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Mapping genes that predict treatment outcome in admixed populations

Abstract

There is great interest in characterizing the genetic architecture underlying drug response. For many drugs, gene-based dosing models explain a considerable amount of the overall variation in treatment outcome. As such, prescription drug labels are increasingly being modified to contain pharmacogenetic information. Genetic data must, however, be interpreted within the context of relevant clinical covariates. Even the most predictive models improve with the addition of data related to biogeographical ancestry. The current review explores analytical strategies that leverage population structure to more fully characterize genetic determinants of outcome in large clinical practice-based cohorts. The success of this approach will depend upon several key factors: (1) the availability of outcome data from groups of admixed individuals (that is, populations recombined over multiple generations), (2) a measurable difference in treatment outcome (that is, efficacy and toxicity end points), and (3) a measurable difference in allele frequency between the ancestral populations.

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References

  1. Hinds DA, Stuve LL, Nilsen GB, Halperin E, Eskin E, Ballinger DG et al. Whole-genome patterns of common DNA variation in three human populations. Science 2005; 307: 1072–1079.

    Article  CAS  PubMed  Google Scholar 

  2. Kwok PY, Carlson C, Yager TD, Ankener W, Nickerson DA . Comparative analysis of human DNA variations by fluorescence-based sequencing of PCR products. Genomics 1994; 23: 138–144.

    Article  CAS  PubMed  Google Scholar 

  3. Brookes AJ . The essence of SNPs. Gene 1999; 234: 177–186.

    Article  CAS  PubMed  Google Scholar 

  4. Stranger BE, Forrest MS, Dunning M, Ingle CE, Beazley C, Thorne N et al. Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 2007; 315: 848–853.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Risch N, Merikangas K . The future of genetic studies of complex human diseases. Science 1996; 273: 1516–1517.

    Article  CAS  PubMed  Google Scholar 

  6. Prentice RL, Qi L . Aspects of the design and analysis of high-dimensional SNP studies for disease risk estimation. Biostatistics 2006; 7: 339–354.

    Article  PubMed  Google Scholar 

  7. Collins FS, Green ED, Guttmacher AE, Guyer MS . A vision for the future of genomics research. Nature 2003; 422: 835–847.

    Article  CAS  PubMed  Google Scholar 

  8. International HapMap Consortium. A haplotype map of the human genome. Nature 2005; 437: 1299–1320.

    Article  CAS  Google Scholar 

  9. McKeigue PM, Carpenter JR, Parra EJ, Shriver MD . Estimation of admixture and detection of linkage in admixed populations by a Bayesian approach: application to African-American populations. Ann Hum Genet 2000; 64 (Pt 2): 171–186.

    Article  CAS  PubMed  Google Scholar 

  10. Miller RD, Phillips MS, Jo I, Donaldson MA, Studebaker JF, Addleman N et al. High-density single-nucleotide polymorphism maps of the human genome. Genomics 2005; 86: 117–126.

    Article  CAS  PubMed  Google Scholar 

  11. Dickson SP, Wang K, Krantz I, Hakonarson H, Goldstein DB . Rare variants create synthetic genome-wide associations. PLoS Biol 2010; 8: e1000294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Baye TM, Wilke RA, Olivier M . Genomic and geographic distribution of private SNPs and pathways in human populations. Per Med 2009; 6: 623–641.

    Article  CAS  PubMed  Google Scholar 

  13. Reed TE . Caucasian genes in American Negroes. Science 1969; 165: 762–768.

    Article  CAS  PubMed  Google Scholar 

  14. Chakraborty R . Gene admixture in human populations: models and predictions. Am J Phys Anthropol 1986; 29: 1–43.

    Article  Google Scholar 

  15. Rife D . Populations of hybrid origin as source material for the detection of linkage. Am J Hum Genet 1954; 6: 26–33.

    CAS  PubMed  Google Scholar 

  16. Altshuler D, Brookes LD, Chakravarti A, Collins FS, Daly MJ, Donnelly P et al. A haplotype map of the human genome. Nature 2005; 437: 1299–1320.

    Article  CAS  Google Scholar 

  17. Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J et al. Initial sequencing and analysis of the human genome. Nature 2001; 409: 860–921.

    Article  CAS  PubMed  Google Scholar 

  18. McKeigue PM . Prospects for admixture mapping of complex traits. Am J Hum Genet 2005; 76: 1–7.

    Article  CAS  PubMed  Google Scholar 

  19. Smith MW, O'Brien SJ . Mapping by admixture linkage disequilibrium: advances, limitations and guidelines. Nat Rev Genet 2005; 6: 623–632.

    Article  CAS  PubMed  Google Scholar 

  20. Darvasi A, Shifman S . The beauty of admixture. Nat Genet 2005; 37: 118–119.

    Article  CAS  PubMed  Google Scholar 

  21. Smith MW, Patterson N, Lautenberger JA, Truelove AL, McDonald GJ, Waliszewska A et al. A high-density admixture map for disease gene discovery in African Americans. Am J Hum Genet 2004; 74: 1001–1013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Stephens JC, Briscoe D, O'Brien SJ . Mapping by admixture linkage disequilibrium in human populations: limits and guidelines. Am J Hum Genet 1994; 55: 809–824.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. McKeigue PM . Mapping genes underlying ethnic differences in disease risk by linkage disequilibrium in recently admixed populations. Am J Hum Genet 1997; 60: 188–196.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Hirschhorn JN, Daly MJ . Genome-wide association studies for common diseases and complex traits. Nat Rev Genet 2005; 6: 95–108.

    Article  CAS  PubMed  Google Scholar 

  25. Wang WY, Barratt BJ, Clayton DG, Todd JA . Genome-wide association studies: theoretical and practical concerns. Nat Rev Genet 2005; 6: 109–118.

    Article  CAS  PubMed  Google Scholar 

  26. Reich D, Patterson N, De Jager PL, McDonald GJ, Waliszewska A, Tandon A et al. A whole-genome admixture scan finds a candidate locus for multiple sclerosis susceptibility. Nat Genet 2005; 37: 1113–1118.

    Article  CAS  PubMed  Google Scholar 

  27. Craig DW, Stephan DA . Applications of whole-genome high-density SNP genotyping. Expert Rev Mol Diagn 2005; 5: 159–170.

    Article  CAS  PubMed  Google Scholar 

  28. Baye TM, Tiwari HK, Allison DB, Go RC . Database mining for selection of SNP markers useful in admixture mapping. BioData Min 2009; 2: 1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chakraborty R, Weiss KM . Admixture as a tool for finding linked genes and detecting that difference from allelic association between loci. Proc Natl Acad Sci USA 1988; 85: 9119–9123.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Shriver MD, Parra EJ, Dios S, Bonilla C, Norton H, Jovel C et al. Skin pigmentation, biogeographical ancestry and admixture mapping. Hum Genet 2003; 112: 387–399.

    PubMed  Google Scholar 

  31. Reich D, Patterson N . Will admixture mapping work to find disease genes? Philos Trans R Soc Lond B Biol Sci 2005; 360: 1605–1607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. McCarty CA, Peissig P, Caldwell MD, Wilke RA . The Marshfield clinic personalized medicine research project: 2008 scientific update and lessons learned in the first 6 years. Person Med 2008; 5: 529–542.

    Article  Google Scholar 

  33. McCarty CA, Wilke RA . Biobanks and pharmacogenomics. Pharmacogenomics 2010; 11: 637–641.

    Article  CAS  PubMed  Google Scholar 

  34. Kaiser J . Biobanks. Private biobanks spark ethical concerns. Science 2002; 298: 1160.

    Article  PubMed  Google Scholar 

  35. Kaiser J . Genomic medicine. African-American population biobank proposed. Science 2003; 300: 1485.

    Article  CAS  PubMed  Google Scholar 

  36. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D . Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 2006; 38: 904–909.

    Article  CAS  PubMed  Google Scholar 

  37. Seldin MF, Shigeta R, Villoslada P, Selmi C, Tuomilehto J, Silva G et al. European population substructure: clustering of northern and southern populations. PLoS Genet 2006; 2: e143.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Pritchard JK, Stephens M, Rosenberg NA, Donnelly P . Association mapping in structured populations. Am J Hum Genet 2000; 67: 170–181.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kolbe JJ, Larson A, Losos JB, de Queiroz K . Admixture determines genetic diversity and population differentiation in the biological invasion of a lizard species. Biol Lett 2008; 4: 434–437.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Cheng A, Diller DJ, Dixon SL, Egan WJ, Lauri G, Merz Jr KM . Computation of the physio-chemical properties and data mining of large molecular collections. J Comput Chem 2002; 23: 172–183.

    Article  CAS  PubMed  Google Scholar 

  41. Jiang R, Duan J, Windemuth A, Stephens JC, Judson R, Xu C . Genome-wide evaluation of the public SNP databases. Pharmacogenomics 2003; 4: 779–789.

    Article  CAS  PubMed  Google Scholar 

  42. Shriver MD, Kittles RA . Genetic ancestry and the search for personalized genetic histories. Nat Rev Genet 2004; 5: 611–618.

    Article  CAS  PubMed  Google Scholar 

  43. Shriver MD, Smith MW, Jin L, Marcini A, Akey JM, Deka R et al. Ethnic-affiliation estimation by use of population-specific DNA markers. Am J Hum Genet 1997; 60: 957–964.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Parra EJ, Marcini A, Akey J, Martinson J, Batzer MA, Cooper R et al. Estimating African American admixture proportions by use of population-specific alleles. Am J Hum Genet 1998; 63: 1839–1851.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Sherry ST, Ward M, Sirotkin K . dbSNP-database for single nucleotide polymorphisms and other classes of minor genetic variation. Genome Res 1999; 9: 677–679.

    CAS  PubMed  Google Scholar 

  46. Smith MW, Lautenberger JA, Shin HD, Chretien JP, Shrestha S, Gilbert DA et al. Markers for mapping by admixture linkage disequilibrium in African American and Hispanic populations. Am J Hum Genet 2001; 69: 1080–1094.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Collins-Schramm HE, Phillips CM, Operario DJ, Lee JS, Weber JL, Hanson RL et al. Ethnic-difference markers for use in mapping by admixture linkage disequilibrium. Am J Hum Genet 2002; 70: 737–750.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Rosenberg NA, Li LM, Ward R, Pritchard JK . Informativeness of genetic markers for inference of ancestry. Am J Hum Genet 2003; 73: 1402–1422.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Houle JL, Cadigan W, Henry S, Pinnamaneni A, Lundahl S . Database Mining in the Human Genome Initiative. Whitepaper, Biodatabases. com, Amita Corporation, Available: http://www.biodatabases.com/whitepaper.html, 2004.

    Google Scholar 

  50. Glasgow J, Jurisica II, Ng R . Data mining and knowledge discovery in molecular databases. Pac Symp Biocomput 2000; 12): 365–366.

    Google Scholar 

  51. Mackinnon MJ, Glick N . Data mining and knowledge discovery in databases: an overview. Aust NZ J Stat 1999; 41: 255–275.

    Article  Google Scholar 

  52. Shah SC, Kusiak A . Data mining and genetic algorithm based gene/SNP selection. Artif Intell Med 2004; 31: 183–196.

    Article  PubMed  Google Scholar 

  53. Akey JM, Zhang G, Zhang K, Jin L, Shriver MD . Interrogating a high-density SNP map for signatures of natural selection. Genome Res 2002; 12: 1805–1814.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Bonilla C, Parra EJ, Pfaff CL, Dios S, Marshall JA, Hamman RF et al. Admixture in the Hispanics of the San Luis Valley, Colorado, and its implications for complex trait gene mapping. Ann Hum Genet 2004; 68 (Pt 2): 139–153.

    Article  CAS  PubMed  Google Scholar 

  55. Tian C, Hinds DA, Shigeta R, Kittles R, Ballinger DG, Seldin MF . A genomewide single-nucleotide-polymorphism panel with high ancestry information for African American admixture mapping. Am J Hum Genet 2006; 79: 640–649.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Redden DT, Divers J, Vaughan LK, Tiwari HK, Beasley TM, Fernandez JR et al. Regional admixture mapping and structured association testing: conceptual unification and an extensible general linear model. PLoS Genet 2006; 2: e137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Cardon LR, Palmer LJ . Population stratification and spurious allelic association. Lancet 2003; 361: 598–604.

    Article  PubMed  Google Scholar 

  58. Reich DE, Goldstein DB . Detecting association in a case-control study while correcting for population stratification. Genet Epidemiol 2001; 20: 4–16.

    Article  CAS  PubMed  Google Scholar 

  59. Wacholder S, Rothman N, Caporaso N . Population stratification in epidemiologic studies of common genetic variants and cancer: quantification of bias. J Natl Cancer Inst 2000; 92: 1151–1158.

    Article  CAS  PubMed  Google Scholar 

  60. Devlin B, Roeder K . Genomic control for association studies. Biometrics 1999; 55: 997–1004.

    Article  CAS  PubMed  Google Scholar 

  61. Kittles RA, Baffoe-Bonnie AB, Moses TY, Robbins CM, Ahaghotu C, Huusko P et al. A common nonsense mutation in EphB2 is associated with prostate cancer risk in African American men with a positive family history. J Med Genet 2006; 43: 507–511.

    Article  CAS  PubMed  Google Scholar 

  62. Hanis CL, Chakraborty R, Ferrell RE, Schull WJ . Individual admixture estimates: disease associations and individual risk of diabetes and gallbladder disease among Mexican-Americans in Starr County, Texas. Am J Phys Anthropol 1986; 70: 433–441.

    Article  CAS  PubMed  Google Scholar 

  63. McLean CJ, Workman PL . Genetic studies on hybrid populations. II. Estimation of distribution of ancestry. Ann Hum Genet 1973; 36: 459–465.

    Article  Google Scholar 

  64. Falush D, Stephens M, Pritchard JK . Inference of population structure using multilocus genotype data: dominant markers and null alleles. Mol Ecol Notes 2007; 7: 574–578.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Montana G, Hoggart C . Statistical software for gene mapping by admixture linkage disequilibrium. Brief Bioinform 2007; 8: 393–395.

    Article  PubMed  Google Scholar 

  66. Freedman ML, Haiman CA, Patterson N, McDonald GJ, Tandon A, Waliszewska A et al. Admixture mapping identifies 8q24 as a prostate cancer risk locus in African-American men. Proc Natl Acad Sci USA 2006; 103: 14068–14073.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Hoggart CJ, Shriver MD, Kittles RA, Clayton DG, McKeigue PM . Design and analysis of admixture mapping studies. Am J Hum Genet 2004; 74: 965–978.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Falush D, Stephens M, Pritchard JK . Inference of population structure using multilocus genotype data: linked loci and correlated allele frequencies. Genetics 2003; 164: 1567–1587.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Patterson N, Hattangadi N, Lane B, Lohmueller KE, Hafler DA, Oksenberg JR et al. Methods for high-density admixture mapping of disease genes. Am J Hum Genet 2004; 74: 979–1000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Hoggart CJ, Parra EJ, Shriver MD, Bonilla C, Kittles RA, Clayton DG et al. Control of confounding of genetic associations in stratified populations. Am J Hum Genet 2003; 72: 1492–1504.

    Article  CAS  PubMed  Google Scholar 

  71. Tang H, Peng J, Wang P, Risch NJ . Estimation of individual admixture: analytical and study design considerations. Genet Epidemiol 2005; 28: 289–301.

    Article  PubMed  Google Scholar 

  72. Wu B, Liu N, Zhao H . PSMIX: an R package for population structure inference via maximum likelihood method. BMC Bioinformatics 2006; 7: 317.

    Article  CAS  PubMed  Google Scholar 

  73. Wilke RA, Berg RL, Linneman JG, Zhao C, McCarty CA, Krauss RM . Characterization of low-density lipoprotein cholesterol-lowering efficacy for atorvastatin in a population-based DNA biorepository. Basic Clin Pharmacol Toxicol 2008; 103: 354–359.

    Article  CAS  PubMed  Google Scholar 

  74. Link E, Parish S, Armitage J, Bowman L, Heath S, Matsuda F et al. SLCO1B1 variants and statin-induced myopathy—a genomewide study. N Engl J Med 2008; 359: 789–799.

    Article  CAS  PubMed  Google Scholar 

  75. Thompson JF, Hyde CL, Wood LS, Paciga SA, Hinds DA, Cox DR et al. Comprehensive whole-genome and candidate gene analysis for response to statin therapy in the Treating to New Targets (TNT) cohort. Circ Cardiovasc Genet 2009; 2: 173–181.

    Article  CAS  PubMed  Google Scholar 

  76. Barber MJ, Mangravite LM, Hyde CL, Chasman D, Smith J, McCarty CA et al. Genome-wide association of lipid-lowering response to statins in combined study populations. PLoS One 2010; 5: e9763.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. CDC. US death rates due to myocardial infarction. (2000–2006). http://www.cdc.gov/dhdsp/library/pdfs/fsheartdisease.pdf.

  78. Tobert JA . Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors. Nat Rev Drug Discov 2003; 2: 517–526.

    Article  CAS  PubMed  Google Scholar 

  79. Delahoy PJ, Magliano DJ, Webb K, Grobler M, Liew D . The relationship between reduction in low-density lipoprotein cholesterol by statins and reduction in risk of cardiovascular outcomes: an updated meta-analysis. Clin Ther 2009; 31: 236–244.

    Article  CAS  PubMed  Google Scholar 

  80. Nissen SE, Nicholls SJ, Sipahi I, Libby P, Raichlen JS, Ballantyne CM et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006; 295: 1556–1565.

    Article  CAS  PubMed  Google Scholar 

  81. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005; 352: 1425–1435.

    Article  CAS  PubMed  Google Scholar 

  82. Barber MJ, Mangravite LM, Hyde CL, Chasman DI, Smith JD, McCarty CA et al. Genome-wide association of lipid-lowering response to statins in combined study populations. PLoS One 2010; 5: e9763.

    Article  CAS  PubMed  Google Scholar 

  83. Goodman T, Ferro A, Sharma P . Pharmacogenetics of aspirin resistance: a comprehensive systematic review. Br J Clin Pharmacol 2008; 66: 222–232.

    Article  PubMed  Google Scholar 

  84. Mitchell BD, McArdle PF, Shen H, Rampersaud E, Pollin TI, Bielak LF et al. The genetic response to short-term interventions affecting cardiovascular function: rationale and design of the Heredity and Phenotype Intervention (HAPI) Heart Study. Am Heart J 2008; 155: 823–828.

    Article  PubMed  Google Scholar 

  85. Shen H, Herzog W, Drolet M, Pakyz R, Newcomer S, Sack P et al. Aspirin resistance in healthy drug-naive men versus women (from the Heredity and Phenotype Intervention Heart Study). Am J Cardiol 2009; 104: 606–612.

    Article  CAS  PubMed  Google Scholar 

  86. Faraday N, Becker DM, Becker LC . Pharmacogenomics of platelet responsiveness to aspirin. Pharmacogenomics 2007; 8: 1413–1425.

    Article  CAS  PubMed  Google Scholar 

  87. Rumilla K, Chen D, Baudhuin LM . Pharmacogenetics in hemostasis: friend or foe? Semin Thromb Hemost 2009; 35: 42–49.

    Article  PubMed  Google Scholar 

  88. Trenk D, Hochholzer W, Fromm MF, Chialda LE, Pahl A, Valina CM et al. Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol 2008; 51: 1925–1934.

    Article  CAS  PubMed  Google Scholar 

  89. Gurbel PA, Antonino MJ, Tantry US . Recent developments in clopidogrel pharmacology and their relation to clinical outcomes. Expert Opin Drug Metab Toxicol 2009; 5: 989–1004.

    Article  CAS  PubMed  Google Scholar 

  90. Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Meneveau N et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; 360: 363–375.

    Article  CAS  PubMed  Google Scholar 

  91. Cavallari LH, Langaee TY, Momary KM, Shapiro NL, Nutescu EA, Coty WA et al. Genetic and clinical predictors of warfarin dose requirements in African Americans. Clin Pharmacol Ther 2010; 87: 459–464.

    Article  CAS  PubMed  Google Scholar 

  92. Suarez-Kurtz G, Vianna-Jorge R, Perini JA, Pena SD . Detection of CYP2C9*5 in a white Brazilian subject. Clin Pharmacol Ther 2005; 77: 587–588.

    Article  CAS  PubMed  Google Scholar 

  93. Suarez-Kurtz G . Pharmacogenomics in admixed populations. Trends Pharmacol Sci 2005; 26: 196–201.

    Article  CAS  PubMed  Google Scholar 

  94. Pacanowski MA, Gong Y, Cooper-Dehoff RM, Schork NJ, Shriver MD, Langaee TY et al. Beta-adrenergic receptor gene polymorphisms and beta-blocker treatment outcomes in hypertension. Clin Pharmacol Ther 2008; 84: 715–721.

    Article  CAS  PubMed  Google Scholar 

  95. Bijl MJ, Visser LE, van Schaik RH, Kors JA, Witteman JC, Hofman A et al. Genetic variation in the CYP2D6 gene is associated with a lower heart rate and blood pressure in beta-blocker users. Clin Pharmacol Ther 2009; 85: 45–50.

    Article  CAS  PubMed  Google Scholar 

  96. Zineh I, Beitelshees AL, Gaedigk A, Walker JR, Pauly DF, Eberst K et al. Pharmacokinetics and CYP2D6 genotypes do not predict metoprolol adverse events or efficacy in hypertension. Clin Pharmacol Ther 2004; 76: 536–544.

    Article  CAS  PubMed  Google Scholar 

  97. Johnson JA, Burlew BS . Metoprolol metabolism via cytochrome P4502D6 in ethnic populations. Drug Metab Dispos 1996; 24: 350–355.

    CAS  PubMed  Google Scholar 

  98. Turner ST, Schwartz GL, Chapman AB, Boerwinkle E . C825 T polymorphism of the G protein beta(3)-subunit and antihypertensive response to a thiazide diuretic. Hypertension 2001; 37 (2 Part 2): 739–743.

    Article  CAS  PubMed  Google Scholar 

  99. Roden DM, Wilke RA, Kroemer HK, Stein CM . Pharmacogenomics—the genetics of variable drug responses. Circulation 2010; In: press.

    Google Scholar 

  100. Chasman DI, Posada D, Subrahmanyan L, Cook NR, Stanton Jr VP, Ridker PM . Pharmacogenetic study of statin therapy and cholesterol reduction. JAMA 2004; 291: 2821–2827.

    Article  CAS  PubMed  Google Scholar 

  101. Kajinami K, Brousseau ME, Ordovas JM, Schaefer EJ . CYP3A4 genotypes and plasma lipoprotein levels before and after treatment with atorvastatin in primary hypercholesterolemia. Am J Cardiol 2004; 93: 104–107.

    Article  CAS  PubMed  Google Scholar 

  102. Kivisto KT, Niemi M, Schaeffeler E, Pitkala K, Tilvis R, Fromm MF et al. Lipid-lowering response to statins is affected by CYP3A5 polymorphism. Pharmacogenetics 2004; 14: 523–525.

    Article  PubMed  Google Scholar 

  103. Wilke RA, Reif DM, Moore JH . Combinatorial pharmacogenetics. Nat Rev Drug Discov 2005; 4: 911–918.

    Article  CAS  PubMed  Google Scholar 

  104. Schuetz EG, Relling MV, Kishi S, Yang W, Das S, Chen P et al. PharmGKB update: II. CYP3A5, cytochrome P450, family 3, subfamily A, polypeptide 5. Pharmacol Rev 2004; 56: 159.

    Article  CAS  PubMed  Google Scholar 

  105. Ozdemir V, Kalow W, Tang BK, Paterson AD, Walker SE, Endrenyi L et al. Evaluation of the genetic component of variability in CYP3A4 activity: a repeated drug administration method. Pharmacogenetics 2000; 10: 373–388.

    Article  CAS  PubMed  Google Scholar 

  106. Balram C, Zhou Q, Cheung YB, Lee EJ . CYP3A5*3 and *6 single nucleotide polymorphisms in three distinct Asian populations. Eur J Clin Pharmacol 2003; 59: 123–126.

    Article  CAS  PubMed  Google Scholar 

  107. Riedmaier S, Klein K, Hofmann U, Keskitalo JE, Neuvonen PJ, Schwab M et al. UDP-glucuronosyltransferase (UGT) polymorphisms affect atorvastatin lactonization in vitro and in vivo. Clin Pharmacol Ther 2010; 87: 65–73.

    Article  CAS  PubMed  Google Scholar 

  108. Long JC . The genetic structure of admixed populations. Genetics 1991; 127: 417–428.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Waples RS, Gaggiotti O . What is a population? An empirical evaluation of some genetic methods for identifying the number of gene pools and their degree of connectivity. Mol Ecol 2006; 15: 1419–1439.

    Article  CAS  PubMed  Google Scholar 

  110. Jobling M, Hurles M, Tyler-Smith C . Human evolutionary genetics: Origins, Peoples & Disease. Garland, New York, 2004.

    Google Scholar 

  111. Labuda D, Lefebvre JF, Nadeau P, Roy-Gagnon MH . Female-to-male breeding ratio in modern humans-an analysis based on historical recombinations. Am J Hum Genet 2010; 86: 353–363.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Schumacher A, Petronis A . Epigenetics of complex diseases: from general theory to laboratory experiments. Curr Top Microbiol Immunol 2006; 310: 81–115.

    CAS  PubMed  Google Scholar 

  113. Cairney J, Wade TJ . Single parent mothers and mental health care service use. Soc Psychiatry Psychiatr Epidemiol 2002; 37: 236–242.

    Article  PubMed  Google Scholar 

  114. Parra EJ, Kittles RA, Argyropoulos G, Pfaff CL, Hiester K, Bonilla C et al. Ancestral proportions and admixture dynamics in geographically defined African Americans living in South Carolina. Am J Phys Anthropol 2001; 114: 18–29.

    Article  CAS  PubMed  Google Scholar 

  115. Kayser M, Brauer S, Schadlich H, Prinz M, Batzer MA, Zimmerman PA et al. Y chromosome STR haplotypes and the genetic structure of US populations of African, European, and Hispanic ancestry. Genome Res 2003; 13: 624–634.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. McLean Jr DC, Spruill I, Gevao S, Morrison EY, Bernard OS, Argyropoulos G et al. Three novel mtDNA restriction site polymorphisms allow exploration of population affinities of African Americans. Hum Biol 2003; 75: 147–161.

    Article  PubMed  Google Scholar 

  117. Bryc K, Auton A, Nelson MR, Oksenberg JR, Hauser SL, Williams S et al. Genome-wide patterns of population structure and admixture in West Africans and African Americans. Proc Natl Acad Sci USA 2010; 107: 786–791.

    Article  CAS  PubMed  Google Scholar 

  118. Lind JM, Hutcheson-Dilks HB, Williams SM, Moore JH, Essex M, Ruiz-Pesini E et al. Elevated male European and female African contributions to the genomes of African American individuals. Hum Genet 2007; 120: 713–722.

    Article  PubMed  Google Scholar 

  119. Paskind HA . Some differences in response to atropine in white and coloured races. J Am Med Assoc 1921; 76: 104–108.

    Google Scholar 

  120. Temple R, Stockbridge NL . BiDil for heart failure in black patients: the US Food and Drug Administration perspective. Ann Intern Med 2007; 146: 57–62.

    Article  PubMed  Google Scholar 

  121. Hammermeister KE, Fairclough D, Emsermann CB, Hamman R, Ho M, Phibbs S et al. Effectiveness of hydralazine/isosorbide dinitrate in racial/ethnic subgroups with heart failure. Clin Ther 2009; 31: 632–643.

    Article  CAS  PubMed  Google Scholar 

  122. Zhu X, Luke A, Cooper RS, Quertermous T, Hanis C, Mosley T et al. Admixture mapping for hypertension loci with genome-scan markers. Nat Genet 2005; 37: 177–181.

    Article  CAS  PubMed  Google Scholar 

  123. Zhang Q, Lewis CE, Wagenknecht LE, Myers RH, Pankow JS, Hunt SC et al. Genome-wide admixture mapping for coronary artery calcification in African Americans: the NHLBI Family Heart Study. Genet Epidemiol 2008; 32: 264–272.

    Article  PubMed  Google Scholar 

  124. Cheng CY, Kao WH, Patterson N, Tandon A, Haiman CA, Harris TB et al. Admixture mapping of 15 280 African Americans identifies obesity susceptibility loci on chromosomes 5 and X. PLoS Genet 2009; 5: e1000490.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Basu A, Tang H, Arnett D, Gu CC, Mosley T, Kardia S et al. Admixture mapping of quantitative trait loci for BMI in African Americans: evidence for loci on chromosomes 3q, 5q, and 15q. Obesity (Silver Spring) 2009; 17: 1226–1231.

    CAS  Google Scholar 

  126. Reich D, Patterson N, Ramesh V, De Jager PL, McDonald GJ, Tandon A et al. Admixture mapping of an allele affecting interleukin 6 soluble receptor and interleukin 6 levels. Am J Hum Genet 2007; 80: 716–726.

    Article  CAS  PubMed  Google Scholar 

  127. Cornell S, Hartmann D . Ethnicity and Race: Making Identities in a Changing World. Pine Forge Press: Thousand Oaks, CA, 1998.

    Google Scholar 

  128. Agundez JA, Martinez C, Perez-Sala D, Carballo M, Torres MJ, Garcia-Martin E . Pharmacogenomics in aspirin intolerance. Curr Drug Metab 2009; 10: 998–1008.

    Article  CAS  PubMed  Google Scholar 

  129. Klein TE, Altman RB, Eriksson N, Gage BF, Kimmel SE, Lee MT et al. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med 2009; 360: 753–764.

    Article  CAS  PubMed  Google Scholar 

  130. Takeuchi F, McGinnis R, Bourgeois S, Barnes C, Eriksson N, Soranzo N et al. A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose. PLoS Genet 2009; 5: e1000433.

    Article  CAS  PubMed  Google Scholar 

  131. Krauss RM, Mangravite LM, Smith JD, Medina MW, Wang D, Guo X et al. Variation in the 3-hydroxyl-3-methylglutaryl coenzyme a reductase gene is associated with racial differences in low-density lipoprotein cholesterol response to simvastatin treatment. Circulation 2008; 117: 1537–1544.

    Article  CAS  PubMed  Google Scholar 

  132. Wilke RA, Moore JH, Burmester JK . Relative impact of CYP3A genotype and concomitant medication on the severity of atorvastatin-induced muscle damage. Pharmacogenet Genomics 2005; 15: 415–421.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported by P30HL10133, U19A170235, U01HG004608, U01HL069757, K01HL103165 and R01DK080007.

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Correspondence to T M Baye or R A Wilke.

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Baye, T., Wilke, R. Mapping genes that predict treatment outcome in admixed populations. Pharmacogenomics J 10, 465–477 (2010). https://doi.org/10.1038/tpj.2010.71

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  • DOI: https://doi.org/10.1038/tpj.2010.71

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