Pharmacogenetics of the response to β2-agonist drugs: A systematic overview of the field

Pharmacogenomics

Volumn 8, Issue 8, 2007, Pages 933-958

  Contopoulos Ioannidis, Despina G ^a   Kouri, Ioanna ^a   Ioannidis, John P A ^a,b  

^a UNIVERSITY OF IOANNINA   (Greece)

^b TUFTS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

2 agonists; Asthma; Gene; Pharmacogenetics; Polymorphism; Response; Treatment

Indexed keywords

ADAM PROTEIN; ADAM33 PROTEIN; ADENYLATE CYCLASE; ADENYLATE CYCLASE 9; ANTIASTHMATIC AGENT; BETA 2 ADRENERGIC RECEPTOR; BETA 2 ADRENERGIC RECEPTOR STIMULATING AGENT; BRONCHODILATING AGENT; CORTICOSTEROID; FENOTEROL; FORMOTEROL; LONG ACTING DRUG; MONTELUKAST; PLACEBO; SALBUTAMOL; SALMETEROL; SHORT ACTING DRUG; TERBUTALINE; UNCLASSIFIED DRUG; ZAFIRLUKAST;

AREA UNDER THE CURVE; ASTHMA; BRONCHODILATATION; CHRONIC OBSTRUCTIVE LUNG DISEASE; CLINICAL TRIAL; COMBINATION CHEMOTHERAPY; CYSTIC FIBROSIS; DISEASE EXACERBATION; DOSE RESPONSE; DRUG DOSE COMPARISON; EVIDENCE BASED MEDICINE; FORCED EXPIRATORY VOLUME; GENE INTERACTION; GENETIC ASSOCIATION; GENETIC LINKAGE; GENETIC SUSCEPTIBILITY; GENETIC VARIABILITY; GENOTYPE; HAPLOTYPE; HUMAN; MEDLINE; MONOTHERAPY; NONHUMAN; PHARMACOGENETICS; PHENOTYPE; REVIEW; SINGLE DRUG DOSE; SINGLE NUCLEOTIDE POLYMORPHISM; SYSTEMATIC REVIEW; TACHYPHYLAXIS;

ADRENERGIC BETA-AGONISTS; ANIMALS; HUMANS; PHARMACOGENETICS; POLYMORPHISM, GENETIC; RECEPTORS, ADRENERGIC, BETA-2;

EID: 34548720439     PISSN: 14622416     EISSN: 17448042     Source Type: Journal    
DOI: 10.2217/14622416.8.8.933     Document Type: Review

References (116)

1. Masoii M, Fabian D, Holt S, Beasley R: Global burden of asthma. Developed for the Global Initiative for Asthma(2004)
2. Lozano P, Sullivan SD, Smith DH, Weiss KB: The economic burden of asthma In US children: estimates from the National Medical Expenditure Survey. J. Allergy Clin. Immunol. 104(5), 957-963 (1999).
3. Weiss ST, Litonjua AA, Lange C et al.: Overview of the pharmacogenetics of asthma treatment. Pharmacogenomics J. 6(5) 311-326 (2006).
4. Drazen JM, Israel E, Boushey HA et al.: Comparison of regularly scheduled with as-needed use of albuterol in mild asthma. Asthma Clinical Research Network. N. Engl. J. Med. 335(12), 841-847 (1996).
5. Dennis SM, Sharp SJ, Vickers MR et al.: Regular inhaled salbutamol and asthma control: the TRUST randomised trial. Therapy Working Group of the National Asthma Task Force and the MRC General Practice Research Framework. Lancet 355(9216), 1675-1679 (2000).
6. Taylor DR, Sears MR, Herbison GP et al.: Regular inhaled β agonist in asthma: effects on exacerbations and lung function. Thorax 48(2), 134-138 (1993).
7. Drazen JM, Silverman EK, Lee TH: Heterogeneity of therapeutic responses in asthma. Br. Med. Bull. 56(4), 1054-1070 (2000).
8. Palmer LJ, Celedon JC, Chapman HA, Speizer FE, Weiss ST, Silverman EK Genome-wide linkage analysis of bronchodilator responsiveness and post-bronchodilator spirometric phenotypes in chronic obstructive pulmonary disease. Hum. Mol. Genet. 12(10), 1199-1210 (2003).
9. Contopoulos-Ioannidis DG, Aleidou GA, Gouvias TC, Ioannidis JP: An empirical evaluation of multifarious outcomes in pharmacogenetics: β-2 adrenoceptor gene polymorphisms in asthma treatment. Pharmacogenet, Genomics 16(10),705-711 (2006).
10. Asano K, Shiomi T, Hasegawa N et al.: Leukotriene C4 synthase gene A(-444)C polymorphism, and clinical response to a CYS-LT(1) antagonist, pranlukast, in Japanese patients with moderate asthma. Pharmacogenetics 12(7), 565-570 (2002).
11. Aziz I, Lipworth BJ: In vivo effect of albuterol on methacholine-contracted bronchi in conjunction with salmeterol and formoterol. J. Allergy Clin. Immunol. 103(5), 816-822 (1999).
12. Aziz I, Hall IP, McFarlane LC, Lipworth BJ: β2-adrenoceptor regulation and bronchodilator sensitivity after regular treatment with formoterol in subjects with stable asthma. J. Allergy Clin. Immunol. 101(3), 337-341(1998).
13. Bleecker ER, Yancey SW, Baitinger LA et al.: Salmeterol response is not affected by β2-adrenergic receptor genotype in subjects with persistent asthma. J. Allergy Clin. Immunol. 118(4), 809-816 (2006).
14. Buscher R, Eilmes KJ, Grasemann H et al. β adrenoceptor gene polymorphisms in cystic fibrosis lung disease. Pharmacogenetics 12(5), 347-353 (2002).
15. Celedon JC, Lange C, Raby B et al.: The transforming growth factor-β1 (TGFB1) gene is associated with chronic obstructive pulmonary disease (COPD). Hum. Mol. Genet. 13(15), 1649-1656 (2004).
16. Cho SH, Oh SY, Bahn JW et al.: Association between bronchodilating response to short-acting β-agonist and non-synonymous single-nucleotide polymorphisms of β-adrenoceptor gene. Clin. Exp. Allergy 35(9), 1162-1167 (2005).
17. Choudhry S, Ung N, Avila PC et al.: Pharmacogenetic differences in response to albuterol between Puerto Ricans and Mexicans with asthma. Am. J. Respir. Crit. Care Med. 171(6), 563-570 (2005).
18. Choudhry S, Avila PC, Nazario, S et al.: CD 14 tobacco gene-environment interaction modifies asthma severity and immunoglobulin E levels in Latinos with asthma. Am. J. Respir. Crit. Care Med. 172(2), 173-182 (2005).
19. DeMeo DL, Celedon JC, Lange C et al.: Genome-wide linkage of forced mid-expiratory flow in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care 170, 1294-1301 (2004).
20. DeMeo DL, Mariani TJ, Lange C et al.: The SERPINE2 gene is associated with chronic obstructive pulmonary disease. Am. J. Hum. Genet. 78, 253-264 (2006).
21. DeMeo, DL, Lange C, Silverman EK et al.: UnIvariate and multivariate family-based association analysis of the IL- 13 Arg 130Gln polymorphism in the Childhood Asthma Management Program. Genet. Epidemiol. 23(4), 335-348 (2002).
22. Drysdale CM, McGraw DW, Stack CB et al.: Complex promoter and coding region β2-adrenergic receptor haplotypes alter expression and predict in vivo responsiveness. Proc. Natl. Acad. Sci. USA 97(19), 10483-10488 (2000).
23. Eibahlawan L, Binaei S, Christensen ML, Zhang Q, Quasney MW, Dahmer MK: β2-adrenergic receptor polymorphisms in African American children with status asthmaticus. Pediatr. Crit. Care Med. 7 (1), 15-18 (2006).
24. Ferdinands JM, Mannino DM, Gwinn ML, Bray MS: ADRB2 Arg16Gly polymorphism, lung function, and mortality: results from the atherosclerosis risk in communities study. PLoS ONE. 14 (2), E289 (2007).
25. Hall IP, Blakey JD, Al Balushi KA et al.: β2-adrenoceptor polymorphisms and asthma from childhood to middle age in the British 1958 birth cohort: a genetic association study. Lancet 368 (9537), 771-779 (2006).
26. Hancox RJ, Sears MR, Taylor DR: Polymorphism of the β2-adrenoceptor and the response to long-term β2-agonist therapy in asthma. Eur. Respir. J. 11 (3). 589-593 (1998).
27. Hart MA, Konstan MW, Darrah RJ et al.: β2 adrenergic receptor polymorphisms in cystic fibrosis. Pediatr. Pulmunol. 39(6), 544-550 (2005).
28. Hawkins GA, Tantisira K, Meyers DA et al.: Sequence, haplotype and association analysis of ADRβ2 in a multiethnic asthma case - control study. Am. J. Respir. Crit. Care Med. 174(10), 1101-1109 (2006).
29. Hersh CP, DeMeo DL, Lange C et al.: Attempted replication of reported chronic obstructive pulmonary disease candidate gene associations. Am. J. Respir. Cell Mol. Biol. 33, 71-78 (2005).
30. Hersh CP, Soto-Quiros ME, Avila L et al.: Genome-wide linkage analysis of pulmonary function in families of children with asthma in Costa Rica. Thorax 62, 224-230 (2007).
31. Israel E, Chinchilli VM, Ford JG et al.: Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-contmUed cross-over trial. Lancet 364(9444), 1505-1512 (2004).
32. Israel E, Drazen JM, Liggett SB et al.: The effect of polymorphisms of the β(2)-adrenergic receptor on the response to regular use of albuterol in asthma. Am. J. Respir. Crit. Care Med. 162(1), 75-80 (2000).
33. Joos L, Weir TD, Connett JE et al.: Polymorphisms in the β2 adrenergic receptor and bronchodilator response, bronchial hyperresponsiveness and rate of decline in lung function in smokers. Thorax 58(8), 703-707 (2003).
34. Kaiayci O, Birben E, Sackesen C et al.: ALOX5 promoter genotype, asthma severity and LTC production by eosinophils. Allergy 61(1), 97-103 (2006).
35. Kotani Y, Nishimura Y, Maeda H, Yokoyama M et al.: β2-adrenergic receptor polymorphisms affect airway responsiveness to salbutamol in asthmatics. J. Asthma 36(7), 583-590 (1999).
36. 2-adrenergic receptor polymorphisms and response to salbutamol among Indian asthmatics. Pharmacogenomics 6 (4), 399-410 (2005).
37. Lee DK, Jackson CM, Bates CE, Lipworth BJ et al.: Cross tolerance to salbutamol occurs independently of β2 adrenoceptor genotype-16 in asthmatic patients receiving regular formoterol or salmeterol. Thorax 59, 662-667 (2004).
38. Lee DK, Currie GP, Hall IP Lima JJ, Lipworth BJ et al.: The arginine-16 β2-adrenoceptor polymorphism, predisposes to bronchoprotective subsensitivity in patients treated with formoterol and salmeterol. Br. J. Can. Pharmacol. 57 (1), 68-75 (2004).
39. Lima JJ, Thomason DB, Mohamed MH, Eberle LV, Self TH, Johnson JA: Impact of genetic polymorphisms of the β2-adrenergic receptor on albuterol bronchodilator pharmacodynamics. Clin. Pharmacol. Ther. 65(5), 519-525 (1999).
40. Lima JJ, Mohamed MH, Self TH, Eberle LV, Johnson JA.: Importance of β2 adrenergic receptor genotype, gender and race on albuterol-evoked bronchodilation in asthmatics. Pulm. Pharmacol. Ther. 13. 127-134 (2000).
41. Lind DL, Choudhry S, Ung N et al.: ADAM33 is not associated with asthma in Puerto Rican or Mexican populations. Am. J. Respir. Crit. Care Med. 168 (11), 1312-1316 (2003).
42. Lipworth BJ, Hall IP, Tan S, Aziz I, Coutle W: Effects of genetic polymorphism on ex vivo and in vivo function of β2-adrenoceptors in asthmatic-patients. Chest 115 (2), 324-328 (1999).
43. Lipworth BJ, Wilson AM: Dose-response evaluation of the therapeutic index for inhaled budesonide in patients with mild-to-moderate asthma. Am. J. Med. 108(4), 269-275 (2000).
44. Lyon H, Lange C, Lake S et al.: IL10 gene polymorphisms are. associated with asthma phenotypes in children. Genet. Epidemiol. 26(2), 155-165 (2004).
45. Martinez FD, Graves PE, Baidini M, Solomon S, Erickson R: Association between genetic polymorphisms of the β2-adrenoceptor and response to albuterol in children with and without a history of wheezing. J. Clin. Invest. 100(12), 3184-3188 (1997).
46. Ohe M, Munakata M, Hizawa N et al. β2 adrenergic receptor gene restriction fragment length polymorphis and bronchial asthma. Thorax 50(4), 353-359 (1995).
47. Palmer CN, Lipworth BJ, Lee S, Ismail T, Macgregor DF, Mukhopadhyay S: Arginine-16 β2 adrenoceptor genotype predisposes to exacerbations in young asthmatics taking regular salmeterol. Thorax 61, 940-944 (2006).
48. Postma DS, Meyers DA, Jongepter H, Howard TD, Koppelman GH, Bleecker ER: Genome wide screen for pulmonary function in 200 families ascertained for asthma. Am. J. Respir. Crit. Care 172, 446-452 (2005).
49. Raby BA, Klimecki WT, Laprise C et al.: Polymorphisms in Toll-like receptor 4 are not associated with asthma or atopy-related phenotypes. Am. J. Respir. Crit. Care 166, 1449-1456 (2002).
50. Raby BA, Silverman EK, Lazarus R et al.: Chromosome 12q harbors multiple genetic loci related to asthma and asthma-related phenotypes. Hum. Mol. Genet. 16, 1973-1979 (2003).
51. Raby BA, Lazarus R, Silverman EK et al.: Association of vitamin D receptor gene polymorphisms with childhood and adult asthma. Am. J. Respir. Crit. Care 170, 1057-1065 (2004).
52. Raby BA, Silverman EK, Kwiatkowski DJ, Lange C, Lazarus R, Weiss ST. ADAM33 polymorphisms and phenotype associations in childhood asthma. J. Allergy Clin. Immunol. 113, 1071-1078 (2004).
53. Raby BA, Van Steen K, Lazarus R, Celedon JC, Silverman EK, Weiss ST: Eotaxin polymorphisms and serum total IgE levels in children with asthma. J. Allergy Can. Immunol. 117, 298-305 (2006).
54. Raby BA, Hwang E, van Steen K, Tantisira K et al.: T-Bet polymorphisms are associated with asthma and airway hyperresponsiveness. Am. J. Respir. Crit. Care Med. 173, 64-70 (2006).
55. Randolph AG, Lange C, Silverman EK, Lazarus R, Weiss ST: Extended haplotype in the tumor necrosis factor gene cluster is associated with asthma and asthma-related phenotypes. Am. J Respir. Crit. Care Med. 172(6), 687-692 (2005).
56. Randolph AG, Lange C, Silverman EK et al.: The IL12B gene is associated with asthma. Am. J Hum. Genet. 75 (4), 709-715 (2004).
57. Silverman EK, Speizer FE, Weiss ST et al.: Familial aggregation of severe, early-onset COPD. Chest 117, 273-274 (2000).
58. Silverman EK, Kwiatkowski DJ, Sylvia JS et al.: Family-based association analysis of β2-adrenergic receptor polymorphisms in the Childhood Asthma Management Program. J. Allergy Clin. Immunol. 112 (5), 870-876 (2003).
59. Sims EJ, Lipworth BJ: Concomitant occasional use of salbutamol influences bronchoprotective responsiveness afforded by formoterol in patients with the glycine-16 genotype. Eur. J. Clin. Pharmacol. 59, 791-795 (2004).
60. Sims EJ, Jackson CM, Lipworth BJ: Add-on therapy with montelukast or formoterol in patients with the glycine- 16 β2-receptor genotype. Br. J. Clin. Pharmacol. 56(1), 104-111(2003).
61. Snyder EM, Beck KC, Dietz NM, Joyner MJ, Turner ST, Johnson BD: Influence of β2-adrenergic receptor genotype on airway function during exercise in healthy adults. Chest 129(3), 762-770 (2006).
62. Tan S, Hall IP, Dewar J, Dow E, Lipworth B: Association between β2-adrenoceptor polymorphism and susceptibility to bronchodilator desensitization in moderately severe stable asthmatics. Lancet 350(9083), 995-999 (1997).
63. Tanaka G, Sandford AJ, Burkett K et al.: Tumor necrosis factor and lymphotoxin A polymorphisms and lung function in smokers. Eur. Respir. J. 29(1), 34-41 (2007).
64. Tantisira KG, Small KM, Litonjua AA, Weiss ST, Liggett SB: Molecular properties and pharmacogenetics of a polymorphism of adenylyl cyclase type 9 in asthma: interaction between β-agonist and corticosteroid pathways. Hum. Mol. Genet. 14(12), 1671-1677 (2005).
65. Taylor DR, Drazen JM, Herbison GP, Yandava CN, Hancox RJ, Town GI: Asthma exacerbations during long term β agonist use: influence of β(2) adrenoceptor polymorphism. Thorax 55(9), 762-767 (2000).
66. Taylor DR, Epton MI. Kennedy MA et al.: Bronchodilator response in relation to β2-adrenoceptor haplotype in patients with asthma. Am. J. Respir. Crit. Care Med. 172(6), 700-703 (2005).
67. Taylor DR, Hancox RJ, McRae W et al.: The influence of polymorphism at position 16 of the β2-adrenoceptor on the development of tolerance to β-agonist. J. Asthma 37 (8), 691-700 (2000).
68. Telleria JJ, Blanco-Quiros A, Muntion S et al.: Tachyphylaxis to β2-agonists in Spanish asthmatic patients could be modulated by β2-adrenoceptor gene polymorphisms. Respir. Med. 100(6), 1072-1078 (2006).
69. Tsai HJ, Shaikh N, Kho JY et al.: Study of African Americans, Asthma, Genes Environments (SAGE). β2-adrenergic receptor polymorphisms: pharmacogenetic response to bronchodilator among African American asthmatics. Hum. Genet. 119(5), 547-557 (2006).
70. Tsai YJ, Choudhry S, Kho J et al.: The PTGDR gene is not associated with asthma in 3 ethnically diverse populations. J. Allergy. Clin. Immunol. 118, 1242-1248 (2006).
71. van Veen A, Weller FR, Wierenga EA, Jansen HM, Jonkers RE: The influence ot the AA 16 β(2)-adrenoceptor polymorphism on systemic and airway responses in asthma. Pulm. Pharmacol. Ther. (2006) (In Press).
72. van Veen A, Wierenga EA, Westland R et al.: Limited β2-adrenoceptor haplotypes display different agonist mediated airway responses in asthmatics. Respir. Res. 7, 19 (2006).
73. Wechsler ME, Lehman E, Lazarus SC et al.: β-Adrenergic receptor polymorphisms and response to salmeterol. Am. J. Respir. Crit. Care Med. 173(5), 519-526 (2006).
74. Woszczek G, Borowiec M, Ptasinska A, Kosinski S, Pawliczak R, Kowalski ML: β2-ADR haplotypes/polymorphisms associated with bronchodilator response and total IgE in grass allergy. Allergy 60(11), 1412-1417 (2005).
75. Liggett SB: Polymorphisms of the β2-adrenergic receptor and asthma. Am. J. Respir. Crit. Care Med. 156 (4 Pt 2), S156-S162 (1997).
76. Van Eerdewegh P, Little RD, Dupuis J et al.: Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature 418(6896), 426-340 (2002).
77. Kedda MA, Duffy DL, Bradley B, O'Hehir RE, Thompson PJ: ADAM33 haplotypes are associated with asthma in a large Australian population. Eur. J. Hum. Genet. 14(9), 1027-1036 (2006).
78. Blakey J, Halapi E, Bjornsdottir US et al.: Contribution of ADAM33 polymorphisms to the population risk of asthma. Thorax. 60(4), 274-276 (2005).
79. Khoury MJ, Little J, Gwinn M, Ioannidis JP: On the synthesis and interpretation of consistent but weak gene-disease associations in the era of genome-wide association studies. Int. J. Epidemiol. 36(2), 439-445 (2007).
80. Ioannidis JP, Trikalinos TA, Khoury MJ: Implications of small effect sizes of individual genetic variants on the design and interpretation of genetic association studies of complex diseases. Am. J. Epidemiol. 164, 609-614.(2006).
81. Wacholder S, Chanock S, Garcia-Closas M, El Ghormli L, Rothman N: Assessing the probability that a positive report is false: an approach for molecular epidemiology studies. J. Natl. Cancer Inst. 96, 434-442 (2004).
82. Kyas PA, Loizou KT, Ioannidis JP: Selective reporting biases in cancer prognostic factor studies. J. Natl. Cancer Inst. 97 (14), 1043-1055 (2005).
83. Pan Z, Trikalinos TA, Kavvoura FK, Lau J, Ioannidis JP: Local literature bias in genetic epidemiology: an empirical evaluation of the Chinese literature. PLoS Med. 2, E334 (2005).
84. Cainan M, Smith GD, Sterne JA: The publication process itself was the major cause of publication bias in genetic epidemiology. J. Clin. Epidemiol. 59, 1312-1318 (2006).
85. Ioannidis JP: Journals should publish all "null" results and should sparingly publish "positive" results. Cancer Epidemiol. Biomarkers Prev. 15, 186 (2006).
86. Thakkinstian A, McEvoy M, Minelli C et al.: Systematic review and meta-analysis of the association between β2-adrenoceptor polymorphisms and asthma: a HuGE review. Am. J. Epidemiol. 162(3), 201-211 (2005).
87. Ioannidis JP: Why most published research findings are false. PLoS Med 2, E124 (2005).
88. Ioannidis JP: Genetic associations: false or true? Trends Mol. Med. 9, 135-138 (2003).
89. Breast Cancer Association Consortium: Commonly studied single-nucleotide polymorphisms and breast cancer: results from the Breast Cancer Association Consortium. J. Natl. Cancer Inst. 98, 1382-1396 (2006).
90. Ioannidis JP: Common genetic variants for breast cancer: 32 largely refuted candidates and larger prospects. J Natl. Cancer Inst. 98, 1350-1353 (2006).
91. Cox A, Dunning AM, Garcia-Closas M et al.; Breast Cancer Association Consortium: A common coding variant in CASP8 is associated with breast cancer risk. Nat. Genet. 39(3), 352-358 (2007).
92. Cardon LR, Idury RM, Harris TJ, Witte JS, Elston RC: Testing drug response in, the presence of genetic information: sampling issues for clinical trials. Pharmacogenetics 10(6), 503-510 (2000).
93. Carlson CS, Eberle MA, Kruglyak L, Nickerson DA: Mapping complex disease loci in whole-genome association studies. Nature 429, 446-452 (2004).
94. Thomas DC, Haile RW, Duggan D: Recent developments in genome wide association scans: a workshop summary and review. Am. J. Hum. Genet. 77, 337-345 (2005).
95. Wang WY, Barratt BJ, Clayton DG, Todd JA: Genome-wide association studies: theoretical and practical concerns. Nat. Rev. Genet. 6, 109-118 (2005).
96. Hirschhorn JN, Daly MJ: Genome-wide association studies for common diseases and complex traits. Nat. Rev. Genet. 6, 95-108 (2005).
97. Thomas DC: Are we ready for genome-wide association studies? Cancer Epidemiol. Biomarkers Prev. 15, 595-598 (2006).
98. Herbert A, Gerry NP, McQueen MB et al.:, A common genetic variant is associated with adult and childhood obesity. Science 312, 279-283 (2006).
99. Rosskopf D, Bornhorst A, Rimmbach C et al.: Comment on "A common genetic variant is associated with adult and childhood obesity". Science 315, 187 (2007).
100. Loos RJ, Barnhost I, O'rahilly S, Wareham NJ: Comment on "A common genetic variant is associated with adult and childhood obesity". Science 315, 187 (2007).
101. Dina C, Meyre D, Samson C et al.: Comment on "A common genetic variant is associated with adult and childhood obesity. Science 315, 187 (2007).
102. Ioannidis JPA: Non-replication and inconsistency in the genome-wide association era. Hum. Hered. 64(4), 203-213 (2007).
103. Ionnidis JP, Kavvoura FK: Concordance of functional in vitro data and epidemiological associations in complex disease genetics. Genet. Med. 8(9), 583-593 (2006).
104. Cardon LR: Genetics. Delivering new disease genes. Sience 314(5804), 1403-1405 (2006).
105. Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG: Replicationvalidity of genetic association studies. Nat. Genet. 29, 306-309 (2001).
106. Ioannidis JP, Trikalinos TA, Ntzant EE, Contopoulos-loannidis DG: Genetic associations in large versus small studies: an empirical assessment. Lancet 361, 567-571 (2003).
107. Seminara D, Khoury MJ, O'Brien TR et al.: Human Genome Epidemiology Network; the Network of Investigator Networks. The emergence of networks in human genome epidemiology: challenges and opportunities, Epidemiology 18(1), 1-8 (2007).
108. Ioannidis JP, Gwinn M, Little J et al.: Human Genome Epidemiology Networks and the Network of Investigator Networks. A road map for efficient and reliable human genome epidemiology. Nat Genet. 38(1), 3-5 (2006).
109. Giacomini KM, Brett CM, Altman RB et al.: The pharmacogenetics research network: from SNP discovery tp clinical drug response. Clin Pharmacol Ther. 81 (3), 328-345 (2007).
110. Collins FS, Manotio TA: Merging and emerging cohorts: necessary but not sufficient. Nature 445(7125), 259(2007).
111. Frayling TM, Timpson NJ, Weedon MN et al.: A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316(5826), 889-894 (2007).
112. Uitterlinden AG, Ralston SH, Brandt ML et al.: GENOMOS Study. The association between common vitamin D receptor gene variations and osteoporosis: a participant-level meta-analysis. Ann. Intern. Med. 145(4), 255-264 (2006).
113. Lee JS, Tucker MA: Making sense of puzzling genetic association studies: a team approach. Ann. Intern. Med. 145(4), 302-304 (2006).
114. Ioannidis JPA: Molecular evidence-based medicine: evolution and integration of information in the genomic era. Eur. J. Clin. Invest. 37, 340-347 (2007).
115. Greenland S: Tests for interaction in epidemiologic studies: a review and a study of power. Stat. Med. 2, 243-251 (1983).
116. Hunter DJ: Gene-environment interactions in human diseases. Nat. Rev. Genet. 6, 287-298 (2005).