V8 Pharmacogenomics

1. V8 Pharmacogenomics Test 2 Review of lecture V7 + paper 6 .. Biological Sequence Analysis

2. Pharmacogenomics Pharmacogenomics is the branch of pharmacology which deals with the influence of genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with a drug's efficacy or toxicity. By doing so, pharmacogenomics aims to develop rational means to optimise drug therapy, with respect to the patients' genotype, to ensure maximum efficacy with minimal adverse effects. Such approaches promise the advent of "personalized medicine", in which drugs and drug combinations are optimised for each individual's unique genetic makeup. Pharmacogenomics is the whole genome application of pharmacogenetics, which examines the single gene interactions with drugs. www.wikipedia.org Biological Sequence Analysis

3. Expected benefits from pharmacogenomics Pharmacogenomics Licinio, Wang (Eds) Wiley (2002) Biological Sequence Analysis

4. SNPs that influence drug metabolism Pharmacogenomics Licinio, Wang (Eds) Wiley (2002) Biological Sequence Analysis

5. Mutation in TMD4 of 2-adrenergic receptor Well characterized drug target for anti-asthma medication. Thr164Ile mutation occurs at low Frequency. According to homology model mutant Ile interacts with Ser165. This affects ligand binding constant. Pharmacogenomics Licinio, Wang (Eds) Wiley (2002) Biological Sequence Analysis

6. Mutation in TMD4 of 2-adrenergic receptor Green et al. J. Biol. Chem. 268, 23116 (1993) Biological Sequence Analysis

7. Mutations on HIV protease surface Boden & Markowitz, (1998) Biological Sequence Analysis

8. Pharmacogenomics of cigarette smoking WHO: tobacco smoking is responsible for death of ca. 5 million people/year. approximately 22% of adults in the United States are smokers. Although the majority (~80%) of smokers express a desire to quit smoking, less than 5% are able to do so unaided owing to the highly addictive properties of nicotine, the primary psychoactive substance in tobacco smoke. FDA-approved pharmacotherapies to aid smoking cessation include nicotine replacement therapies and the antidepressant bupropion (Zyban). There is large interindividual variability in response and few maintain long-term abstinence.  need to better understand the biological determinants of nicotine dependence (ND) and cessation. What genetic factors determine response to nicotine replacement therapies? Ho & Tyndale, Pharmacogenomics J. 7, 81 (2007) Biological Sequence Analysis

9. Pharmacogenomics of cigarette smoking Cigarette smoking is a complex behavior that includes a number of stages such as initiation, experimentation, regular use, dependence, cessation and relapse. Although environmental factors such as the influence of family members, peers and culture undoubtedly affects one’s smoking behaviors at these stages, genetics also has a substantial role. Numerous twin, adoption and family studies have been performed on the heritability of ‘ever’ smoking. Once smoking is initiated, the heritability for persistence to regular smoking has been estimated at 28–84%, for number of cigarettes smoked at 45–86% and for diagnosed ND at 31– 75%. A genetic influence on nicotine withdrawal symptoms and smoking cessation has also been identified with heritability estimated at 26–48 and 50–58%, respectively. Taken together, these studies suggest a substantial genetic contribution to most aspects of smoking. Ho & Tyndale, Pharmacogenomics J. 7, 81 (2007) Biological Sequence Analysis

10. Genome-wide linkage studies Genome-wide linkage studies have become more feasible with the availability of denser markers, higher throughput and cost-effective genotyping methods. Some of the loci associated with ND are near genes of known biological relevance, including the - 1-opioid receptor (OPRM1) on chromosome 6, - serotonin receptor5A on chromosome 7 - 2-nicotinic acetylcholine receptor (CHRNA2) and - 1A-adrenergic receptor (ADRA1A) on chromosome 8. Loci identified with other smoking phenotypes also contain some biologically interesting candidates, such as a region on chromosome 5q located near the dopamine receptor (D1) gene. Ho & Tyndale, Pharmacogenomics J. 7, 81 (2007) Biological Sequence Analysis

11. Ho & Tyndale, Pharmacogenomics J. 7, 81 (2007) Biological Sequence Analysis

12. Dopaminergic system The dopaminergic system has received considerable attention because its role in the rewarding properties of nicotine is well established. Dopamine receptors are a class of G-protein-coupled receptors with five different subtypes (D1–D5) encoded by the genes DRD1–5. Genome-wide linkage analyses have implicated a region near DRD2 on chromosome 11q23 with cigarette consumption. Genetic variation in DRD2 has been investigated; the TaqI A1 variant is a 32806 CT substitution at 10 kb downstream of DRD2 and lies within a novel, as yet uncharacterized, kinase gene ANKK1. Some studies, but not all, found the TaqI A1 allele resulted in a lower density of D2 receptors in the human striatum in vitro and in vivo. Ho & Tyndale, Pharmacogenomics J. 7, 81 (2007) Biological Sequence Analysis

13. Dopamine receptor Dopamine receptors are prominent in the vertebrate central nervous system. The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors. dopamine • Dopamine receptors have key roles in many processes, including • the control of motivation, • learning, and • fine motor movement, as well as • modulation of neuroendocrine signaling. • Abnormal dopamine receptor signaling and dopaminergic nerve function is implicated in several neuropsychiatric disorders. www.wikipedia.org Biological Sequence Analysis

14. Dopaminergic system The Taq1 B1 allele is a second RFLP that lies 913 bp upstream of the start codon in exon 2 of DRD2, suggesting that it may be a better marker for association studies of substance abuse. It is in significant linkage disequilibrium with the Taq1 A1 allele. In population genetics, linkage disequilibrium is the non-random association of alleles at two or more loci, not necessarily on the same chromosome. Linkage disequilibrium describes a situation in which some combinations of alleles or genetic markers occur more or less frequently in a population than would be expected from a random formation of haplotypes from alleles based on their frequencies. Non-random associations between polymorphisms at different loci are measured by the degree of linkage disequilibrium (LD). Linkage disequilibrium is generally caused by genetic linkage and the rate of recombination; rate of mutation; random drift or non-random mating; and population structure. Similar to the Taq1 A1 allele, individuals with the Taq1 B1 allele were more likely to have ever smoked and started smoking at an earlier age. A 48-bp variable number tandem repeat in exon 3 of DRD4 has also been of interest; genome-wide linkage analyses have implicated a region on chromosome 11p15.5 near DRD4 with habitual smoking. Ho & Tyndale, Pharmacogenomics J. 7, 81 (2007) Biological Sequence Analysis

15. Dopaminergic system In African Americans, but not Caucasians, the long (L) allele (containing 6–10 repeats) has been associated with a greater risk of current smoking, and a shorter time before the first cigarette in the morning compared to the short (S) allele (containing 2–5 repeats). Individuals with the L-allele also experienced greater craving, more arousal, less positive affect and more attention to smoking cues than individuals with the S-allele. In adolescents, the L-allele (seven-repeat) increased the risk of smoking and novelty seeking in males; however, another study failed to replicate these findings. Ho & Tyndale, Pharmacogenomics J. 7, 81 (2007) Biological Sequence Analysis

16. Drug transporters and their cellular localizations OAT: organic anion transporter OCT: organic cation transporter PepTs: peptide transporters MDRs: multi-drug resistant proteins MRPs: multidrug resistance-related proteins BCRP: breast cancer resistance protein Pharmacogenomics Licinio, Wang (Eds) Wiley (2002) Biological Sequence Analysis

17. V9: pharmacogenomics of efflux pump P-glycoprotein Pharmacogenomics Licinio, Wang (Eds) Wiley (2002) Biological Sequence Analysis