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β-Arrestins 1 and 2 are associated with nicotine dependence in European American smokers

Molecular Psychiatry volume 13, pages 398–406 (2008)Cite this article

Abstract

On the basis of our previous identified linkage regions for nicotine dependence (ND), we selected seven and four single nucleotide polymorphisms (SNPs) in the β-arrestins 1 (ARRB1) and 2 (ARRB2), respectively, to determine the associations of the two genes with ND in a total of 2037 subjects from 602 nuclear families of European American (EA) and African American (AA) origin. ND was assessed by Smoking Quantity (SQ), the Heaviness of Smoking Index (HSI) and the Fagerström Test for ND (FTND) score. Individual SNP analysis indicated that SNPs rs472112 within ARRB1 and rs4790694 within ARRB2 in the EA sample was significantly associated with HSI and FTND score, and the association of rs4790694 for ARRB2 remained significant after correction for multiple testing. Haplotype analysis revealed that haplotype C-G-C-G-G-T within ARRB1 at a frequency of 20%, formed by SNPs rs528833, rs1320709, rs480174, rs5786130, rs611908 and rs472112, was positively associated with HSI and FTND in EAs. We also found a haplotype within ARRB2, C-C-A-T at a frequency of 10.7%, formed by SNPs rs3786047, rs4522461, rs1045280 and rs4790694, that showed a significant positive association with HSI and FTND in the EA sample. No significant associations for either individual SNPs or major haplotype of both ARRB1 and ARRB2 were found in the AA sample. Further, the strength of these associations increased after removing the SQ component from HSI and FTND scores in both the EA and AA samples, suggesting that ARRB1 and ARRB2 play an important role in biological processes involved in the regulation of smoking urgency (that is time to smoke first cigarette). In summary, our results provide the first evidence of a significant association for ARRB1 and ARRB2 variants with ND in an EA sample.

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References

  1. Peto R, Lopez AD, Boreham J, Thun M, Heath Jr C . Mortality from tobacco in developed countries: indirect estimation from national vital statistics. Lancet 1992; 339: 1268–1278.

    Article  CAS  PubMed  Google Scholar 

  2. Li MD, Cheng R, Ma JZ, Swan GE . A meta-analysis of estimated genetic and environmental effects on smoking behavior in male and female adult twins. Addiction 2003; 98: 23–31.

    Article  PubMed  Google Scholar 

  3. Li MD, Ma JZ, Beuten J . Progress in searching for susceptibility loci and genes for smoking-related behaviour. Clin Genet 2004; 66: 382–392.

    Article  CAS  PubMed  Google Scholar 

  4. Tyndale RF . Genetics of alcohol and tobacco use in humans. Ann Med 2003; 35: 94–121.

    Article  CAS  PubMed  Google Scholar 

  5. Munafo MR, Clark TG, Johnstone EC, Murphy FG, Walton RT . The genetics basis for smoking behavior: a systematic review and meta-analysis. Nicotine Tob Res 2004; 6: 583–597.

    Article  CAS  PubMed  Google Scholar 

  6. Li MD, Ma JZ, Cheng R, Dupont RT, Williams NJ, Crews KM et al. A genome-wide scan to identify loci for smoking rate in the Framingham Heart Study population. BMC Genet 2003; 4 (Suppl 1): S103.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Li MD, Payne TJ, Ma JZ, Lou XY, Zhang D, Dupont RT et al. A genomewide search finds major susceptibility loci for nicotine dependence on chromosome 10 in African Americans. Am J Hum Genet 2006; 79: 745–751.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wang D, Ma JZ, Li MD . Mapping and verification of susceptibility loci for smoking quantity using permutation linkage analysis. Pharmacogenomics J 2005; 5: 166–172.

    Article  PubMed  Google Scholar 

  9. Calabrese G, Sallese M, Stornaiuolo A, Morizio E, Palka G, De Blasi A . Assignment of the beta-arrestin 1 gene (ARRB1) to human chromosome 11q13. Genomics 1994; 24: 169–171.

    Article  CAS  PubMed  Google Scholar 

  10. Calabrese G, Sallese M, Stornaiuolo A, Stuppia L, Palka G, De Blasi A . Chromosome mapping of the human arrestin (SAG), beta-arrestin 2 (ARRB2), and beta-adrenergic receptor kinase 2 (ADRBK2) genes. Genomics 1994; 23: 286–288.

    Article  CAS  PubMed  Google Scholar 

  11. Beaulieu JM, Caron MG . Beta-arrestin goes nuclear. Cell 2005; 123: 755–757.

    Article  CAS  PubMed  Google Scholar 

  12. Lefkowitz RJ, Shenoy SK . Transduction of receptor signals by beta-arrestins. Science 2005; 308: 512–517.

    Article  CAS  PubMed  Google Scholar 

  13. Baron JA . Cigarette smoking and Parkinson's disease. Neurology 1986; 36: 1490–1496.

    Article  CAS  PubMed  Google Scholar 

  14. Conner DA, Mathier MA, Mortensen RM, Christe M, Vatner SF, Seidman CE et al. Beta-arrestin1 knockout mice appear normal but demonstrate altered cardiac responses to beta-adrenergic stimulation. Circ Res 1997; 81: 1021–1026.

    Article  CAS  PubMed  Google Scholar 

  15. Bohn LM, Lefkowitz RJ, Gainetdinov RR, Peppel K, Caron MG, Lin FT . Enhanced morphine analgesia in mice lacking beta-arrestin 2. Science 1999; 286: 2495–2498.

    Article  CAS  PubMed  Google Scholar 

  16. Bohn LM, Gainetdinov RR, Lin FT, Lefkowitz RJ, Caron MG . Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence. Nature 2000; 408: 720–723.

    Article  CAS  PubMed  Google Scholar 

  17. Oakley RH, Laporte SA, Holt JA, Caron MG, Barak LS . Differential affinities of visual arrestin, beta arrestin1, and beta arrestin2 for G protein-coupled receptors delineate two major classes of receptors. J Biol Chem 2000; 275: 17201–17210.

    Article  CAS  PubMed  Google Scholar 

  18. Hasebe K, Kawai K, Suzuki T, Kawamura K, Tanaka T, Narita M et al. Possible pharmacotherapy of the opioid kappa receptor agonist for drug dependence. Ann NY Acad Sci 2004; 1025: 404–413.

    Article  CAS  PubMed  Google Scholar 

  19. Contet C, Kieffer BL, Befort K . Mu opioid receptor: a gateway to drug addiction. Curr Opin Neurobiol 2004; 14: 370–378.

    Article  CAS  PubMed  Google Scholar 

  20. Whistler JL, Chuang HH, Chu P, Jan LY, von Zastrow M . Functional dissociation of mu opioid receptor signaling and endocytosis: implications for the biology of opiate tolerance and addiction. Neuron 1999; 23: 737–746.

    Article  CAS  PubMed  Google Scholar 

  21. Haberstock-Debic H, Kim KA, Yu YJ, von Zastrow M . Morphine promotes rapid, arrestin-dependent endocytosis of mu-opioid receptors in striatal neurons. J Neurosci 2005; 25: 7847–7857.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kieffer BL, Gaveriaux-Ruff C . Exploring the opioid system by gene knockout. Prog Neurobiol 2002; 66: 285–306.

    Article  CAS  PubMed  Google Scholar 

  23. Walters CL, Cleck JN, Kuo YC, Blendy JA . Mu-opioid receptor and CREB activation are required for nicotine reward. Neuron 2005; 46: 933–943.

    Article  CAS  PubMed  Google Scholar 

  24. Cen B, Yu Q, Guo J, Wu Y, Ling K, Cheng Z et al. Direct binding of beta-arrestins to two distinct intracellular domains of the delta opioid receptor. J Neurochem 2001; 76: 1887–1894.

    Article  CAS  PubMed  Google Scholar 

  25. Gainetdinov RR, Premont RT, Bohn LM, Lefkowitz RJ, Caron MG . Desensitization of G protein-coupled receptors and neuronal functions. Annu Rev Neurosci 2004; 27: 107–144.

    Article  CAS  PubMed  Google Scholar 

  26. Bradaia A, Berton F, Ferrari S, Luscher C . Beta-arrestin2, interacting with phosphodiesterase 4, regulates synaptic release probability and presynaptic inhibition by opioids. Proc Natl Acad Sci USA 2005; 102: 3034–3039.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Nestler EJ . Molecular neurobiology of addiction. Am J Addict 2001; 10: 201–217.

    Article  CAS  PubMed  Google Scholar 

  28. Brunzell DH, Russell DS, Picciotto MR . In vivo nicotine treatment regulates mesocorticolimbic CREB and ERK signaling in C57Bl/6J mice. J Neurochem 2003; 84: 1431–1441.

    Article  CAS  PubMed  Google Scholar 

  29. Thomas GM, Huganir RL . MAPK cascade signalling and synaptic plasticity. Nat Rev Neurosci 2004; 5: 173–183.

    Article  CAS  PubMed  Google Scholar 

  30. Valjent E, Pages C, Herve D, Girault JA, Caboche J . Addictive and non-addictive drugs induce distinct and specific patterns of ERK activation in mouse brain. Eur J Neurosci 2004; 19: 1826–1836.

    Article  PubMed  Google Scholar 

  31. Terwilliger RZ, Ortiz J, Guitart X, Nestler EJ . Chronic morphine administration increases beta-adrenergic receptor kinase (beta ARK) levels in the rat locus coeruleus. J Neurochem 1994; 63: 1983–1986.

    Article  CAS  PubMed  Google Scholar 

  32. Heatherton TF, Kozlowski LT, Frecker RC, Fagerstrom KO . The Fagerstrom Test for nicotine dependence: a revision of the Fagerstrom Tolerance Questionnaire. Br J Addict 1991; 86: 1119–1127.

    CAS  PubMed  Google Scholar 

  33. Swan GE . The need for dissemination of evidence-based results from research on nicotine and tobacco. Nicotine Tob Res 2003; 5: 7–8.

    Article  CAS  PubMed  Google Scholar 

  34. Beuten J, Ma JZ, Payne TJ, Dupont RT, Crews KM, Somes G et al. Single- and multilocus allelic variants within the GABAB receptor subunit 2 (GABAB2) gene are significantly associated with nicotine dependence. Am J Hum Genet 2005; 76: 859–864.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Li MD, Beuten J, Ma JZ, Payne TJ, Lou XY, Garcia V et al. Ethnic- and gender-specific association of the nicotinic acetylcholine receptor alpha4 subunit gene (CHRNA4) with nicotine dependence. Hum Mol Genet 2005; 14: 1211–1219.

    Article  CAS  PubMed  Google Scholar 

  36. Ma JZ, Beuten J, Payne TJ, Dupont RT, Elston RC, Li MD . Haplotype analysis indicates an association between the DOPA decarboxylase (DDC) gene and nicotine dependence. Hum Mol Genet 2005; 14: 1691–1698.

    Article  CAS  PubMed  Google Scholar 

  37. Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.

    Article  CAS  PubMed  Google Scholar 

  38. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B et al. The structure of haplotype blocks in the human genome. Science 2002; 296: 2225–2229.

    Article  CAS  PubMed  Google Scholar 

  39. O'Connell JR, Weeks DE . PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 1998; 63: 259–266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lange C, Silverman EK, Xu X, Weiss ST, Laird NM . A multivariate family-based association test using generalized estimating equations: FBAT-GEE. Biostatistics 2003; 4: 195–206.

    Article  PubMed  Google Scholar 

  41. Horvath S, Xu X, Lake SL, Silverman EK, Weiss ST, Laird NM . Family-based tests for associating haplotypes with general phenotype data: application to asthma genetics. Genet Epidemiol 2004; 26: 61–69.

    Article  PubMed  Google Scholar 

  42. Heath AC, Kirk KM, Meyer JM, Martin NG . Genetic and social determinants of initiation and age at onset of smoking in Australian twins. Behav Genet 1999; 29: 395–407.

    Article  CAS  PubMed  Google Scholar 

  43. Madden PA, Heath AC, Pedersen NL, Kaprio J, Koskenvuo MJ, Martin NG . The genetics of smoking persistence in men and women: a multicultural study. Behav Genet 1999; 29: 423–431.

    Article  CAS  PubMed  Google Scholar 

  44. Perez-Stable EJ, Herrera B, Jacob III P, Benowitz NL . Nicotine metabolism and intake in black and white smokers. JAMA 1998; 280: 152–156.

    Article  CAS  PubMed  Google Scholar 

  45. Nyholt DR . A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am J Hum Genet 2004; 74: 765–769.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. McDonald PH, Chow CW, Miller WE, Laporte SA, Field ME, Lin FT et al. Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3. Science 2000; 290: 1574–1577.

    Article  CAS  PubMed  Google Scholar 

  47. Burchard EG, Ziv E, Coyle N, Gomez SL, Tang H, Karter AJ et al. The importance of race and ethnic background in biomedical research and clinical practice. New Engl J Med 2003; 348: 1170–1175.

    Article  PubMed  Google Scholar 

  48. Bamshad M, Wooding S, Salisbury BA, Stephens JC . Deconstructing the relationship between genetics and race. Nat Rev Genet 2004; 5: 598–609.

    Article  CAS  PubMed  Google Scholar 

  49. Benowitz NL, Perez-Stable EJ, Fong I, Modin G, Herrera B, Jacob III P . Ethnic differences in N-glucuronidation of nicotine and cotinine. J Pharmacol Exp Ther 1999; 291: 1196–1203.

    CAS  PubMed  Google Scholar 

  50. Radzius A, Gallo JJ, Epstein DH, Gorelick DA, Cadet JL, Uhl GE et al. A factor analysis of the Fagerstrom Test for Nicotine Dependence (FTND). Nicotine Tob Res 2003; 5: 240–255.

    Article  Google Scholar 

  51. Richardson CG, Ratner PA . A confirmatory factor analysis of the Fagerstrom Test for Nicotine Dependence. Addict Behav 2005; 30: 697–709.

    Article  PubMed  Google Scholar 

  52. Nonnemaker JM, Homsi G . Measurement properties of the Fagerstrom Test for nicotine dependence adapted for use in an adolescent sample. Addict Behav 2007; 32: 181–186.

    Article  PubMed  Google Scholar 

  53. Moolchan ET, Radzius A, Epstein DH, Uhl G, Gorelick DA, Cadet JL et al. The Fagerstrom test for nicotine dependence and the diagnostic interview schedule: do they diagnose the same smokers? Addict Behav 2002; 27: 101–113.

    Article  PubMed  Google Scholar 

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Acknowledgements

We acknowledge the invaluable contributions made by all donors for participating and providing blood samples to the study. Many clinical and research staff in The University of Texas Health Science Center at San Antonio, University of Tennessee Health Science Center and the ACT Center of the University of Mississippi Medical Center have been involved in clinical recruitment and genetic analysis. We thank all of them for their dedicated work. This project was funded by a grant from the National Institute on Drug Abuse to Ming D Li (DA-12844).

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Authors and Affiliations

  1. Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, VA, USA

    D Sun & M D Li

  2. Department of Animal Genetics and Breeding, China Agricultural University, Beijing, PR China

    D Sun

  3. Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA

    J Z Ma

  4. ACT Center for Tobacco Treatment, Education and Research, University of Mississippi Medical Center, Jackson, MS, USA

    T J Payne

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  1. D Sun
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Correspondence to M D Li.

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Sun, D., Ma, J., Payne, T. et al. β-Arrestins 1 and 2 are associated with nicotine dependence in European American smokers. Mol Psychiatry 13, 398–406 (2008). https://doi.org/10.1038/sj.mp.4002036

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