanning a 90-kbp region.
CHRNA5	TT	The protein encoded by CHRNA5 gene is a nicotinic acetylcholine receptor subunit and a member of a superfamily of ligand-gated ion channels that mediate fast signal transmission at synapses. These receptors are thought to be heteropentamers composed of separate but similar subunits. Defects in this gene have been linked to susceptibility to lung cancer type 2
ALDH1A1	AA	Liver cystolic aldehyde dehydrogenase 1 (ALDH1A1) is involved in the degradation of dopamine (DA) in the ventral tegmental area (VTA). This role in the regulation of DA degradation may be important in the development and maintenance of excessive alcohol consumption because VTA DA function can be ethanol induced via increased DA neuron firing, and the VTA lies within the mesolimbic system, which functions in reward, motivation and various substance disorders, including alcohol dependence. ALDH1A1 has been previously associated with both alcohol dependence and alcohol consumption behaviour, and has been implicated in alcohol-induced flushing and alcohol sensitivity in Caucasians.
GAD2	AG	GABA is produced by decarboxylation of L-glutamic acid by two enzymes: glutamic acid decarboxylase-67 (GAD67) and glutamic acid decarboxylase65 (GAD65), which are products of two different genes located on chromosomes 2 (GAD1) and 10 (GAD2), respectively. Animals deleted for GAD2 maintain normal whole brain GABA levels, but show behavioral differences compared to wild-type animals, including increased anxiety behavior in open-field and zero-maze paradigms and decreased response to benzodiazepines and pentobarbital. Most of the sequence differences between GAD2 and GAD1 are located in exons 1–3, while in the other areas of the coding sequence, especially in the area of the cofactor pyridoxal 50 phosphate (PLP) binding site, the genes show a high degree of homology. Considering that GABA is the most ubiquitous inhibitory neurotransmitter in brain, these genes are potential candidates for susceptibility to psychiatric disorders in which GABA dysfunction has been implicated.
PKNOX2	TT	PKNOX2 (PBX/Knotted 1 Homeobox 2) is a Protein Coding gene. Diseases associated with PKNOX2 include Substance Dependence and Hydrolethalus Syndrome. Gene Ontology annotations related to this gene include sequence-specific DNA binding and actin monomer binding. Homeodomain proteins are sequence-specific transcription factors that share a highly conserved DNA-binding domain and play fundamental roles in cell proliferation, differentiation, and death.
AKR1C3	GG	AKR1C3, is a member of the aldo-keto reductase (AKR) superfamily with comparatively broad substrate specificity including estrogenic and androgenic steroid hormones, prostaglandins, drugs, and polycyclic aromatic hydrocarbons. In addition to its 3-keto reductase function, the AKR1C3 gene product displays prominent 17-keto reductase activity. This 17-keto reductase activity is involved in the formation of testosterone from androstenedione. Testosterone is then converted by 5a-R and 3a-HSD activities to the neuroactive steroid 3aandrostanediol, which is a potent anticonvulsant and GABAA receptor modulating compound, whose clinical importance has not been as thoroughly studied as that of allopregnanolone. Finally, the AKR1C3 gene product also has 3b-HSD activity, producing the inactive steroid 3b-androstanediol. It is plausible that the polymorphism in the AKR1C3 gene examined here affects the relative 17b-, 3a- and 3bHSD activities of the gene product, thereby regulating the relative abundance of various steroids, only some of which positively modulate GABAA receptor function.
SERINC2	CT, AG	SERINC2 encodes serine incorporator 2 (Serinc2) that belongs to a cell membrane carrier protein family of Serinc1–5. High concentration of Serinc2 is seen in neurons of the hippocampus and cerebral cortex. Serinc2 co-localizes with lipid biosynthetic enzymes (i.e., serine palmitoyltransferase) in endoplasmic reticulum membranes and interacts with an intracellular serine-synthesizing protein complex that included 3-phosphoglycerate dehydrogenase. It serves as an effector molecule that incorporates serine into membranes and facilitates the synthesis of two serine-derived membrane lipids, phosphatidylserine and sphingolipids (long-chain amino alcohols). Phosphatidylserine is a phospholipid component of cell membranes, with the highest concentrations in the brain. At least 25 intervention studies suggested that consumption of phosphatidylserine supplement may reduce the risk of dementia and cognitive dysfunction in the elderly. Alcohol consumption can increase sphingosine levels in the rat brains. Activity of sphingolipid metabolism enzyme, i.e., acid sphingomyelinase (ASM), was also increased in alcohol-dependent patients. The function of Serinc2 altered by the alleles of functional SERINC2 variants may be implicated in the synthesis of phosphatidylserine and sphingolipids and might thus be relevant for the occurrence of alcohol dependence. Alternatively, Serinc2 might play a role in alcohol dependence by virtue of the glutaminergic pathway. This pathway is widely known to play important roles in alcohol intoxication and withdrawal.
POMC	CT	Pro-opiomelanocortin (POMC), encoded by the polycistronic POMC gene (or POMC) on chromosome 2p23.3, is a polypeptide precursor protein with 241 amino acid residues. As many as 10 functionally different peptides can be derived from POMC via extensive tissue-specific post-translational processing. These peptides include adrenocorticotropin (ACTH), B- and G-lipotropin (B- and G-LPH), A-, B-, and G-melanocyte-stimulating hormone (A-, B-, and G-MSH), corticotropin-like intermediate lobe peptide (CLIP), and B-endorphin. These peptides play crucial roles in numerous biological processes such as pain, energy homeostasis, melanocyte stimulation, and immune modulation. Among these biologically active peptides, ACTH and B-endorphin are two principal components of the hypothalamic-pituitary-adrenal (HPA) axis. ACTH mediates the stress response in vertebrates. Stress induces the secretion of corticotropin-release hormone (CRH) from the hypothalamus, which stimulates ACTH synthesis and release from the anterior pituitary. ACTH, in turn, promotes the release of glucocorticoids (e.g, cortisol, a major stress hormone) from the adrenal cortex. Through negative feedback, glucocorticoids regulate the expression of CRH and ACTH. B-endorphin, an endogenous opioid peptide exerting potent analgesic and euphoric effects through interaction with opioid receptors, is made in neurons of the brain stem, as well as those in the hypothalamus and pituitary. It produces behavioral effects similar to exogenous opioids and is released in the nucleus accumbens (NAc), the major brain reward center. Based on these actions, both ACTH and B-endorphin have been implicated in craving use of drugs and alcohol. Consumption of drugs or alcohol can, in turn, alter HPA function, and modulate the production of ACTH, B-endorphin, or glucocorticoid hormones. Cocaine administration activates the opioid system and the HPA axis, and enhances the secretion of B-endorphin, ACTH and corticosterone in rat, mouse, and human. Similarly, acute ethanol administration induces an increase in the release of pituitary B-endorphin.

do's and dont's

1. Be aware of the signs and consequences of alcohol abuse.

2. Seek professional help and treatment while dealing with alcohol addiction.

1. Quitting alcohol consumption gradually, rather than abruptly, can help avoid withdrawal symptoms.

2. Do not ignore the problem and give up easily.