Association Analysis of CYP2A6 Gene Variant (rs1801272A>T) with Nicotine Metabolism and Smoking Tendency among Pakistani Youth: CYP2A6 Gene Variant (rs1801272A>T) with Nicotine Metabolism and Smoking Tendency

Iqra Yasmin; Haider Ali; Muhammad Rafeh; Muhammad Sikandar; Abdul Kashif; Muhammad Salahuddin; Ammad Shafeeq; Rashid Saif

doi:10.54393/pbmj.v8i6.1236

Authors

Iqra Yasmin Department of Biotechnology, Qarshi University, Lahore, Pakistan
Haider Ali Department of Biotechnology, Qarshi University, Lahore, Pakistan
Muhammad Rafeh Department of Biotechnology, Qarshi University, Lahore, Pakistan
Muhammad Sikandar Department of Biotechnology, Qarshi University, Lahore, Pakistan
Abdul Kashif Department of Biotechnology, Qarshi University, Lahore, Pakistan
Muhammad Salahuddin Department of Biotechnology, Qarshi University, Lahore, Pakistan
Ammad Shafeeq Department of Biotechnology, Qarshi University, Lahore, Pakistan
Rashid Saif Department of Biotechnology, Qarshi University, Lahore, Pakistan https://orcid.org/0000-0001-8915-242X

DOI:

https://doi.org/10.54393/pbmj.v8i6.1236

Keywords:

Smoking Genetics, Cytochrome Gene, CYP2A6 Variants, c.479T>A Locus

Abstract

Cytochrome P450 2A6 (CYP2A6) is a key enzyme in nicotine metabolism, with its genetic variants playing a role in smoking behavior. Particularly, g.40848628A>T is significantly associated with nicotine metabolism and smoking tendency in different populations. Objectives: To examine the genetic diversity of this locus and association analysis within smokers and non-smokers cohorts among Pakistani youth. Methods: The allele-specific ARMS PCR genotyping technique was applied to examine a total of 100 samples as a case-control study of n=50 from each cohort. Results: From the sampled individuals, 92% were found to be homozygous wild-type (AA), 7% were heterozygous (AT), and 1% were homozygous mutant (TT). PLINK software was used for the Chi-square test yielded, χ² (1, n=100) =2.91, p=0.088, suggesting a non-significant trend towards association, where alternative allele frequencies were calculated as 0.07 and 0.02 in cases and control cohorts, respectively. Similarly, Hardy-Weinberg Equilibrium (HWE) p=0.1714 indicates genotype frequencies did not significantly deviate from HW expectations and no error or selection in the overall samples. The carriers of the alternative allele have 3.688 times higher odds of being affected by the condition compared to non-carriers with the reference allele. Conclusions: It was concluded that future studies with a larger sample size may help to clarify the population structure of the subject locus. Genome-wide association studies using next-generation sequencing may also aid in predicting nicotine metabolism and resistance to smoking cessation in the Pakistani population.

References

Tomaz PR, Kajita MS, Santos JR, Scholz J, Abe TO, Gaya PV et al. Cytochrome P450 2A6 and 2B6 polymorphisms and smoking cessation success in patients treated with varenicline. European journal of Clinical Pharmacology. 2019 Nov; 75: 1541-5. doi: 10.1007/s00228-019-02731-z.

Yuan JM, Nelson HH, Carmella SG, Wang R, Kuriger-Laber J, Jin A et al. CYP2A6 genetic polymorphisms and biomarkers of tobacco smoke constituents in relation to risk of lung cancer in the Singapore Chinese Health Study. Carcinogenesis. 2017 Apr; 38(4): 411-8. doi: 10.1093/carcin/bgx012.

Verde Z, Santiago C, Rodríguez González-Moro JM, de Lucas Ramos P, López Martín S, Bandrés F et al. ‘Smoking genes’: a genetic association study. PLOS One. 2011 Oct; 6(10): e26668. doi: 10.1371/journal.pone.0026668.

Jones SK, Wolf BJ, Froeliger B, Wallace K, Carpenter MJ, Alberg AJ. Nicotine metabolism predicted by CYP2A6 genotypes in relation to smoking cessation: a systematic review. Nicotine and Tobacco Research. 2022 May; 24(5): 633-42. doi: 10.1093/ntr/ntab175.

Reitsma MB, Kendrick PJ, Ababneh E, Abbafati C, Abbasi-Kangevari M, Abdoli A et al. Spatial, temporal, and demographic patterns in prevalence of smoking tobacco use and attributable disease burden in 204 countries and territories, 1990–2019: a systematic analysis from the Global Burden of Disease Study 2019. The Lancet. 2021 Jun; 397(10292): 2337-60.

Schoedel KA, Hoffmann EB, Rao Y, Sellers EM, Tyndale RF. Ethnic variation in CYP2A6 and association of genetically slow nicotine metabolism and smoking in adult Caucasians. Pharmacogenetics and Genomics. 2004 Sep; 14(9): 615-26. doi: 10.1097/00008571-200409000-00006.

Siddiqi K, Siddiqui F, Boeckmann M, Islam Z, Khan A, Dobbie F et al. Attitudes of smokers towards tobacco control policies: findings from the Studying Tobacco users of Pakistan (STOP) survey. Tobacco Control. 2022 Jan; 31(1): 112-6. doi: 10.1136/tobaccocontrol-2020-055995.

Al Koudsi N, O'Loughlin J, Rodriguez D, Audrain-McGovern J, Tyndale RF. The genetic aspects of nicotine metabolism and their impact on adolescent nicotine dependence. Journal of Pediatric Biochemistry. 2010 Jun; 1(02): 105-23. doi: 10.1055/s-0036-1586369.

Pehlivan S, Uysal MA, Cagatay T, Nursal AF, Cinar CK, Erkan F et al. CYP2A6 gene variants may explain smoking status in a Turkish cohort. Psychiatry and Clinical Psychopharmacology. 2019 Jul; 29(3): 340-5. doi: 10.1080/24750573.2018.1547177.

Perez-Paramo YX, Watson CJ, Chen G, Thomas CE, Adams-Haduch J, Wang R et al. Impact of genetic variants in the nicotine metabolism pathway on nicotine metabolite levels in smokers. Cancer Epidemiology, Biomarkers and Prevention. 2023 Jan; 32(1): 54-65. doi: 10.1158/1055-9965.EPI-22-0868.

Consortium GP, Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM. A global reference for human genetic variation. Nature. 2015 Oct; 526(7571): 68-74.

Chenoweth MJ, Lerman C, Knight J, Tyndale RF. Influence of CYP2A6 genetic variation, nicotine dependence severity, and treatment on smoking cessation success. Nicotine and Tobacco Research. 2023 Jun; 25(6): 1207-11. doi: 10.1093/ntr/ntac268.

Amjad G, Saif R, Hussain MG. Genetic Association of CYP1A2 Gene Variant (rs762551) with Caffeine Induced-Hypertension Susceptibility and Cytochrome P450 1A2 Protein Analyses. bioRxiv. 2023 Oct: 2023-10. doi: 10.1101/2023.10.07.561327.

Khalid A, Ashraf H, Asim H, Ayman M, Saif R. Association Analysis of LCORL Genetic Variant (rs657074013) with Wither-Height in Pakistani Goats: Association of LCORL Variant (rs657074013) with Goat Height. Futuristic Biotechnology. 2023 Sep: 46-50. doi: 10.54393/fbt.v3i02.46.

Murphy SE. Nicotine metabolism and smoking: ethnic differences in the role of P450 2A6. Chemical Research in Toxicology. 2017 Jan; 30(1): 410-9. doi: 10.1021/acs.chemrestox.6b00387.

Bergen AW, Michel M, Nishita D, Krasnow R, Javitz HS, Conneely KN et al. Drug metabolizing enzyme and transporter gene variation, nicotine metabolism, prospective abstinence, and cigarette consumption. PLOS One. 2015 Jul; 10(7): e0126113. doi: 10.1371/journal.pone.0126113.

Pérez-Rubio G, López-Flores LA, Ramírez-Venegas A, Noé-Díaz V, García-Gómez L, Ambrocio-Ortiz E et al. Genetic polymorphisms in CYP2A6 are associated with a risk of cigarette smoking and predispose to smoking at younger ages. Gene. 2017 Sep; 628: 205-10. doi: 10.1016/j.gene.2017.07.051.

Langlois AW, Chenoweth MJ, Twesigomwe D, Scantamburlo G, Whirl‐Carrillo M, Sangkuhl K et al. PharmVar GeneFocus: CYP2A6. Clinical Pharmacology & Therapeutics. 2024 Oct; 116(4): 948-62. doi: 10.1002/cpt.3387.

Ezzeldin N, El-Lebedy D, Darwish A, El Bastawisy A, Abd Elaziz SH, Hassan MM et al. Association of genetic polymorphisms CYP2A6* 2 rs1801272 and CYP2A6* 9 rs28399433 with tobacco-induced lung Cancer: case-control study in an Egyptian population. BioMed Central Cancer. 2018 Dec; 18: 1-9. doi: 10.1186/s12885-018-4342-5.

Giratallah H, Chenoweth MJ, Pouget JG, El-Boraie A, Alsaafin A, Lerman C et al. CYP2A6 associates with respiratory disease risk and younger age of diagnosis: a phenome-wide association Mendelian Randomization study. Human Molecular Genetics. 2024 Jan; 33(2): 198-210. doi: 10.1093/hmg/ddad172.

Perez-Paramo YX and Lazarus P. Pharmacogenetics factors influencing smoking cessation success; the importance of nicotine metabolism. Expert Opinion on Drug Metabolism and Toxicology. 2021 Mar; 17(3): 333-49. doi: 10.1080/17425255.2021.1863948.