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Pharmacogenetics and respiratory disease

Pharmacogenetics and respiratory disease. Genetic biomarkers for treatment of disease and targeting of treatments. Dr John W Holloway. Pharmacogenomics.

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Pharmacogenetics and respiratory disease

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  1. Pharmacogenetics and respiratory disease Genetic biomarkers for treatment of disease and targeting of treatments Dr John W Holloway

  2. Pharmacogenomics • Polymorphism in a gene either in a single nucleotide (SNP) or in a series of associated alleles (haplotype) may cause variable responses to drug therapy: • Pharmacodynamics – drug actions • Pharmacokinetics – drug metabolism (e.g warfarin) • Adverse effects • Matching drug therapy to the patient genotype may improve drug efficacy or reduce adverse events

  3. Characteristics favouring the cost-effectiveness of pharmacogenomics-based therapies Severe outcome (mortality, quality of life, expensive care) Difficulty of monitoring drug levels or predicting response Strong association between genotype and clinical outcome High frequency of variant genotype Availability of cheap genotyping assay Veenstra & Higashi AAPS Pharmsci 2000;2(3):29

  4. Targeting of therapies Determination of the likelihood of an individual responding to a particular therapy (pharmacogenetics) and individualised treatment plans Sub classification of disease on the basis of genetics and targeting of specific therapies based on this classification Pharmacogenomics I

  5. Fluticasone superior Montelukast superior Identifying sub-groups of responders will improve targeting of drug therapy 8 week crossover trial of: Oral montelukast (5-10 mg/d) versus Inhaled fluticasone (200 ug/d) 126 mild-moderate asthmatic children (aged 6-17y) FEV1: forced expiratory volume Szefler et al. JACI 2005115:233-242

  6. Beta-2 agonists • Theophylline • Glucocorticoids • Anti-muscarinic drugs • Leukotriene modifiers

  7. Beta-2 agonists: Albuterol Salmeterol Acutedesensitisation β2-AR P Chronicdownregulation cyclic AMP Bronchial smooth muscle relaxation Protein kinase A AC: adenylate cyclase AR: adrenoceptor AMP: adenosine monophosphate Gs:G-protein Smooth muscle cell membrane β2-AR AC Gs Reduces chronic response to LABA? Reduces acute response to rescue medication?

  8. Frequencies: Arg16>Gly 36% Gln27>Glu 43% Others: <0.1% Arg:39% Glu:43% Met: <0.01% Ile: 0.03% Beta-2 adrenoceptor Reihsaus et al. AJRCMB 1993;8:334-9, Liggett AJRCCM 1997;156:S156-S162 Hall, Chest 2006;130:1873-8

  9. Transfected CH fibroblasts • Beta-2 receptor down-regulation by isoprenaline is: • Decreased by Arg16->Gly • Increased by Gln27->Glu (Isoprenaline) Green et al. AJRCMB 1995;13:25-33

  10. Arg/Gly-16 polymorphism in 2AR receptor reduces FEV1 response to Beta-2 agonist in children p = 0.007 6 5 Odds ratio of >15% increase in FEV1 after 180ug salbuterol 4 3 2 1 Arg16/Arg16 Arg16/Gly16 Gly16/Gly16 n = 38 n = 103 n = 124 Martinez FD et al. J Clin Invest 1997; 100:3184-3188

  11. Arg/Gly16 polymorphism in 2AR and response to regular albuterol use Israel E et al. Am J Respir Crit Care Med 2000; 162:75-80

  12. Albuterol Albuterol Time Mild asthmatics with Arg16/Arg16 genotype show decline in morning peak flow during regular albuterol therapy (4 x daily for 16 weeks) Albuterol Albuterol as-needed Beta-2 receptor expression Arg16/Arg16n=28 Gly16/Gly16n=62 0 Gly16/Gly16 receptors are already down-regulated by endogenous catecholamines and do not fall further Israel E et al. AJRCCM 2000;162:75-80 Israel E et al. The Lancet 2004;364(9444):1505-12

  13. ADRB2 polymorphisms and Long Acting Beta Agonists (LABAs) Arg16/Arg16 individuals may also have impaired responses to LABAs such as Salmeterol Treatment Genotype Total exacerbations TotalOR(p values) Not on salmeterol GlyGly 48 (33%) 97145 1.26(p = 0.149)* ArgGly 61 (35%) 117178 ArgArg 25 (41% 3459 Total 132 248382 On regular salmeterol GlyGly 26 (41%) 3763 1.79(p = 0.020)* ArgGly 39 (51%) 3776 ArgArg 16 (64%) 925 Total 81 83164 Wechsler ME et al. AJRCCM 2006;173:519-26 Palmer CN et al. Thorax 2006;61:940-44

  14. Inhaled corticosteroids may protect against receptor desensitisation in patients taking long-acting beta-2 agonists 183 mild-moderate asthmatics Salmeterol 100ug/d plus fluticasone (200ug/d) • No differences between codon 16 genotypes in: • FEV1, morning PEF • Symptom scores • Rescue medication Genetic influence on receptor desensitisation may still be important in patients who receive only beta-2 agonists and over-use them. Bleecker ER et al. JACI 2006;118:809-16 Bleecker ER et al. Lancet 2007;370:2118-25

  15. -1429 T -1343 A -1023 G -654 G -468 C -367 T -47 T -20 T NF-IL6 SP2 A G A A G C C C Beta-2 adrenoceptor gene (ADRB2) Chr 5q31.32 16 27 34 164 5’ ADRB2 3’ BUP 1 exon, 1200bp • BUP (Beta Upstream Protein): suppresses b2-AR expression • Arg19>Cys enhances expression and resists desensitisation • Eight SNPS in 5’-UTR (frequencies 33-67%) • Commonest haplotype (-20C, -47C, -367C, -468G) reduces transcription in COS-7 cells • Further SNPS in 3’-UTR • Highly complex and predictability may be poor Scott et al.1999 BJP 126:841-4 ; Drysdale et al.2000 PNAS 97(19):10483-8; Moore et al.2000 ARCCM 162:2117-24; Weiss et al.2006 Pharmacogenomics J 6:311-26

  16. Beta-2 agonists: Albuterol Salmeterol cyclic AMP Bronchial smooth muscle relaxation Protein kinase A Interaction between steroid treatment and b-agonist response: Adenylyl Cyclase 9 polymorphism β2-AR AC Gs • 436 asthmatic children randomised to budesonide vs. placebo for 4 years (CAMP) • Met772 AC9 SNP carriers show significantly better acute response to albuterol after steroid treatment Tantisira KG et al. Hum Mol Genet 2005;14:1671-77

  17. Beta-2 agonists • Theophylline • Glucocorticoids • Anti-muscarinic drugs • Leukotriene modifiers

  18. Corticotrophin-releasing hormone receptor-1 (CRHR1) CRH hypothalamus • Defects in CRHR1 may reduce endogenous suppression of allergic inflammation • May enhance effect of GC drug therapy • Three SNPs in CRHR1 enhanced FEV1 response to inhaled GC for 6-8 weeks in >1100 adult & pediatric asthmatics CRHR1 ACTH (adrenocorticotrophic hormone frompituitary) rs242941 Cortisol adrenals Glucocorticoid drug GR Anti-inflammatory effects T allele freq ~30% Tantisira et al. Hum Mol Gen 2004;13:1353-9

  19. T-bet (TBX21) polymorphism predicts response to inhaled corticosteroid TBX21 • H33Q polymorphism of T-bet increases induction of Th1 gene transcription • May enhance effect of GC drug therapy • H33Q SNP in T-bet enhanced improvement in PC20 in response to inhaled GC over 4 years in >700 pediatric asthmatics rs2240017 Enhances Th1 gene transcription (e.g. IFN-g) Suppresses Th2 transcription (IL4, IL5) Q allele freq ~4.5% Tantisira et al. PNAS 2004;101:18099-104

  20. Beta-2 agonists • Theophylline • Glucocorticoids • Anti-muscarinic drugs • Leukotriene modifiers

  21. Phospholipase A2 Arachidonate 5-lipoxygenase (5-LO) FLAP zileuton LTA4 montelukast pranlukast LTA4 hydrolase LTC4 synthase CysLT1 receptor LTC4/D4/E4 LTB4 MRP1 CysLT2 receptor BLT1, BLT2 receptors

  22. Frequency Normal allele: 5 (82%) Variant alleles: 3 (3%) 4 (15%) 6 (<1%) 5-Lipoxygenase (ALOX5) Sp1/Egr-1 tandem repeats in ALOX5 promoter 1 2 3 4 5 (-176 to -147) In KH et al. J Clin Invest. 1997;99:1130-7

  23. mRNA Variants Wild-type Variants (non5/non5) Wild-type (5/5) Variant 5-LO alleles reduce 5-LO mRNA transcripts and leukotriene C4 synthesis in human eosinophils Kalayci et al. Allergy 2006;61:97-103

  24. 5-LO genotype and bronchodilator response to an oral 5-LO inhibitor (ABT-761) for 12 weeks in asthmatics • Heterozygotes (n=40) have same response as wildtype, so variant 5-LO alleles are recessive. • Variant 5-LO homozygotes (6% of patients) show no response to LT modifier. n=64 n=64 n=10 Drazen et al. Nature Genetics 1999;22:168-70

  25. Klotsman et al. 2007 • Two 12-week trials of montelukast in 174 asthmatics • 25 polymorphisms in 10 genes including PLA2, 5-LO, FLAP, LTC4S, CysLTR1, CysLT2, and CYP 2C9 and 3A4 • 5-LO (p<0.01) and CysLTR2 (p<0.05) linked to peak flow (PEF) • PEF increase 18-25% in variant genotypes (10-13% of patients) • PEF increase only 8-10% in wild-type Montelukast pharmacogenetic studies Lima et al. 2004 • 252 asthmatics receiving montelukast for >6 months • 29 polymorphisms in 5-LO, LTA4H, LTC4S, MRP1, CysLTR1 • 5-LO and MRP1 SNPs linked to FEV1 (p<0.05) • LTC4S -444A/C and a SNP in LTA4H linked to exacerbations (-76%) • 5-LO tandem GC repeat variants: reduced exacerbations (-73%) Lima et al. AJRCCM 2004;173:379-85 Klotzman et al. Pharmacogenet Gen 2007;17:189-196

  26. Identification of novel pharmacological targets Identification of novel asthma susceptibility genes leading to new pharmacological targets and pathways for novel therapeutics Pharmacogenomics II

  27. Genetic variability and Leukotriene B4 Phospholipase A2 Arachidonate 5-lipoxygenase (5-LO) FLAP zileuton LTA4 LTC4 synthase LTA4 hydrolase montelukast pranlukast increased LTB4 in cardiovascular disease (stroke, MI). Genetic variation in FLAP (ALOX5AP) and LTA4H associated with increased LTB4 production and risk of disease LTB4 LTC4/D4/E4 CysLT1 receptor MRP1 Helgadottir A et al. Nat Genet. 2004;36:233-9, Nat Genet. 2006;38:68-74 BLT1, BLT2 receptors CysLT2 receptor

  28. Genetic association suggests a role for Leukotriene B4 in asthma ALOX5AP Holloway JW et al. The role of LTA4H and ALOX5AP polymorphism in Asthma and Allergy Susceptibility. Allergy 2008 (In Press)

  29. Genetic association suggests a role for Leukotriene B4 in asthma LTA4H Holloway JW et al. The role of LTA4H and ALOX5AP polymorphism in Asthma and Allergy Susceptibility. Allergy 2008 (In Press)

  30. Phospholipase A2 Arachidonate 5-lipoxygenase (5-LO) FLAP zileuton LTA4 montelukast pranlukast LTA4 hydrolase LTC4 synthase CysLT1 receptor LTC4/D4/E4 LTB4 MRP1 CysLT2 receptor BLT1, BLT2 receptors

  31. SUMMARY Drug class Candidate gene Pharmacogenetic effect Beta-2 agonists ADRB2 Probable (Arg16Gly) but clinical relevance unclear AC9 Possible PDE4 family Not known Theophylline Possible CYP 1A2 GR Glucocorticoids Possible (Asp363Ser) CRHR1 Possible TBX21 Possible Anti-muscarinics M2 receptor Not known M3 receptor Unlikely ALOX5 (5-LO) Yes (GC tandem repeats) Leukotriene modifiers LTC4S Probable (-444A/C) MRP1, LTA4H, CysLTR1/2 Possible Updated from Hall & Sayers, 2007 ERJ 29:1239-45 FLAP Unlikely

  32. Barriers to Pharmacogenomics Progress Complexity of finding gene variations that affect drug response - 10 million SNPs in human genome & infinite haplotypes - Linking specific genes to drug responses Limited drug alternatives for many diseases Disincentives for drug companies to fragment their market with multiple versions of drugs, particularly for small sub-groups Extra complexity for drug prescribers and dispensers US Human Genome Program

  33. Pharmacological treatment of disease Now: Risk factor Health maintenance Generalised treatment (diet, lifestyle) (biomarker, symptoms) ONE SIZE FITS ALL Future: Predisposition Early detection Personalised, early, effective therapies Genes PERSONALISED

  34. Acknowledgements University of Southampton Tony Sampson Ian Sayers Stephen Holgate • Sheila Barton • Matthew Rose-Zerilli Sonia Mall Shu Ye Salman Siddiqui University of Nottingham Ian Sayers Ajou University, S Korea Hae-Sim Park Asthma UK Medical Research Council Merck & Co. Genome Therapeutics Corporation

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