Genetic CYP2A6 Polymorphism May Worsen Glycohemoglobin Levels: Study among Javanese Indonesian Smokers

Christine Patramurti (1) , Dita Maria Virginia (2)
(1) Sanata Dharma University , Indonesia
(2) Sanata Dharma University , Indonesia


We have examined the inactive CYP2A6 alleles gene, including CYP2A6*4, CYP2A6*7, and CYP2A6*9, associated with glycohemoglobin levels among Javanese Indonesian smokers. There are 106 smokers participating in this study. Due to the number of cigarettes smoked per day, there are three groups of smokers: light, intermediate, and heavy smokers, with 98.7% being light and intermediated smokers while the rest are heavy smokers. All participants had smoked for more than 10 years, indicating they had been exposed to nicotine for a long time. Based on their genotype, there were four groups of smokers, including fast, intermediate, slow, and poor metabolizers. Most fast and intermediate metabolizers have HbA1c levels in the normal range (<5.7). On the other hand, most slow metabolizers have Hb1c levels >5.7, and all fast metabolizers have HbA1c levels >5.7, indicating that they the prediabetes and diabetes. The chi-square test showed a relationship between CYP2A6 polymorphism and HbA1c levels among the participants (P-value 0.000 <0.005 and χ2=54.6, df=1). The presence of an inactive allele will worsen the HbA1c levels in smokers.

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1. Wahidin M, Achadi A, Sitorus N, Handayani R. Overview of Diabetes Mellitus and its Risk Factors in Indonesia: An Analysis of Basic Health Research Data. Southeast Asian J Trop Med Public Health. 2022;53(Suppl 2):642-59.
2. Siregar FA, Asfriyati, Makmur T, Bestari R, Lubis IA, Zein U. Identifying Adult Population at Risk for Undiagnosed Diabetes Mellitus in Medan City, Indonesia Targeted on Diabetes Prevention. Med Arch. 2023;77(6):455-9. DOI: 10.5455/medarh.2023.77.455-459; PMCID: PMC10834042; PMID: 38313111
3. Prabowo MH, Febrinasari RP, Pamungkasari EP, Mahendradhata Y, Pulkki-Brännström AM, Probandari A. Health-related Quality of Life of Patients with Diabetes Mellitus Measured With the Bahasa Indonesia Version of EQ-5D in Primary Care Settings in Indonesia. J Prev Med Public Health. 2023;56(5):467-74. DOI: 10.3961/jpmph.23.229; PMCID: PMC10579634; PMID: 37828874
4. Galicia-Garcia U, Benito-Vicente A, Jebari S, Larrea-Sebal A, Siddiqi H, Uribe KB, et al. Pathophysiology of Type 2 Diabetes Mellitus. Int J Mol Sci. 2020;21(17):6275. DOI: 10.3390/ijms21176275; PMCID: PMC7503727; PMID: 32872570
5. Arifin H, Chou KR, Ibrahim K, Fitri SUR, Pradipta RO, Rias YA, et al. Analysis of Modifiable, Non-Modifiable, and Physiological Risk Factors of Non-Communicable Diseases in Indonesia: Evidence from the 2018 Indonesian Basic Health Research. J Multidiscip Healthc. 2022;15:2203-21. DOI: 10.2147/jmdh.s382191; PMCID: PMC9532265; PMID: 36213176
6. Patramurti C, Virginia DM, Fenty F, Setiawan CH, Julianus J, Hendra P, et al. High Frequency of CYP2A6*4, CYP2A6*7, and CYP2A6*9 Alleles Detected Among Patients with Type 2 Diabetic: Genetic Study in The Private Hospital in Yogyakarta. J Farmasi Sains Komunitas JFSK. 2022;19(2):53-61. DOI: 10.24071/jpsc.003902
7. Liu X, Bragg F, Yang L, Kartsonaki C, Guo Y, Du H, et al. Smoking and smoking cessation in relation to risk of diabetes in Chinese men and women: a 9-year prospective study of 0·5 million people. Lancet Public Health. 2018;3(4):167–76. DOI: 10.1016/s2468-2667(18)30026-4; PMCID: PMC5887081; PMID: 29548855
8. Hong JW, Ku CR, Noh JH, Ko KS, Rhee BD, Kim DJ. Association between self-reported smoking and hemoglobin A1c in a Korean population without diabetes: The 2011-2012 Korean national health and nutrition examination survey. PLoS One. 2015;10(5):e0126746. DOI: 10.1371/journal.pone.0126746; PMCID: PMC4444290; PMID: 26011526
9. Vlassopoulos A, Lean MEJ, Combet E. Influence of Smoking and Diet on Glycated Haemoglobin and 'Pre-Diabetes’ Categorisation: A Cross-Sectional Analysis. BMC Public Health. 2013;13:1013. DOI: 10.1186/1471-2458-13-1013; PMCID: PMC4029457; PMID: 24499114
10. Kaiafa G, Veneti S, Polychronopoulos G, Pilalas D, Daios S, Kanellos I, et al. Is HbA1c an ideal biomarker of well-controlled diabetes? Postgrad Med J. 2021;97(1148):380-3. DOI: 10.1136/postgradmedj-2020-138756; PMCID: PMC10016911; PMID: 32913038
11. Kaplan AK, Sezgin Y. Evaluation of the Relationship Between Smoking and Insulin Resistance: A Case-Control Study. Cureus. 2023;15(3):e36684. DOI: 10.7759/cureus.36684; PMCID: PMC10039987; PMID: 36987444
12. Benowitz NL, St Helen G, Dempsey DA, Jacob 3rd P, Tyndale RF. Disposition kinetics and metabolism of nicotine and cotinine in African American smokers: impact of CYP2A6 genetic variation and enzymatic activity. Pharmacogenet Genomics. 2016;26(7):340-50. DOI: 10.1097/fpc.0000000000000222; PMCID: PMC4892970; PMID: 27035242
13. Patramurti C, Fenty F. Genetic Polymorphism Cytochrome P4502a6 Allel *4 And *9: Studi On Glycohemoglobine Level Among Javanese Indonesian Smokers. Pharm Sci Res. 2019;6(2):82-8. DOI: 10.7454/psr.v6i2.4488
14. Liu T, Xie C-B, Ma W-J, Chen W-Q. Association between CYP2A6 genetic polymorphisms and lung cancer: a meta-analysis of case-control studies. Environ Mol Mutagen. 2013;54(2):133–40. DOI: 10.1002/em.21751; PMID: 23203414
15. Patramurti C, Nurrochmad A, Martono S, Science P, Mada G, Chemistry P. Polymorphism of Cytochrome P450 2A6 (CYP2A6*1 and CYP2A6*4) among Javanese Indonesian Smoker and Non Smoker. Indones J Pharm. 2015;26(1):11–9. DOI: 10.14499/indonesianjpharm26iss1pp11
16. Patramurti C, Fenty F. Association of Smoking Behaviour and Glycohemoglobine Levels Among Adults Javanese Indonesian Smokers. J Farmasi Sains Komunitas JFSK. 2020;17(2):76–85. DOI: 10.24071/jpsc.002408
17. Patramurti C, Virginia DM. Distribution of cytochrome P450*4 (CYP2A6*4) allele gene among Javanese Indonesian T2DM patients. Pharmaciana. 2021;11(1):25–38. DOI: 10.12928/pharmaciana.v11i1.18468
18. Aryanti GAKW, Priastana IKA. Modified Fagerstrom Tolerance Questionnaire (Adolescents) Indonesian Version: Validity and Reliability Study. Indones J Health Res. 2019;2(1):16-22. DOI: 10.32805/ijhr.2019.2.1.28
19. Feng X, Qian Z, Zhang B, Guo E, Wang L, Liu P, et al. Number of Cigarettes Smoked Per Day, Smoking Index, and Intracranial Aneurysm Rupture: A Case-Control Study. Front Neurol. 2018;9:380. DOI: 10.3389/fneur.2018.00380; PMCID: PMC5990590; PMID: 29904368
20. Lin M, Chu M, Li X, Ma H, Fang Z, Mao L, et al. Factors influencing adolescent experimental and current smoking behaviors based on social cognitive theory: A cross-sectional study in Xiamen. Front Public Health. 2023;11:1093264. DOI: 10.3389/fpubh.2023.1093264; PMCID: PMC10073720; PMID: 37033036
21. Noubiap JJ, Nansseu JR, Endomba FT, Ngouo A, Nkeck JR, Nyaga UF, et al. Active smoking among people with diabetes mellitus or hypertension in Africa: a systematic review and meta-analysis. Sci Rep. 2019;9(1):588. DOI: 10.1038/s41598-018-37858-z; PMCID: PMC6345945; PMID: 30679752
22. Akter S, Goto A, Mizoue T. Smoking and the risk of type 2 diabetes in Japan: A systematic review and meta-analysis. J Epidemiol. 2017;27(12):553–61. DOI: 10.1016/; PMCID: PMC5623034; PMID: 28716381
23. Akkuzulu H, Aypak C, Özdemir A, Görpelioǧlu S. Impact of smoking and nicotine addiction on HbA1clevels and diabetic microvascular complications. Clin Diabetol. 2020;9(2):112–7. DOI: 10.5603/DK.2020.0004
24. Maddatu J, Anderson-baucum E, Evans-molina C, Physiology I. Smoking and the Risk of Type 2 Diabetes. Transl Res. 2017;184:101–7. DOI: 10.1016/j.trsl.2017.02.004; PMCID: PMC5429867; PMID: 28336465
25. Campagna D, Alamo A, Pino A Di, Russo C, Calogero AE, Purrello F, et al. Smoking and diabetes: dangerous liaisons and confusing relationships. Diabetol Metab Syndr. 2019;11:85. DOI: 10.1186/s13098-019-0482-2; PMCID: PMC6813988; PMID: 31666811
26. Yuan S, Larsson SC. A causal relationship between cigarette smoking and type 2 diabetes mellitus: A Mendelian randomization study. Sci Rep. 2019;9(1):19342. DOI: 10.1038/s41598-019-56014-9; PMCID: PMC6920406; PMID: 31852999
27. Sliwińska-Mossoń M, Milnerowicz H. Influence of tobacco smoking on lipase activity in patients with pancreatitis. Przegla̧d Lek. 2005;62(10):1058–61. PMID: 16521953
28. Bajaj M. Nicotine and Insulin Resistance: When the Smoke Clears. Diabetes. 2012;61(12):3078–80. DOI: 10.2337/db12-1100; PMCID: PMC3501863; PMID: 23172960
29. Xie X, Liu Q, Wu J, Wakui M. Impact of cigarette smoking in type 2 diabetes development. Acta Pharmacol Sin. 2009;30(6):784–7. DOI: 10.1038/aps.2009.49; PMCID: PMC4002374; PMID: 19434055
30. Morimoto A, Tatsumi Y, Deura K, Mizuno S, Ohno Y, Watanabe S. Impact of cigarette smoking on impaired insulin secretion and insulin resistance in Japanese men: The Saku Study. J Diabetes Investig. 2013;4(3):274–80. DOI: 10.1111/jdi.12019; PMCID: PMC4015664; PMID: 24843666
31. Somm E, Schwitzgebel VM, Vauthay DM, Camm EJ, Chen CY, Giacobino JP, et al. Prenatal nicotine exposure alters early pancreatic islet and adipose tissue development with consequences on the control of body weight and glucose metabolism later in life. Endocrinology. 2008;149(12):6289–99. DOI: 10.1210/en.2008-0361; PMID: 18687784
32. Sherwani SI, Khan HA, Ekhzaimy A, Masood A, Sakharkar MK. Significance of HbA1c Test in Diagnosis and Prognosis of Diabetic Patients. Biomark Insights. 2016;11:95-104. DOI: 10.4137/bmi.s38440; PMCID: PMC4933534; PMID: 27398023
33. Soelistijo SA, Novida H, Rudijanto A, Soewondo P, Suastika K, Manaf A, et al. Konsensus Pengendalian dan Pencegahan Diabetes Melitus Tipe 2 di Indonesia 2015. Jakarta: Pengurus Besar Perkumpulan Endokrinologi Indonesia; 2015. p. 78.
34. Choi DW, Jeon J, Lee SA, Han KT, Park EC, Jang SI. Association between smoking behavior patterns and glycated hemoglobin levels in a general population. Int J Environ Res Public Health. 2018;15(10):2260. DOI: 10.3390/ijerph15102260; PMCID: PMC6210515; PMID: 30332732
35. Chawla A, Chawla R, Jaggi S. Microvasular and macrovascular complications in diabetes mellitus: Distinct or continuum? Indian J Endocrinol Metab. 2016;20(4):546-51. DOI: 10.4103/2230-8210.183480; PMCID: PMC4911847; PMID: 27366724
36. Soewondo P, Ferrario A, Tahapary DL. Challenges in diabetes management in Indonesia: a literature review. Global Health. 2013;9:63. DOI: 10.1186/1744-8603-9-63; PMCID: PMC3901560; PMID: 24299164
37. Raunio H, Rahnasto-Rilla M. CYP2A6: genetics, structure, regulation, and function. Drug Metabol Drug Interact. 2012;27(2):73–88. DOI: 10.1515/dmdi-2012-0001; PMID: 22706231
38. Ismail L, Materwala H, Al Kaabi J. Association of risk factors with type 2 diabetes: A systematic review. Comput Struct Biotechnol J. 2021;19:1759-85. DOI: 10.1016/j.csbj.2021.03.003; PMCID: PMC8050730; PMID: 33897980
39. Chenoweth MJ, O’Loughlin J, Sylvestre MP, Tyndale RF. CYP2A6 slow nicotine metabolism is associated with increased quitting by adolescent smokers. Pharmacogenet Genomics. 2013;23(4):232–5. DOI: 10.1097/fpc.0b013e32835f834d; PMCID: PMC3744214; PMID: 23462429
40. O’Loughlin J, Paradis G, Kim W, DiFranza J, Meshefedjian G, McMillan-Davey E, et al. Genetically decreased CYP2A6 and the risk of tobacco dependence: a prospective study of novice smokers. Tob Control. 2004;13(4):422–8. DOI: 10.1136/tc.2003.007070; PMCID: PMC1747926; PMID: 15564629
41. 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. 2004;14(9):615–26. DOI: 10.1097/00008571-200409000-00006; PMID: 15475735
42. Peamkrasatam S, Sriwatanakul K, Kiyotani K, Fujieda M, Yamazaki H, Kamataki T, et al. In vivo Evaluation of Coumarin and Nicotine as Probe Drugs to Predict the Metabolic Capacity of CYP2A6 Due to Genetic Polymorphism in Thais. Drug Metab Pharmacokinet. 2006;21(6):475–84. DOI: 10.2133/dmpk.21.475; PMID: 17220563
43. Malaiyandi V, Goodz SD, Sellers EM, Tyndale RF. CYP2A6 genotype, phenotype, and the use of nicotine metabolites as biomarkers during Ad libitum smoking. Cancer Epidemiol Biomarkers Prev. 2006;15(10):1812–9. DOI: 10.1158/1055-9965.epi-05-0723; PMID: 17035386
44. Liu T, David SP, Tyndale RF, Wang H, Zhou Q, Ding P, et al. Associations of CYP2A6 genotype with smoking behaviors in southern China. Addiction. 2011;106(5):985–94. DOI: 10.1111/j.1360-0443.2010.03353.x; PMCID: PMC3074015; PMID: 21205058
45. von Weymarn LB, Retzlaff C, Murphy SE. CYP2A6- and CYP2A13-Catalyzed Metabolism of the Nicotine. J Pharmacol Exp Ther. 2012;343(2):307-15. DOI: 10.1124/jpet.112.195255; PMCID: PMC3477218; PMID: 22869927
46. Başpınar MM, Basat O. Does a High Pre-Treatment Nicotine Dependence Increase the Post-Cessation Diabetes Risk? Turkish J Fam Med Prim Care. 2021;15(2):244–50. DOI: 10.21763/tjfmpc.776077
47. Yalcin E, de la Monte S. Tobacco nitrosamines as culprits in disease: mechanisms reviewed. J Physiol Bhiochem. 2017;72(1):107-20. DOI: 10.1007/s13105-016-0465-9; PMCID: PMC4868960; PMID: 26767836
48. Yuan J, 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;38(4):411-8. DOI: 10.1093/carcin/bgx012; PMCID: PMC6248819; PMID: 28182203
49. Liu Y, Xu Y, Li F, Chen H, Guo S. CYP2A6 deletion polymorphism is associated with decreased susceptibility of lung cancer in Asian smokers: a meta-analysis. Tumour Biol. 2013;34(5):2651-7. DOI: 10.1007/s13277-013-0815-y; PMID: 23649654
50. Bergman BC, Perreault L, Hunerdosse D, Kerege A, Playdon M, Samek AM, et al. Novel and Reversible Mechanisms of Smoking-Induced Insulin Resistance in Humans. Diabetes. 2012;61(12):3156-66. DOI: 10.2337/db12-0418; PMCID: PMC3501865; PMID: 22966072
51. Cho NH, Chan JCN, Jang HC, Lim S, Kim HL, Choi SH. Cigarette smoking is an independent risk factor for type 2 diabetes: a four-year community-based prospective study. J Clin Endocrinol. 2009;71(5):679–85. DOI: 10.1111/j.1365-2265.2009.03586.x; PMID: 19508609
52. Sobue S, Sekiguchi K, Kikkawa H, Akasaki M, Irie S. Comparison of nicotine pharmacokinetics in healthy Japanese male smokers following application of the transdermal nicotine patch and cigarette smoking. Biol Pharm Bull. 2006;29(5):1068–73. DOI: 10.1248/bpb.29.1068; PMID: 16651750
53. Nilsson PM, Gudbjörnsdottir S, Eliasson B, Cederholm J, Steering Committee of the Swedish National Diabetes Register. Smoking is associated with increased HbA1c values and microalbuminuria in patients with diabetes--data from the National Diabetes Register in Sweden. Diabetes Metab. 2004;30(3):261–8. DOI: 10.1016/s1262-3636(07)70117-9; PMID: 15223978
54. Minematsu N, Nakamura H, Furuuchi M, Nakajima T, Takahashi S, Tateno H, et al. Limitation of cigarette consumption by CYP2A6*4, *7 and *9 polymorphisms. Eur Respir J. 2006;27(2):289–92. DOI: 10.1183/09031936.06.00056305; PMID: 16452582
55. Fujieda M, Yamazaki H, Saito T, Kiyotani K, Gyamfi MA, Sakurai M, et al. Evaluation of CYP2A6 genetic polymorphisms as determinants of smoking behavior and tobacco-related lung cancer risk in male Japanese smokers. Carcinogenesis. 2004;25(12):2451–8. DOI: 10.1093/carcin/bgh258; PMID: 15308589
56. Ando M, Hamajima N, Ariyoshi N, Kamataki T, Matsuo K. Association of CYP2A6 gene deletion with cigarette smoking status in Japanese adults. J Epidemiol. 2003;13(3):176–81. DOI: 10.2188/jea.13.176; PMCID: PMC9634051; PMID: 12749606
57. Hermansach R, Bachtiar A. An Overview of Active Smokers’ Perceptions of the Policy of Inclusion of Pictorial Warnings of the Dangers of Smoking Oncigarette Packs in Pondok Gede Sub-District, Bekasi City. J Indones Health Policy Adm. 2021;6(3):192-8. DOI: 10.7454/ihpa.v6i3.4466
58. Tan YL, Dorotheo U. The Tobacco Control Atlas ASEAN Region, Fourth Edition. Bangkok: Southeast Asia Tobacco Control Alliance (SEATCA); 2018. p. 105.


Christine Patramurti (Primary Contact)
Dita Maria Virginia
Author Biographies

Christine Patramurti, Sanata Dharma University

Department of Pharmaceutical Chemistry, Universitas Sanata Dharma, Sleman, Yogyakarta Special Region, Indonesia

Dita Maria Virginia, Sanata Dharma University

Department of Pharmacology and Clinical Pharmacy, Universitas Sanata Dharma, Sleman, Yogyakarta Special Region, Indonesia

Patramurti C, Virginia DM. Genetic CYP2A6 Polymorphism May Worsen Glycohemoglobin Levels: Study among Javanese Indonesian Smokers. Borneo J Pharm [Internet]. 2024Feb.29 [cited 2024May24];7(1):29-3. Available from:

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