Evolving Knowledge of Opioid Genetics in Cancer Pain

Clinical Oncology

Volumn 23, Issue 6, 2011, Pages 418-428

  Droney, J ^a,b   Riley, J ^a,b,c   Ross, J R ^a,b,c  

^a IMPERIAL COLLEGE LONDON   (United Kingdom)

^b ROYAL MARSDEN HOSPITAL   (United Kingdom)

^c ROYAL BROMPTON HOSPITAL   (United Kingdom)

Author keywords

Morphine; Opioid; Pharmacogenetics; Single nucleotide polymorphism; Variation

Indexed keywords

ADENINE; ALFENTANIL; ASPARAGINE; BETA ADRENERGIC RECEPTOR BLOCKING AGENT; BETA ARRESTIN; BETA ENDORPHIN; CATECHOL METHYLTRANSFERASE; CODEINE; CORTICOSTEROID; CYTOCHROME P450 2D6; CYTOSINE; DNA; FENTANYL; GUANINE; METHIONINE; MORPHINE; MORPHINE 3 GLUCURONIDE; MORPHINE 6 GLUCURONIDE; MU OPIATE RECEPTOR; MULTIDRUG RESISTANCE PROTEIN 1; OPIATE; OPRM PROTEIN; PROTEIN; PROTON PUMP INHIBITOR; SEROTONIN 3 AGONIST; SODIUM CHANNEL NAV1.7; STAT6 PROTEIN; THYMINE; UNCLASSIFIED DRUG; UNINDEXED DRUG; VALINE;

ANALGESIA; ARTICLE; BINDING AFFINITY; BLOOD BRAIN BARRIER; CANCER PAIN; CANCER PATIENT; CONFUSION; DISEASE SEVERITY; DROWSINESS; DRUG DOSE ESCALATION; DRUG DOSE TITRATION; DRUG ELIMINATION; DRUG MEGADOSE; DRUG METABOLISM; DRUG RESPONSE; DRUG TRANSPORT; ENZYME ACTIVITY; GENE EXPRESSION; GENE INTERACTION; GENE LINKAGE DISEQUILIBRIUM; GENETIC ASSOCIATION; GENETIC VARIABILITY; GENOTYPE; HALLUCINATION; HUMAN; KNOCKOUT MOUSE; META ANALYSIS (TOPIC); NOCICEPTION; NONHUMAN; PATIENT CONTROLLED ANALGESIA; PHARMACOGENETICS; PHARMACOGENOMICS; PREDICTION; PRIORITY JOURNAL; RECEPTOR BINDING; SINGLE NUCLEOTIDE POLYMORPHISM; UNSPECIFIED SIDE EFFECT;

ANALGESICS, OPIOID; HUMANS; NEOPLASMS; PAIN; PHARMACOGENETICS;

EID: 79959750262     PISSN: 09366555     EISSN: 14332981     Source Type: Journal    
DOI: 10.1016/j.clon.2011.04.015     Document Type: Article

References (108)

1. Innocenti F., Undevia S.D., Iyer L., et al. Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 2004, 22(8):1382-1388.
2. Mallal S., Phillips E., Carosi G., et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med 2008, 358(6):568-579.
3. Higashi M.K., Veenstra D.L., Kondo L.M., et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 2002, 287(13):1690-1698.
4. Limdi N.A., Beasley T.M., Crowley M.R., et al. VKORC1 polymorphisms, haplotypes and haplotype groups on warfarin dose among African-Americans and European-Americans. Pharmacogenomics 2008, 9(10):1445-1458.
5. Schwarz U.I., Ritchie M.D., Bradford Y., et al. Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med 2008, 358(10):999-1008.
6. Cancer pain relief 1996, World Health Organization, World Health Organization, Geneva. 2nd ed.
7. Kasai S., Hayashida M., Sora I., Ikeda K. Candidate gene polymorphisms predicting individual sensitivity to opioids. Naunyn Schmiedebergs Arch Pharmacol 2008, 377(4-6):269-281.
8. Riley J., Ross J.R., Rutter D., et al. No pain relief from morphine? Individual variation in sensitivity to morphine and the need to switch to an alternative opioid in cancer patients. Support Care Cancer 2006, 14(1):56-64.
9. Cherny N., Ripamonti C., Pereira J., et al. Strategies to manage the adverse effects of oral morphine: an evidence-based report. J Clin Oncol 2001, 19(9):2542-2554.
10. Mercadante S., Bruera E. Opioid switching: a systematic and critical review. Cancer Treat Rev 2006, 32(4):304-315.
11. Ross J.R., Rutter D., Welsh K., et al. Clinical response to morphine in cancer patients and genetic variation in candidate genes. Pharmacogenomics J 2005, 5(5):324-336.
12. Klepstad P., Rakvag T.T., Kaasa S., et al. The 118 A > G polymorphism in the human micro-opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease. Acta Anaesthesiol Scand 2004, 48(10):1232-1239.
13. Coulbault L., Beaussier M., Verstuyft C., et al. Environmental and genetic factors associated with morphine response in the postoperative period. Clin Pharmacol Ther 2006, 79(4):316-324.
14. Chou W.Y., Yang L.C., Lu H.F., et al. Association of mu-opioid receptor gene polymorphism (A118G) with variations in morphine consumption for analgesia after total knee arthroplasty. Acta Anaesthesiol Scand 2006, 50(7):787-792.
15. Riley J., Ross J.R., Rutter D., et al. A retrospective study of the association between haematological and biochemical parameters and morphine intolerance in patients with cancer pain. Palliat Med 2004, 18(1):19-24.
16. Kloke M., Rapp M., Bosse B., Kloke O. Toxicity and/or insufficient analgesia by opioid therapy: risk factors and the impact of changing the opioid. A retrospective analysis of 273 patients observed at a single center. Support Care Cancer 2000, 8(6):479-486.
17. Mercadante S., Ferrera P., Villari P., Casuccio A., Intravaia G., Mangione S. Frequency, indications, outcomes, and predictive factors of opioid switching in an acute palliative care unit. J Pain Symptom Manage 2009, 37(4):632-641.
18. McQuay H.J., Carroll D., Faura C.C., Gavaghan D.J., Hand C.W., Moore R.A. Oral morphine in cancer pain: influences on morphine and metabolite concentration. Clin Pharmacol Ther 1990, 48(3):236-244.
19. Sear J.W., Hand C.W., Moore R.A., McQuay H.J. Studies on morphine disposition: influence of renal failure on the kinetics of morphine and its metabolites. Br J Anaesth 1989, 62(1):28-32.
20. Sora I., Takahashi N., Funada M., et al. Opiate receptor knockout mice define mu receptor roles in endogenous nociceptive responses and morphine-induced analgesia. Proc Natl Acad Sci USA 1997, 94(4):1544-1549.
21. Matthes H.W., Maldonado R., Simonin F., et al. Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene. Nature 1996, 383(6603):819-823.
22. Clarke S., Kitchen I. Opioid analgesia: new information from gene knockout studies. Curr Opin Anaesthesiol 1999, 12:609-614.
23. Roy S., Liu H.C., Loh H.H. mu-Opioid receptor-knockout mice: the role of mu-opioid receptor in gastrointestinal transit. Brain Res Mol Brain Res 1998, 56(1-2):281-283.
24. Ikeda K., Ide S., Han W., Hayashida M., Uhl G.R., Sora I. How individual sensitivity to opiates can be predicted by gene analyses. Trends Pharmacol Sci 2005, 26(6):311-317.
25. Ikeda K., Ichikawa T., Kobayashi T., Kumanishi T., Oike S., Yano R. Unique behavioural phenotypes of recombinant-inbred CXBK mice: partial deficiency of sensitivity to mu- and kappa-agonists. Neurosci Res 1999, 34(3):149-155.
26. Lacroix-Fralish M.L., Ledoux J.B., Mogil J.S. The Pain Genes Database: an interactive web browser of pain-related transgenic knockout studies. Pain 2007, 131(1-2):3-4.
27. Dayer P., Desmeules J., Leemann T., Striberni R. Bioactivation of the narcotic drug codeine in human liver is mediated by the polymorphic monooxygenase catalyzing debrisoquine 4-hydroxylation (cytochrome P-450 dbl/bufI). Biochem Biophys Res Commun 1988, 152(1):411-416.
28. Sindrup S.H., Brosen K., Bjerring P., et al. Codeine increases pain thresholds to copper vapor laser stimuli in extensive but not poor metabolizers of sparteine. Clin Pharmacol Ther 1990, 48(6):686-693.
29. Kirchheiner J., Schmidt H., Tzvetkov M., et al. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J 2007, 7(4):257-265.
30. Lotsch J., Rohrbacher M., Schmidt H., Doehring A., Brockmoller J., Geisslinger G. Can extremely low or high morphine formation from codeine be predicted prior to therapy initiation?. Pain 2009, 144(1-2):119-124.
31. Koren G., Cairns J., Chitayat D., Gaedigk A., Leeder S.J. Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. Lancet 2006, 368(9536):704.
32. Madadi P., Ross C.J., Hayden M.R., et al. Pharmacogenetics of neonatal opioid toxicity following maternal use of codeine during breastfeeding: a case-control study. Clin Pharmacol Ther 2009, 85(1):31-35.
33. Chou W.Y., Wang C.H., Liu P.H., Liu C.C., Tseng C.C., Jawan B. Human opioid receptor A118G polymorphism affects intravenous patient-controlled analgesia morphine consumption after total abdominal hysterectomy. Anesthesiology 2006, 105(2):334-337.
34. Sia A.T., Lim Y., Lim E.C., et al. A118G single nucleotide polymorphism of human mu-opioid receptor gene influences pain perception and patient-controlled intravenous morphine consumption after intrathecal morphine for postcesarean analgesia. Anesthesiology 2008, 109(3):520-526.
35. Landau R., Kern C., Columb M.O., Smiley R.M., Blouin J.L. Genetic variability of the mu-opioid receptor influences intrathecal fentanyl analgesia requirements in laboring women. Pain 2008, 139(1):5-14.
36. Oertel B.G., Schmidt R., Schneider A., Geisslinger G., Lotsch J. The mu-opioid receptor gene polymorphism 118A>G depletes alfentanil-induced analgesia and protects against respiratory depression in homozygous carriers. Pharmacogenet Genom 2006, 16(9):625-636.
37. Fillingim R.B., Kaplan L., Staud R., et al. The A118G single nucleotide polymorphism of the mu-opioid receptor gene (OPRM1) is associated with pressure pain sensitivity in humans. J Pain 2005, 6(3):159-167.
38. Skarke C., Darimont J., Schmidt H., Geisslinger G., Lotsch J. Analgesic effects of morphine and morphine-6-glucuronide in a transcutaneous electrical pain model in healthy volunteers. Clin Pharmacol Ther 2003, 73(1):107-121.
39. Riva A., Kohane I.S. A SNP-centric database for the investigation of the human genome. BMC Bioinformatics 2004, 5:33.
40. HapMap frequency data on SNP databbase, NCBI (National Centre for Biotechnology Information) 2009, NCBI, NCBI, Available at. http://www.ncbi.nlm.nih.gov.
41. Lotsch J., Skarke C., Grosch S., Darimont J., Schmidt H., Geisslinger G. The polymorphism A118G of the human mu-opioid receptor gene decreases the pupil constrictory effect of morphine-6-glucuronide but not that of morphine. Pharmacogenetics 2002, 12(1):3-9.
42. Reyes-Gibby C.C., Shete S., Rakvag T., et al. Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain: OPRM1 and COMT gene. Pain 2007, 130(1-2):25-30.
43. Campa D., Gioia A., Tomei A., Poli P., Barale R. Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief. Clin Pharmacol Ther 2008, 83(4):559-566.
44. Walter C., Lotsch J. Meta-analysis of the relevance of the OPRM1 118A>G genetic variant for pain treatment. Pain 2009, 146(3):270-275.
45. Bond C., LaForge K.S., Tian M., et al. Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction. Proc Natl Acad Sci USA 1998, 95(16):9608-9613.
46. Kroslak T., LaForge K.S., Gianotti R.J., Ho A., Nielsen D.A., Kreek M.J. The single nucleotide polymorphism A118G alters functional properties of the human mu opioid receptor. J Neurochem 2007, 103(1):77-87.
47. 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(3):553-560.
48. Zhang Y., Wang D., Johnson A.D., Papp A.C., Sadee W. Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A118G. J Biol Chem 2005, 280(38):32618-32624.
49. George S.R., Kertesz M. Met-enkephalin concentrations in striatum respond reciprocally to alterations in dopamine neurotransmission. Peptides 1987, 8(3):487-492.
50. Zubieta J.K., Heitzeg M.M., Smith Y.R., et al. COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science 2003, 299(5610):1240-1243.
51. Diatchenko L., Nackley A.G., Slade G.D., et al. Catechol-O-methyltransferase gene polymorphisms are associated with multiple pain-evoking stimuli. Pain 2006, 125(3):216-224.
52. Nackley A.G., Tan K.S., Fecho K., Flood P., Diatchenko L., Maixner W. Catechol-O-methyltransferase inhibition increases pain sensitivity through activation of both beta2- and beta3-adrenergic receptors. Pain 2007, 128(3):199-208.
53. Shield A.J., Thomae B.A., Eckloff B.W., Wieben E.D., Weinshilboum R.M. Human catechol O-methyltransferase genetic variation: gene resequencing and functional characterization of variant allozymes. Mol Psychiatry 2004, 9(2):151-160.
54. Diatchenko L., Slade G.D., Nackley A.G., et al. Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet 2005, 14(1):135-143.
55. Nackley A.G., Shabalina S.A., Tchivileva I.E., et al. Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure. Science 2006, 314(5807):1930-1933.
56. Kim H., Neubert J.K., San Miguel A., et al. Genetic influence on variability in human acute experimental pain sensitivity associated with gender, ethnicity and psychological temperament. Pain 2004, 109(3):488-496.
57. Kim H., Lee H., Rowan J., Brahim J., Dionne R.A. Genetic polymorphisms in monoamine neurotransmitter systems show only weak association with acute post-surgical pain in humans. Mol Pain 2006, 2:24.
58. Rakvag T.T., Klepstad P., Baar C., et al. The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene may influence morphine requirements in cancer pain patients. Pain 2005, 116(1-2):73-78.
59. Chen J.F., Aloyo V.J., Weiss B. Continuous treatment with the D2 dopamine receptor agonist quinpirole decreases D2 dopamine receptors, D2 dopamine receptor messenger RNA and proenkephalin messenger RNA, and increases mu opioid receptors in mouse striatum. Neuroscience 1993, 54(3):669-680.
60. Rakvag T.T., Ross J.R., Sato H., Skorpen F., Kaasa S., Klepstad P. Genetic variation in the catechol-O-methyltransferase (COMT) gene and morphine requirements in cancer patients with pain. Mol Pain 2008, 4:64.
61. Ross J.R., Riley J., Taegetmeyer A.B., et al. Genetic variation and response to morphine in cancer patients: catechol-o-methyltransferase and multidrug resistance-1 gene polymorphisms are associated with central side effects. Cancer 2008, 112(6):1390-1403.
62. Cordon-Cardo C., O'Brien J.P., Casals D., et al. Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci USA 1989, 86(2):695-698.
63. King M., Su W., Chang A., Zuckerman A., Pasternak G.W. Transport of opioids from the brain to the periphery by P-glycoprotein: peripheral actions of central drugs. Nat Neurosci 2001, 4(3):268-274.
64. Xie R., Hammarlund-Udenaes M., de Boer A.G., de Lange E.C. The role of P-glycoprotein in blood-brain barrier transport of morphine: transcortical microdialysis studies in mdr1a (-/-) and mdr1a (+/+) mice. Br J Pharmacol 1999, 128(3):563-568.
65. Okura T., Morita Y., Ito Y., Kagawa Y., Yamada S. Effects of quinidine on antinociception and pharmacokinetics of morphine in rats. J Pharm Pharmacol 2009, 61(5):593-597.
66. Balayssac D., Cayre A., Ling B., et al. Increase in morphine antinociceptive activity by a P-glycoprotein inhibitor in cisplatin-induced neuropathy. Neurosci Lett 2009, 465(1):108-112.
67. Park H.J., Shinn H.K., Ryu S.H., Lee H.S., Park C.S., Kang J.H. Genetic polymorphisms in the ABCB1 gene and the effects of fentanyl in Koreans. Clin Pharmacol Ther 2007, 81(4):539-546.
68. Hoffmeyer S., Burk O., von Richter O., et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 2000, 97(7):3473-3478.
69. Skarke C., Jarrar M., Schmidt H., et al. Effects of ABCB1 (multidrug resistance transporter) gene mutations on disposition and central nervous effects of loperamide in healthy volunteers. Pharmacogenetics 2003, 13(11):651-660.
70. Kim R.B., Leake B.F., Choo E.F., et al. Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther 2001, 70(2):189-199.
71. Morita N., Yasumori T., Nakayama K. Human MDR1 polymorphism: G2677T/A and C3435T have no effect on MDR1 transport activities. Biochem Pharmacol 2003, 65(11):1843-1852.
72. Reyes-Gibby C.C., El O.B., Spitz M.R., et al. The influence of tumor necrosis factor-alpha -308 G/A and IL-6 -174 G/C on pain and analgesia response in lung cancer patients receiving supportive care. Cancer Epidemiol Biomarkers Prev 2008, 17(11):3262-3267.
73. Raehal K.M., Bohn L.M. Mu opioid receptor regulation and opiate responsiveness. AAPS J 2005, 7(3):E587-E591.
74. Bohn L.M., Lefkowitz R.J., Gainetdinov R.R., Peppel K., Caron M.G., Lin F.T. Enhanced morphine analgesia in mice lacking beta-arrestin 2. Science 1999, 286(5449):2495-2498.
75. Sawyer M.B., Innocenti F., Das S., et al. A pharmacogenetic study of uridine diphosphate-glucuronosyltransferase 2B7 in patients receiving morphine. Clin Pharmacol Ther 2003, 73(6):566-574.
76. Holthe M., Rakvag T.N., Klepstad P., et al. Sequence variations in the UDP-glucuronosyltransferase 2B7 (UGT2B7) gene: identification of 10 novel single nucleotide polymorphisms (SNPs) and analysis of their relevance to morphine glucuronidation in cancer patients. Pharmacogenomics J 2003, 3(1):17-26.
77. Holthe M., Klepstad P., Zahlsen K., et al. Morphine glucuronide-to-morphine plasma ratios are unaffected by the UGT2B7 H268Y and UGT1A1*28 polymorphisms in cancer patients on chronic morphine therapy. Eur J Clin Pharmacol 2002, 58(5):353-356.
78. Mogil J.S., Ritchie J., Smith S.B., et al. Melanocortin-1 receptor gene variants affect pain and mu-opioid analgesia in mice and humans. J Med Genet 2005, 42(7):583-587.
79. Tegeder I., Costigan M., Griffin R.S., et al. GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence. Nat Med 2006, 12(11):1269-1277.
80. Hjermstad M.J., Fainsinger R., Kaasa S. Assessment and classification of cancer pain. Curr Opin Support Palliat Care 2009, 3(1):24-30.
81. Hjermstad M.J., Gibbins J., Haugen D.F., Caraceni A., Loge J.H., Kaasa S. Pain assessment tools in palliative care: an urgent need for consensus. Palliat Med 2008, 22(8):895-903.
82. Diatchenko L., Nackley A.G., Tchivileva I.E., Shabalina S.A., Maixner W. Genetic architecture of human pain perception. Trends Genet 2007, 23(12):605-613.
83. Cardon L.R., Palmer L.J. Population stratification and spurious allelic association. Lancet 2003, 361(9357):598-604.
84. Kim H., Clark D., Dionne R.A. Genetic contributions to clinical pain and analgesia: avoiding pitfalls in genetic research. J Pain 2009, 10(7):663-693.
85. Bair M.J., Robinson R.L., Katon W., Kroenke K. Depression and pain comorbidity: a literature review. Arch Intern Med 2003, 163(20):2433-2445.
86. Knudsen A.K., Brunelli C., Kaasa S., et al. Which variables are associated with pain intensity and treatment response in advanced cancer patients? - implications for a future classification system for cancer pain. Eur J Pain 2011, 15(3):320-327.
87. Rousseaux C., Thuru X., Gelot A., et al. Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat Med 2007, 13(1):35-37.
88. Wang W.Y., Barratt B.J., Clayton D.G., Todd J.A. Genome-wide association studies: theoretical and practical concerns. Nat Rev Genet 2005, 6(2):109-118.
89. Zondervan K.T., Cardon L.R. The complex interplay among factors that influence allelic association. Nat Rev Genet 2004, 5(2):89-100.
90. Hirschhorn J.N., Daly M.J. Genome-wide association studies for common diseases and complex traits. Nat Rev Genet 2005, 6(2):95-108.
91. Chanock S.J., Manolio T., Boehnke M., et al. Replicating genotype-phenotype associations. Nature 2007, 447(7145):655-660.
92. Greene C.S., Penrod N.M., Williams S.M., Moore J.H. Failure to replicate a genetic association may provide important clues about genetic architecture. PLoS One 2009, 4(6):e5639.
93. Cox J.J., Reimann F., Nicholas A.K., et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature 2006, 444(7121):894-898.
94. Fertleman C.R., Baker M.D., Parker K.A., et al. SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes. Neuron 2006, 52(5):767-774.
95. Moore J.H. The ubiquitous nature of epistasis in determining susceptibility to common human diseases. Hum Hered 2003, 56(1-3):73-82.
96. Thornton-Wells T.A., Moore J.H., Haines J.L. Genetics, statistics and human disease: analytical retooling for complexity. Trends Genet 2004, 20(12):640-647.
97. Lin P.I., Vance J.M., Pericak-Vance M.A., Martin E.R. No gene is an island: the flip-flop phenomenon. Am J Hum Genet 2007, 80(3):531-538.
98. Ioannidis J.P., Trikalinos T.A., Khoury M.J. Implications of small effect sizes of individual genetic variants on the design and interpretation of genetic association studies of complex diseases. Am J Epidemiol 2006, 164(7):609-614.
99. Millstein J., Conti D.V., Gilliland F.D., Gauderman W.J. A testing framework for identifying susceptibility genes in the presence of epistasis. Am J Hum Genet 2006, 78(1):15-27.
100. Wilke R.A., Mareedu R.K., Moore J.H. The pathway less traveled: moving from candidate genes to candidate pathways in the analysis of genome-wide data from large scale pharmacogenetic association studies. Curr Pharmacogenomics Person Med 2008, 6(3):150-159.
101. Cordell H.J. Epistasis: what it means, what it doesn't mean, and statistical methods to detect it in humans. Hum Mol Genet 2002, 11(20):2463-2468.
102. Novembre J., Johnson T., Bryc K., et al. Genes mirror geography within Europe. Nature 2008, 456(7218):98-101.
103. Lotsch J., von H.N., Freynhagen R., et al. Cross-sectional analysis of the influence of currently known pharmacogenetic modulators on opioid therapy in outpatient pain centers. Pharmacogenet Genom 2009, 19(6):429-436.
104. Pan L., Xu J., Yu R., Xu M.M., Pan Y.X., Pasternak G.W. Identification and characterization of six new alternatively spliced variants of the human mu opioid receptor gene. Oprm. Neuroscience 2005, 133(1):209-220.
105. Pan Y.X. Diversity and complexity of the mu opioid receptor gene: alternative pre-mRNA splicing and promoters. DNA Cell Biol 2005, 24(11):736-750.
106. Shabalina S.A., Zaykin D.V., Gris P., et al. Expansion of the human {micro}-opioid receptor gene architecture: novel functional variants. Hum Mol Genet 2009, 18(6):1037-1051.
107. Ioannidis J.P., Trikalinos T.A., Ntzani E.E., Contopoulos-Ioannidis D.G. Genetic associations in large versus small studies: an empirical assessment. Lancet 2003, 361(9357):567-571.
108. Moonesinghe R., Yang Q., Khoury M.J. Sample size requirements to detect the effect of a group of genetic variants in case-control studies. Emerg Themes Epidemiol 2008, 5:24.