**7. Pharmacogenetics of alcoholism**

The sequencing of the human genome has become the foundation for one of the most significant scientific contribution, the idea that although all human individuals are genetically similar, each retains a unique genetic identity. The publication of the human blueprint has triggered an explosion in pharmaceutical research to utilize this knowledge in the prescription of drugs for various ailments including alcoholism to be tailored according to the genetic makeup of susceptible individuals or in other words personalized medicine.

Just before half a century ago the Human Genome Project, scientists had realized that inheritance was an important factor which accounts for individual variation in drug response (Kalow, 1962; Venter et al., 2001). This led to the birth of the term Pharmacogenetics. Pharmacogenetics is the study of the role of inter-individual genetic variation in drug response. Although human beings are 99.9% similar in their genetic makeup, 0.1% variability in terms of single-nucleotide polymorphisms is significantly accountable for an individual's susceptibility to diseases and inter- and intra-individual variation of drug response (Brooks, 1999).

On the basis of our current understanding of neurobiology numerous candidate genes have been implicated in the etiology and response to treatments for different addictions including alcoholism. The focus is on functional genetic variants of proteins involved in the neural response to alcohol including alcohol sensitivity, reward and tolerance and variants of the enzyme involved in metabolism of alcohol.

## **8. Genetic predictors of medication response**

The inter-individual variation in drug response results in categorization of alcoholic patients into responders and nonresponders. The responders experience therapeutic efficacy with a particular drug given in therapeutic range without any toxicity or adverse effects. The nonresponders do not show any therapeutic effect, even when the administered drug reaches to peak level in blood, leading to ineffective treatment, known as poor as poor metabolizers. Therefore the traditional approach of one dose fits for all is no longer helpful in predicting the therapeutic efficacy of a drug. The pharmacogenetics focuses on identifying genetic factors that is with are responsible responsible for variability in pharmacotherapeutic effect both in terms of pharmacodynamics and efficacy (Evans &Johnson, 2001). The field has greatly benefitted from advances in molecular genetic tools, developments in bioinformatics and functional genomics for identifying genetic variants.

Genetic factors can account for interindividual differences in drug toxicity and efficacy in many ways e.g. the variability in genes may lead to differences in drug metabolism and disposition through functional differences in activity of enzymes or drug transporters (Ray et al., 2010a). Alternatively genetic variation may impact a drug's target such as particular receptor. Genetic variants that may modulate the effects of naltrexane have been identified in the gene coding for µ OPRM1, which is the primary target of naltrexaone (Oslin et al., 2003). One of the most widely studied SNPs in OPRM1 is +118A/G (rs 1799971) located in the +118 position of exon1 one which encodes for Asn40Asp substitution (Bond et al., 1998). This A/G substitution has been reported to affect the receptor affinity for endogenous ligands, β-endorphin leading to gain in function such that the G variant was thought to bind β-endorphin with greater affinity than A allele. However, some recent studies have shown

The sequencing of the human genome has become the foundation for one of the most significant scientific contribution, the idea that although all human individuals are genetically similar, each retains a unique genetic identity. The publication of the human blueprint has triggered an explosion in pharmaceutical research to utilize this knowledge in the prescription of drugs for various ailments including alcoholism to be tailored according to the genetic makeup of susceptible individuals or in other words personalized medicine. Just before half a century ago the Human Genome Project, scientists had realized that inheritance was an important factor which accounts for individual variation in drug response (Kalow, 1962; Venter et al., 2001). This led to the birth of the term Pharmacogenetics. Pharmacogenetics is the study of the role of inter-individual genetic variation in drug response. Although human beings are 99.9% similar in their genetic makeup, 0.1% variability in terms of single-nucleotide polymorphisms is significantly accountable for an individual's susceptibility to diseases and inter- and intra-individual

On the basis of our current understanding of neurobiology numerous candidate genes have been implicated in the etiology and response to treatments for different addictions including alcoholism. The focus is on functional genetic variants of proteins involved in the neural response to alcohol including alcohol sensitivity, reward and tolerance and variants of the

The inter-individual variation in drug response results in categorization of alcoholic patients into responders and nonresponders. The responders experience therapeutic efficacy with a particular drug given in therapeutic range without any toxicity or adverse effects. The nonresponders do not show any therapeutic effect, even when the administered drug reaches to peak level in blood, leading to ineffective treatment, known as poor as poor metabolizers. Therefore the traditional approach of one dose fits for all is no longer helpful in predicting the therapeutic efficacy of a drug. The pharmacogenetics focuses on identifying genetic factors that is with are responsible responsible for variability in pharmacotherapeutic effect both in terms of pharmacodynamics and efficacy (Evans &Johnson, 2001). The field has greatly benefitted from advances in molecular genetic tools, developments in bioinformatics and functional genomics for identifying genetic variants.

Genetic factors can account for interindividual differences in drug toxicity and efficacy in many ways e.g. the variability in genes may lead to differences in drug metabolism and disposition through functional differences in activity of enzymes or drug transporters (Ray et al., 2010a). Alternatively genetic variation may impact a drug's target such as particular receptor. Genetic variants that may modulate the effects of naltrexane have been identified in the gene coding for µ OPRM1, which is the primary target of naltrexaone (Oslin et al., 2003). One of the most widely studied SNPs in OPRM1 is +118A/G (rs 1799971) located in the +118 position of exon1 one which encodes for Asn40Asp substitution (Bond et al., 1998). This A/G substitution has been reported to affect the receptor affinity for endogenous ligands, β-endorphin leading to gain in function such that the G variant was thought to bind β-endorphin with greater affinity than A allele. However, some recent studies have shown

**7. Pharmacogenetics of alcoholism** 

variation of drug response (Brooks, 1999).

enzyme involved in metabolism of alcohol.

**8. Genetic predictors of medication response** 

that G allele has a loss of function rather than a gain. Further, the results of the study testing the relationship between this SNP of the OPRM1 gene and alcoholism have shown inconsistent results, some support the association of this SNP and alcohol dependence while others have failed to replicate this association (Schinka et al., 2002; Kranzler et al., 1998; Town et al., 1999). Further, this SNP of OPRM1 gene has also been associated with a differential response in clinical trials of naltrexone. Oslin et al. (2003) has reported that this SNP is associated with clinical response to naltrexaone among alcohol dependent patients such that individuals with at least one copy of the G allele, coding for more potent OPRM1 receptor reported lower relapse rates and longer time to return to heavy drinking after treatment with naltrexone, in comparison with individuals who were homozygous for the A allele.

It has been reported that persons of Asian descent possess an ALDH2\*2 genetic variant (Quertemont et al., 2004). ALDH2\*2 genetic variant of the ALDH enzyme metabolizes slowly and leads to accumulation of acetaldehyde (Edenberg, 2007). When the individuals bearing this variant drink alcohol they develop high acetaldehyde blood concentration and experience of flushing reaction similar to that seen in combination of ethanol and disulfiram. ALDH2\*2 variation is the best characterized genetic factor protecting against the development of alcohol dependence. Pharmacogenomic studies suggest that it is highly unlikely that disulfiram will be helpful in treating the patients who have genetically compromised ALDH.

In addition disulfiram chelates copper and thus inhibits copper containing enzyme dopamine beta hydroxylase which further inhibits norepinephrine and dopamine in brain (Haile et al., 2009). The individuals harboring TT allele of dopamine beta hydroxylase (DβH) gene with C1021T polymorphism respond better to disulfiram treatment and need less dose whereas carriers (CT) would need intermediate dose and those with CC allele need maximum concentration to reach the efficacy level.

Acamprosate, is a drug used for abstinence and maintenance as it reduces craving in alcoholic patients who have undergone detoxification (De Witte et al., 2005). The effective acamprosate response in alcohol dependent subjects may be influenced by genetically controlled variation of NMDA receptor and the type of glutaminergic mGLU5 receptor. Confirmation of this hypothesis could lead to development of effective individualized treatment and recommendation for alcohol dependent patients based on pharmacogenetically relevant genetic variant.

Ondansetron, an antagonist of serotonin is important in the treatment of alcoholism. Serotonin transporter gene is an important regulator of neuronal 5-HT's function. The genetic difference in this gene may modulate the severity of alcohol consumption and predict the therapeutic response to 5-HT3 receptor antagonist ondansetron. A variable tandem repeat polymorphism (5-HTT LPR) is common in the promoter region of 5-HTT gene which alters the transcriptional activity. Two important variants are long (insertion LL) and short (SS) version. It has been reported in a randomized clinical trial that individuals with LL genotype (Homozygous for the long version) of 5-HTT gene showed significant results in improvements of alcoholism with treatment of ondansetron as compared to LS and SS genotype (Johnson et al., 2011).

Another functional T/G polymorphism (rs1042173) as in the 3/ untranslated region of the 5- HTT gene may alter the therapeutic response in alcoholism treatment with ondansetron in

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alcohol addiction treatment (Jhonsan et al., 2011). The effect of ondensateron will be higher in individuals possessing the combination of LL genotype and TT genotype of 5-HTT gene.

Fig. 2. Alcoholism Treatment: A Treatment approach to use a trio of Pharmacotherapy using pharmacological agents, where a traditional approach of "One dose for all" is used and Psychotherapy – an important part of treatment in alcoholism and Pharmacogenetics based on Genetic makeup of the Individual for better and effective treatment in alcoholism
