The presentation describes and discusses the pharmacogenetic aspects of Nicotine and its implication in the treatment of nicotine addiction.

1. PHARMACOGENOMICS OF
NICOTINE
Dr Udit Panda
PDF, CAM

2. DEFINITIONS
• PHARMACOGENETICS: The Study of how a single target gene or a group of related
genes affect a person’s response to drugs
• A science combining knowledge of Pharmacology + Genetics
• PHARMACOGENOMIS: Boarder variations at the level of genome in context to
drug response
• Pharmacogenomics includes Pharmacogenetics
• PRECISION MEDICINE: Personalization of both Pharmacological and Behavioural
Treatments

3. PHARMACOGENOMICS OF NICOTINE
• GENES WITH HIGH ASSOCIATION IN GWA STUDIES:
• CHRNA5 (nAcH Receptor α5 Subunit)
• CYP2A6 (Cytochrome P450 2A6)
• DBH(Dopamine beta-hydroxylase)
• CHRNA4 (nAcH Receptor α4 Subunit)
• GENES SELECTED IN CANDIDATE GENE STUDIES:
• COMT (Catechol-o-methyl transferase)
• DRD2 (Dopamine Receptor D2)
• DRD4 (Dopamine Receptor D4)
• CYP2B6 (Cytochrome P450 2B6)

4. CHRNA5 Gene-Chromosome 15q25
• Significant association in GWAS
• Nicotine dependence- rs16969968(A allele), rs880395(C allele)- High Vs
Low Risk Haplotype
• Smoking heaviness/ CPD (Cigarettes Per Day)
• Biomarkers of smoking (Cotinine, CO levels)
• Difficulty in quitting
• Complications like COPD, Lung Cancers
• Delayed smoking cessation, Early onset of complications
(Nancy LS et al, 2017)

5. CHRNA5-A3-B4- Pharmacogenomics
• Differential response to various pharmacological cessation approach
• rs1051730, rs588765, rs2036527 and rs16969968- Interaction with
Nicotine Outcome
• SNP- rs16969968: Changes Aspartic Acid to Asparagine- Higher
response to NRT in European population, Not replicated

6. (Salloum LC et al, 2018)

7. CYP2A6-Chromosome 19q13
• Metabolism of Nicotine and Cotinine
• Significant association in GWAS
• Smoking heaviness/ CPD (Cigarettes Per Day)
• Biomarker of nicotine metabolism- NMR
• EGLN-2: Gene associated with response to hypoxia, Independently
associated with smoking behavior and efficiency
(Katrina GC el al,2019)

8. BIOMARKER OF CYP2A6 ACTIVITY
• NMR- Nicotine Metabolite Ratio
• Plasma/ Salivary 3’ Hydroxycotinine/ Cotinine
• Basing Upon NMR, FAST VS SLOW METABOLIZER
• Higher NMR= Faster Nicotine Metabolism High CYP2A6 Activity
• Genetic Variation in CYP2A6= Individual Variation in NMR
• CYP 2A6 intervening sequence four (IVS4) variant, rs56113850 =
reduced NMR activity- GWAS association in multiethnic populations

9. • Slow metabolizer: Low consumption, Dependence, nChAr availability, cue
response, Higher smoking cessation rate in absence of pharmacotherapy
• Slow metabolizers have more success with NRT, Counselling or Cold
Turkey- Based on NMR Study
• Cotinine/Cotinine+ Nicotine= Another estimate for CYP2A6 activity
• Basing on above method: Fast metabolizer show more response to NRT
• Faster metabolizers better quit on Varelicline Vs Nicotine Patch. Slower
metabolizer: Similar efficacy with Patch Vs Varenicline
(Zhang Y et al, 2016)(Chen LS et al, 2014)

10. Pharmacogenomics of CYP2A6
• Moderates the outcome of NRT but not Bupropion
(Salloum LC et al, 2018)

11. DBH Gene- Chromosome 9q34
• DBH rs3025343 polymorphism and smoking cessation
• RCT on 744 smokers- GA/AA of DBH and CC/Ct of DRD2- OR of
abstinence on NRT 3.59 (Johnston EC et al, 2014)
(Salloum LC et al, 2018)

12. CHRNA4-Chromosome 20q13
• CT/TT genotypes of CHRNA4 rs1044396 polymorphism- comparable
efficacy of “V” with “V+BP” and “BP+NRT” (Santosh JR et al, 2015)
• CC variant of CHRNA4 shown low success rate of Varenicline
• CHRNA4 rs1044396 polymorphism moderates the effect of
varenicline when compared with combined varenicline and bupropion
or NRT and bupropion.
(Salloum LC et al, 2018)

13. COMT GENE- Chromosome 22q11
• Val108/158Met polymorphism rs4680 , COMT gene- Effect of NRT
• Likelihood of abstinence Met/Met group > Val/Val or Val/Met group
on NRT
• SNP variant rs165599 moderates the effect of bupropion
(Salloum LC et al, 2018)

14. DRD2 Gene- Chromosome 11q23
• Most studied gene prior to GSWA era
• Taq1A or rs1800497- Moderating effect of Bupropion
• Taq1A CC genotype significantly higher rates of abstinence with
Bupropion, no difference when possessing one or two T alleles
(Lerman C et al, 2005)

15. (Salloum LC et al, 2018)

16. DRD4 gene- Chromosome 11p15
• VNTR polymorphism in EXON-III of DRD4 Gene Low DRD4 mRNA
expression
• Higher Response to Bupropion
(Leventhal AM, 2012)
(Salloum LC et al, 2018)

17. CYP2B6 Gene- Chromosome 19q13
• Metabolize Bupropion to Hydroxybupropion (active form)
• CYP2B6*4 and CYP2B6*6 moderate effect of Bupropion but not
Varenicline on abstinence (Ma H, 2018)
(Salloum LC et al, 2018)

18. EPIGENETIC MODIFICATION
• DNA METHYLATION- Methyl group attach to Cytosine-Guanine (CpG)
dinucleotide
• Analogous to GWAS with SNPs
• 200 replicated methylation sites- AHRR( Aryl Hydrocarbon Receptor
Repressor), CPOX (Coproporphyrinogen oxidase), F2RL3 most known
• Presence prior to smoking, concurrent to smoking, partial reversal upon
abstinence
(Philibert RA et al, 2012)

19. POSSIBLE USE OF DNA METHYLATION
Evaluation of
Smoking
Cessation
Predict
Complication
Risk (F2RL3)
Role in NMR
Smoking
status/history

20. CONCLUSION
• Pharmacokinetic Markers Genes: CYP2A4
• Pharmacodynamic Marker Genes: CHRNA5, DBH, CHRNA4Efficacy of NRT:
• Pharmacokinetic Markers Genes: COMT, CYP2B6
• Pharmacodynamic Marker Genes:DRD2, DRD4
Efficacy of
BUPROPION:
• Pharmacokinetic Marker Gene: OCT2
• Pharmacodynamic Marker Gene: CHRNA4
Efficacy of
VARENICLINE:

21. DISCREPANT RESULTS- Possible Causes
• Sample ascertainment
• Low Study Power
• Concurrent Non-Pharmacological T/T
• Other Confounders like comorbid mental illness, SUD
• Most studies on European ancestry, no ethnic variability
• Shortcomings in Study Designs:
• Lack of randomization
• Lack of Placebo control

22. THANK YOU