Advertisement

Human Genetics

, Volume 135, Issue 12, pp 1389–1397 | Cite as

Associations of cytochrome P450 oxidoreductase genetic polymorphisms with smoking cessation in a Chinese population

  • Huijie Li
  • Suyun Li
  • Qiang Wang
  • Chongqi JiaEmail author
Original Investigation

Abstract

Recently, a single nucleotide polymorphism (SNP) A503V (rs1057868) in cytochrome P450 oxidoreductase (POR) gene was reported to influence nicotine metabolism. Considering the importance of nicotine metabolism to smoking cessation, the aim of this study was to investigate the association between POR gene polymorphisms and smoking cessation in a Chinese population. A case–control study was conducted with 363 successful smoking quitters as the cases, and 345 failed smoking quitters as the controls. Eight tagSNPs which cover the entire gene and four functional SNPs were selected and genotyped. Logistic regression was used to explore the relationship between POR SNPs and smoking cessation in codominant, additive, dominant and recessive models. After adjustment for potential confounders, multiple logistic regression analysis indicated that POR rs3823884 and rs3898649 were associated with increased possibility of smoking cessation. Meanwhile, POR rs17685 and rs239953 were shown to have negative effect on successful smoking cessation. No significant differences in the distribution of haplotypes between cases and controls were detected. In conclusion, this study reveals that four SNPs in the POR gene (rs3823884, rs3898649, rs239953 and rs17685) may affect the susceptibility of smoking cessation in a Chinese Han population.

Keywords

Smoking Cessation Minor Allele Frequency Flavin Adenine Dinucleotide Nicotine Metabolism Smoking Onset 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

This study is sponsored by a Grant from the National Natural Science Foundation of China (No: 81273150). We thank the local Health Bureau, local Center for Disease Control and Prevention, other relevant governments and persons, the investigators, and respondents for their support to this research.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Funding

This study was funded by a Grant from the National Natural Science Foundation of China (No: 81273150).

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

439_2016_1728_MOESM1_ESM.docx (45 kb)
Supplementary material 1 (DOCX 44 kb)

References

  1. Agrawal V, Huang N, Miller WL (2008) Pharmacogenetics of P450 oxidoreductase: effect of sequence variants on activities of CYP1A2 and CYP2C19. Pharmacogenet Genom 18:569–576. doi: 10.1097/FPC.0b013e32830054ac CrossRefGoogle Scholar
  2. Agrawal V, Choi JH, Giacomini KM, Miller WL (2010) Substrate-specific modulation of CYP3A4 activity by genetic variants of cytochrome P450 oxidoreductase. Pharmacogenet Genom 20:611–618. doi: 10.1097/FPC.0b013e32833e0cb5 CrossRefGoogle Scholar
  3. Audrain-McGovern J, Al Koudsi N, Rodriguez D, Wileyto EP, Shields PG, Tyndale RF (2007) The role of CYP2A6 in the emergence of nicotine dependence in adolescents. Pediatrics 119:e264–e274. doi: 10.1542/peds.2006-1583 CrossRefPubMedGoogle Scholar
  4. Barrett LW, Fletcher S, Wilton SD (2012) Regulation of eukaryotic gene expression by the untranslated gene regions and other non-coding elements. Cell Mol Life Sci 69:3613–3634. doi: 10.1007/s00018-012-0990-9 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Ben Taleb Z, Ward KD, Asfar T, Jaber R, Auf R, Maziak W (2016) Predictors of nicotine withdrawal symptoms: findings from the first randomized smoking cessation trial in a low-income country setting. Int J Public Health. doi: 10.1007/s00038-016-0818-8 PubMedGoogle Scholar
  6. Benowitz NL (2010) Nicotine addiction. N Engl J Med 362:2295–2303. doi: 10.1056/NEJMra0809890 CrossRefPubMedPubMedCentralGoogle Scholar
  7. Benowitz NL, Pomerleau OF, Pomerleau CS, Jacob P 3rd (2003) Nicotine metabolite ratio as a predictor of cigarette consumption. Nicotine Tob Res 5:621–624. doi: 10.1080/1462220031000158717 CrossRefPubMedGoogle Scholar
  8. Benowitz NL, Hukkanen J, Jacob P, 3rd (2009) Nicotine chemistry, metabolism, kinetics and biomarkers. Handb Exp Pharmacol: 29–60. doi:  10.1007/978-3-540-69248-5_2
  9. Broms U, Silventoinen K, Madden PA, Heath AC, Kaprio J (2006) Genetic architecture of smoking behavior: a study of Finnish adult twins. Twin Res Hum Genet 9:64–72. doi: 10.1375/twin.9.1.64 CrossRefPubMedGoogle Scholar
  10. Chenoweth MJ, O’Loughlin J, Sylvestre MP, Tyndale RF (2013) CYP2A6 slow nicotine metabolism is associated with increased quitting by adolescent smokers. Pharmacogenet Genom 23:232–235. doi: 10.1097/FPC.0b013e32835f834d CrossRefGoogle Scholar
  11. Chenoweth MJ, Novalen M, Hawk LW Jr, Schnoll RA, George TP, Cinciripini PM, Lerman C, Tyndale RF (2014a) Known and novel sources of variability in the nicotine metabolite ratio in a large sample of treatment-seeking smokers. Cancer Epidemiol Biomark Prev 23:1773–1782. doi: 10.1158/1055-9965.epi-14-0427 CrossRefGoogle Scholar
  12. Chenoweth MJ, Zhu AZ, Sanderson Cox L, Ahluwalia JS, Benowitz NL, Tyndale RF (2014b) Variation in P450 oxidoreductase (POR) A503V and flavin-containing monooxygenase (FMO)-3 E158 K is associated with minor alterations in nicotine metabolism, but does not alter cigarette consumption. Pharmacogenet Genom 24:172–176. doi: 10.1097/fpc.0000000000000031 CrossRefGoogle Scholar
  13. Chenoweth MJ, Schnoll RA, Novalen M, Hawk LW Jr, George TP, Cinciripini PM, Lerman C, Tyndale RF (2016) The nicotine metabolite ratio is associated with early smoking abstinence even after controlling for factors that influence the nicotine metabolite ratio. Nicotine Tob Res 18:491–495. doi: 10.1093/ntr/ntv125 CrossRefPubMedGoogle Scholar
  14. de Jonge H, Metalidis C, Naesens M, Lambrechts D, Kuypers DR (2011) The P450 oxidoreductase *28 SNP is associated with low initial tacrolimus exposure and increased dose requirements in CYP3A5-expressing renal recipients. Pharmacogenomics 12:1281–1291. doi: 10.2217/pgs.11.77 CrossRefPubMedGoogle Scholar
  15. Dobrinas M, Cornuz J, Pedrido L, Eap CB (2012) Influence of cytochrome P450 oxidoreductase genetic polymorphisms on CYP1A2 activity and inducibility by smoking. Pharmacogenet Genom 22:143–151. doi: 10.1097/FPC.0b013e32834e9e1a CrossRefGoogle Scholar
  16. El-Serafi I, Afsharian P, Moshfegh A, Hassan M, Terelius Y (2015) Cytochrome P450 oxidoreductase influences CYP2B6 activity in cyclophosphamide bioactivation. PLoS One 10:e0141979. doi: 10.1371/journal.pone.0141979 CrossRefPubMedPubMedCentralGoogle Scholar
  17. Gomes AM, Winter S, Klein K, Turpeinen M, Schaeffeler E, Schwab M, Zanger UM (2009) Pharmacogenomics of human liver cytochrome P450 oxidoreductase: multifactorial analysis and impact on microsomal drug oxidation. Pharmacogenomics 10:579–599. doi: 10.2217/pgs.09.7 CrossRefPubMedGoogle Scholar
  18. Gruder CL, Trinidad DR, Palmer PH, Xie B, Li L, Johnson CA (2013) Tobacco smoking, quitting, and relapsing among adult males in Mainland China: the China seven cities study. Nicotine Tob Res 15:223–230. doi: 10.1093/ntr/nts116 CrossRefPubMedGoogle Scholar
  19. Gu J, Weng Y, Zhang QY, Cui H, Behr M, Wu L, Yang W, Zhang L, Ding X (2003) Liver-specific deletion of the NADPH-cytochrome P450 reductase gene: impact on plasma cholesterol homeostasis and the function and regulation of microsomal cytochrome P450 and heme oxygenase. J Biol Chem 278:25895–25901. doi: 10.1074/jbc.M303125200 CrossRefPubMedGoogle Scholar
  20. Gutierrez A, Grunau A, Paine M, Munro AW, Wolf CR, Roberts GC, Scrutton NS (2003) Electron transfer in human cytochrome P450 reductase. Biochem Soc Trans 31:497–501. doi: 10.1042/bst0310497 CrossRefPubMedGoogle Scholar
  21. Hardie TL, Moss HB, Lynch KG (2006) Genetic correlations between smoking initiation and smoking behaviors in a twin sample. Addict Behav 31:2030–2037. doi: 10.1016/j.addbeh.2006.02.010 CrossRefPubMedGoogle Scholar
  22. Hart SN, Zhong XB (2008) P450 oxidoreductase: genetic polymorphisms and implications for drug metabolism and toxicity. Expert Opin Drug Metab Toxicol 4:439–452. doi: 10.1517/17425255.4.4.439 CrossRefPubMedGoogle Scholar
  23. Hart SN, Wang S, Nakamoto K, Wesselman C, Li Y, Zhong XB (2008) Genetic polymorphisms in cytochrome P450 oxidoreductase influence microsomal P450-catalyzed drug metabolism. Pharmacogenet Genom 18:11–24. doi: 10.1097/FPC.0b013e3282f2f121 CrossRefGoogle Scholar
  24. Ho KS, Choi BW, Chan H, Ching KW (2016) Evaluation of biological, psychosocial, and interventional predictors for success of a smoking cessation programme in Hong Kong. Hong Kong Med J 22:158–164. doi: 10.12809/hkmj154549 PubMedGoogle Scholar
  25. Hu L, Zhuo W, He YJ, Zhou HH, Fan L (2012) Pharmacogenetics of P450 oxidoreductase: implications in drug metabolism and therapy. Pharmacogenet Genom 22:812–819. doi: 10.1097/FPC.0b013e328358d92b CrossRefGoogle Scholar
  26. Huang N, Pandey AV, Agrawal V, Reardon W, Lapunzina PD, Mowat D, Jabs EW, Van Vliet G, Sack J, Fluck CE, Miller WL (2005) Diversity and function of mutations in P450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis. Am J Hum Genet 76:729–749. doi: 10.1086/429417 CrossRefPubMedPubMedCentralGoogle Scholar
  27. Huang N, Agrawal V, Giacomini KM, Miller WL (2008) Genetics of P450 oxidoreductase: sequence variation in 842 individuals of four ethnicities and activities of 15 missense mutations. Proc Natl Acad Sci USA 105:1733–1738. doi: 10.1073/pnas.0711621105 CrossRefPubMedPubMedCentralGoogle Scholar
  28. Lv J, Hu L, Zhuo W, Zhang C, Zhou H, Fan L (2016) Effects of the selected cytochrome P450 oxidoreductase genetic polymorphisms on cytochrome P450 2B6 activity as measured by bupropion hydroxylation. Pharmacogenet Genom 26:80–87. doi: 10.1097/fpc.0000000000000190 CrossRefGoogle Scholar
  29. Miller WL (2005) Minireview: regulation of steroidogenesis by electron transfer. Endocrinology 146:2544–2550. doi: 10.1210/en.2005-0096 CrossRefPubMedGoogle Scholar
  30. Miller WL, Huang N, Agrawal V, Giacomini KM (2009) Genetic variation in human P450 oxidoreductase. Mol Cell Endocrinol 300:180–184. doi: 10.1016/j.mce.2008.09.017 CrossRefPubMedGoogle Scholar
  31. Miller WL, Agrawal V, Sandee D, Tee MK, Huang N, Choi JH, Morrissey K, Giacomini KM (2011) Consequences of POR mutations and polymorphisms. Mol Cell Endocrinol 336:174–179. doi: 10.1016/j.mce.2010.10.022 CrossRefPubMedGoogle Scholar
  32. Mons U, Muezzinler A, Gellert C, Schottker B, Abnet CC et al (2015) Impact of smoking and smoking cessation on cardiovascular events and mortality among older adults: meta-analysis of individual participant data from prospective cohort studies of the CHANCES consortium. BMJ 350:h1551. doi: 10.1136/bmj.h1551 CrossRefPubMedPubMedCentralGoogle Scholar
  33. Mwenifumbo JC, Tyndale RF (2009) Molecular genetics of nicotine metabolism. Handb Exp Pharmacol: 235–259. doi:  10.1007/978-3-540-69248-5_9
  34. Qian J, Cai M, Gao J, Tang S, Xu L, Critchley JA (2010) Trends in smoking and quitting in China from 1993 to 2003: national Health Service Survey data. Bull World Health Organ 88:769–776. doi: 10.2471/BLT.09.064709 CrossRefPubMedPubMedCentralGoogle Scholar
  35. Saito Y, Yamamoto N, Katori N, Maekawa K, Fukushima-Uesaka H, Sugimoto D, Kurose K, Sai K, Kaniwa N, Sawada J, Kunitoh H, Ohe Y, Yoshida T, Matsumura Y, Saijo N, Okuda H, Tamura T (2011) Genetic polymorphisms and haplotypes of POR, encoding cytochrome P450 oxidoreductase, in a Japanese population. Drug Metab Pharmacokinet 26:107–116. doi: 10.2133/dmpk.DMPK-10-SC-096 CrossRefPubMedGoogle Scholar
  36. Sandee D, Morrissey K, Agrawal V, Tam HK, Kramer MA, Tracy TS, Giacomini KM, Miller WL (2010) Effects of genetic variants of human P450 oxidoreductase on catalysis by CYP2D6 in vitro. Pharmacogenet Genom 20:677–686. doi: 10.1097/FPC.0b013e32833f4f9b CrossRefGoogle Scholar
  37. Schnoll RA, Patterson F, Wileyto EP, Tyndale RF, Benowitz N, Lerman C (2009) Nicotine metabolic rate predicts successful smoking cessation with transdermal nicotine: a validation study. Pharmacol Biochem Behav 92:6–11. doi: 10.1016/j.pbb.2008.10.016 CrossRefPubMedGoogle Scholar
  38. Schnoll RA, George TP, Hawk L, Cinciripini P, Wileyto P, Tyndale RF (2014) The relationship between the nicotine metabolite ratio and three self-report measures of nicotine dependence across sex and race. Psychopharmacology 231:2515–2523. doi: 10.1007/s00213-013-3421-1 CrossRefPubMedPubMedCentralGoogle Scholar
  39. Scott RR, Miller WL (2008) Genetic and clinical features of P450 oxidoreductase deficiency. Horm Res 69:266–275. doi: 10.1159/000114857 CrossRefPubMedGoogle Scholar
  40. Scott RR, Gomes LG, Huang N, Van Vliet G, Miller WL (2007) Apparent manifesting heterozygosity in P450 oxidoreductase deficiency and its effect on coexisting 21-hydroxylase deficiency. J Clin Endocrinol Metab 92:2318–2322. doi: 10.1210/jc.2006-2345 CrossRefPubMedGoogle Scholar
  41. Sofuoglu M, Herman AI, Nadim H, Jatlow P (2012) Rapid nicotine clearance is associated with greater reward and heart rate increases from intravenous nicotine. Neuropsychopharmacology 37:1509–1516. doi: 10.1038/npp.2011.336 CrossRefPubMedPubMedCentralGoogle Scholar
  42. Tamaki Y, Arai T, Sugimura H, Sasaki T, Honda M, Muroi Y, Matsubara Y, Kanno S, Ishikawa M, Hirasawa N, Hiratsuka M (2011) Association between cancer risk and drug-metabolizing enzyme gene (CYP2A6, CYP2A13, CYP4B1, SULT1A1, GSTM1, and GSTT1) polymorphisms in cases of lung cancer in Japan. Drug Metab Pharmacokinet 26:516–522. doi: 10.2133/dmpk.DMPK-11-RG-046 CrossRefPubMedGoogle Scholar
  43. van Osch FH, Jochems SH, van Schooten FJ, Bryan RT, Zeegers MP (2016) Quantified relations between exposure to tobacco smoking and bladder cancer risk: a meta-analysis of 89 observational studies. Int J Epidemiol. doi: 10.1093/ije/dyw044 PubMedGoogle Scholar
  44. Vaz LR, Coleman T, Cooper S, Aveyard P, Leonardi-Bee J, SNAP trial team (2015) The nicotine metabolite ratio in pregnancy measured by trans-3′-hydroxycotinine to cotinine ratio: characteristics and relationship with smoking cessation. Nicotine Tob Res 17:1318–1323. doi: 10.1093/ntr/ntu342 CrossRefPubMedGoogle Scholar
  45. von Weymarn LB, Retzlaff C, Murphy SE (2012) CYP2A6- and CYP2A13-catalyzed metabolism of the nicotine Delta5′(1′) iminium ion. J Pharmacol Exp Ther 343:307–315. doi: 10.1124/jpet.112.195255 CrossRefGoogle Scholar
  46. Wassenaar CA, Dong Q, Wei Q, Amos CI, Spitz MR, Tyndale RF (2011) Relationship between CYP2A6 and CHRNA5-CHRNA3-CHRNB4 variation and smoking behaviors and lung cancer risk. J Natl Cancer Inst 103:1342–1346. doi: 10.1093/jnci/djr237 CrossRefPubMedPubMedCentralGoogle Scholar
  47. World Health Organization (1998) Guidelines for controlling and monitoring the tobacco epidemicGoogle Scholar
  48. World Health Organization (2015) WHO report on the global tobacco epidemic, 2015: Raising taxes on tobaccoGoogle Scholar
  49. Wu L, Gu J, Cui H, Zhang QY, Behr M, Fang C, Weng Y, Kluetzman K, Swiatek PJ, Yang W, Kaminsky L, Ding X (2005) Transgenic mice with a hypomorphic NADPH-cytochrome P450 reductase gene: effects on development, reproduction, and microsomal cytochrome P450. J Pharmacol Exp Ther 312:35–43. doi: 10.1124/jpet.104.073353 CrossRefPubMedGoogle Scholar
  50. Xian H, Scherrer JF, Madden PA, Lyons MJ, Tsuang M, True WR, Eisen SA (2003) The heritability of failed smoking cessation and nicotine withdrawal in twins who smoked and attempted to quit. Nicotine Tob Res 5:245–254. doi: 10.1080/1462220031000073667 CrossRefPubMedGoogle Scholar
  51. Xian H, Scherrer JF, Madden PA, Lyons MJ, Tsuang M, True WR, Eisen SA (2005) Latent class typology of nicotine withdrawal: genetic contributions and association with failed smoking cessation and psychiatric disorders. Psychol Med 35:409–419. doi: 10.1017/S0033291704003289 CrossRefPubMedGoogle Scholar
  52. Xiao X, Ma G, Li S, Wang M, Liu N, Ma L, Zhang Z, Chu H, Wang SL (2015) Functional POR A503V is associated with the risk of bladder cancer in a Chinese population. Sci Rep 5:11751. doi: 10.1038/srep11751 CrossRefPubMedPubMedCentralGoogle Scholar
  53. Xue X, Gong L, Qi X, Wu Y, Xing G, Yao J, Luan Y, Xiao Y, Li Y, Wu X, Chen M, Gu J, Ren J (2011) Knockout of hepatic P450 reductase aggravates triptolide-induced toxicity. Toxicol Lett 205:47–54. doi: 10.1016/j.toxlet.2011.05.003 CrossRefPubMedGoogle Scholar
  54. Yang G (2011) Global adult tobacco survey (GATS) China 2010 Country Report. Chinese Three Gorge Press, BeijingGoogle Scholar
  55. Yang GFZ, Chen X, Yuan H, Yang H, Huang Y, Ouyang D, Tan Z, Tan H, Huang Z, Zhou H (2011) Effects of the CYP oxidoreductase Ala503Val polymorphism on CYP3A activity in vivo: a randomized, open-label, crossover study in healthy Chinese men. Clin Ther 33:2060–2070. doi: 10.1016/j.clinthera.2011.11.004 CrossRefPubMedGoogle Scholar
  56. Yuan JM, Nelson HH, Butler LM, Carmella SG, Wang R, Kuriger-Laber JK, Adams-Haduch J, Hecht SS, Gao YT, Murphy SE (2016) Genetic determinants of cytochrome P450 2A6 activity and biomarkers of tobacco smoke exposure in relation to risk of lung cancer development in the Shanghai cohort study. Int J Cancer 138:2161–2171. doi: 10.1002/ijc.29963 CrossRefPubMedGoogle Scholar
  57. Zhang X, Li L, Ding X, Kaminsky LS (2011) Identification of cytochrome P450 oxidoreductase gene variants that are significantly associated with the interindividual variations in warfarin maintenance dose. Drug Metab Dispos 39:1433–1439. doi: 10.1124/dmd.111.038836 CrossRefPubMedPubMedCentralGoogle Scholar
  58. Zhang JJ, Zhang H, Ding XL, Ma S, Miao LY (2013) Effect of the P450 oxidoreductase 28 polymorphism on the pharmacokinetics of tacrolimus in Chinese healthy male volunteers. Eur J Clin Pharmacol 69:807–812. doi: 10.1007/s00228-012-1432-1 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.Department of EpidemiologyShandong UniversityJinanPeople’s Republic of China

Personalised recommendations