The AAPS Journal

, Volume 8, Issue 3, pp E515–E520 | Cite as

Searching for polymorphisms that affect gene expression and mRNA processing: Example ABCB1 (MDR1)

Article

Abstract

Cis-acting genetic variations can affect the amount and structure of mRNA/protein. Genomic surveys indicate that polymorphisms affecting transcription and mRNA processing, including splicing and turnover, may account for main share of genetic factors in human phenotypic variability; however, most of these polymorphisms remain yet to be discovered. We use allelic expression imbalance (AEI) as a quantitative phenotype in the search for functionalcis-acting polymorphisms in many genes includingABCB1 (multidrug resistance 1 gene, MDR1, Pgp). Previous studies have shown that ABCB1 activity correlates with a synonymous polymorphism. C3435T; however, the functional polymorphism and molecular mechanisms underlying this clinical association remained unknown. Analysis of allele-specific expression in liver autopsy samples and in vitro expression experiments showed that C3435T represents a main functional polymorphism, accounting for 1.5-to 2-fold changes in mRNA levels. The mechanism appears to involve increased mRNA turnover, probably as a result of different folding structures calculated for mRNA with the Mfold program. Other examples of the successful application of AEI analysis for studying functional polymorphism include5-HTT (serotonin transporter, SLC6A4) andOPRM1 (μ opioid receptor). AEI is therefore a powerful approach for detectingcis-acting polymorphisms affecting gene expression and mRNA processing.

Keywords

ABCB1 allele-specific expression mRNA stability cis-acting polymorphism 

References

  1. 1.
    Johnson AD, Wang D, Sadee W. Polymorphisms affecting gene regulation and mRNA processing: broad implications for pharmacogenetics.Pharmacol Ther. 2005;106:19–38.CrossRefPubMedGoogle Scholar
  2. 2.
    Levine M. How insects lose their limbs.Nature. 2002;415:848–849.CrossRefPubMedGoogle Scholar
  3. 3.
    Bray NJ, Buckland PR, Owen MJ, O’Donovan MC. Cis-acting variation in the expression of a high proportion of genes in human brain.Hum Genet. 2003;113: 149–153.PubMedGoogle Scholar
  4. 4.
    Yan H, Yuan W, Velculescu VE, Vogelstein B, Kinzler KW. Allelic variation in human gene expression.Science. 2002;297:1143.CrossRefPubMedGoogle Scholar
  5. 5.
    Wang D, Johnson AD, Papp AC, Kroetz DL, Sadee W. Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435C>T affects mRNA stability.Pharmacogenet Genomics 2005;15:693–704.CrossRefPubMedGoogle Scholar
  6. 6.
    Zhang Y, Wang D, Johnson AD, Papp AC, Sadee W. Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A118G.J Biol Chem. 2005;280: 32618–32624.CrossRefPubMedGoogle Scholar
  7. 7.
    Schwab M, Eichelbaum M, Fromm MF. Genetic polymorphisms of the human MDR1 drug transporter.Annu Rev Pharmacol Toxicol. 2003;43:285–307.CrossRefPubMedGoogle Scholar
  8. 8.
    Lepper ER, Nooter K, Verweij J, Acharya MR, Figg WD, Sparreboom A. Mechanisms of resistance to anticancer drugs: the role of the polymorphic ABC transporters ABCB1 and ABCG2.Pharmacogenomics. 2005;6:115–138.CrossRefPubMedGoogle Scholar
  9. 9.
    Pauli-Magnus C, Kroetz DL. Functional implications of genetic polymorphisms in the multidrug resistance gene MDR1 (ABCB1).Pharm Res. 2004;21:904–913.CrossRefPubMedGoogle Scholar
  10. 10.
    Duan J, Wainwright MS, Comeron JM, et al. Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor.Hum Mol Genet 2003;12: 205–216.CrossRefPubMedGoogle Scholar
  11. 11.
    Bond C, LaForge KS, Tian M, et al. Single-nucleotide polymorphisms in the human mu opioid receptor gene alters betaendorphin binding and activity: possible implications for opiate addiction.Proc Natl Acad Sci USA. 1998;95:9608–9613.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Beyer A, Koch T, Schroder H, Schulz S, Hollt V. Effect of the A118G polymorphism on binding affinity, potency and agonist-mediated endocytosis, desensitization, and resensitization of the human mu-opioid receptor.J Neurochem. 2004;89:553–560.CrossRefPubMedGoogle Scholar
  13. 13.
    Lim JE, Papp A, Pinsonneault J, Sadee W, Saffen D. Allelic expression of serotonin transporter (SERT) mRNA in human pons: lack of correlation with the polymorphism SERTLPR.Mol Psychiatry. 2006;11:649–662.CrossRefPubMedGoogle Scholar
  14. 14.
    Wang D, Papp AC, Binkley PF, Johnson JA, Sadee W. Highly variable mRNA expression and splicing of L-type voltage-dependent calcium channel alpha subunit IC in human heart tissues.Pharmacogenet Genom. 2006; In press.Google Scholar
  15. 15.
    Grewal SI, Moazed D. Heterochromatin and epigenetic control of gene expression.Science. 2003;301:798–802.CrossRefPubMedGoogle Scholar
  16. 16.
    Pinsonneault JK, Papp AC, Sadee W. A Helic mRNA expression of x-linked monamine oxidase a (MAOA) in human brain: dissection of epigenetics and genetic factors.Hum Mol Genet. 2006; In press.Google Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2006

Authors and Affiliations

  1. 1.Department of Pharmacology, Program in Pharmacogenetics, College of Medicine and Public HealthThe Ohio State UniversityColumbusUSA

Personalised recommendations