Race, ethnicity, ancestry, and pharmacogenetics.
ABSTRACT Pharmacogenetics is the study of how genetic variation influences the response to drugs. The concepts of race, ethnicity, and ancestry have long had a strong influence on pharmacogenetic discovery and on our understanding of population-level differences in drug response. The primary goal of pharmacogenetics, however, is to identify the individual genetic determinants of drug activity so that therapy can be tailored to the individual patient. This article describes the relationship between the concepts of race, ethnicity, and ancestry and how these concepts have been applied to pharmacogenetics, and it provides examples of the benefits and pitfalls associated with the use of racial or ethnic labels in genetic studies. The future of pharmacogenetics, including the study of rare genetic variation and what this means for racial or ethnic disparities in pharmacogenetic discovery, is also discussed.
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ABSTRACT: The rapid progress currently being made in genomic science has created interest in potential clinical applications; however, formal translational research has been limited thus far. Studies of population genetics have demonstrated substantial variation in allele frequencies and haplotype structure at loci of medical relevance and the genetic background of patient cohorts may often be complex. To describe the heterogeneity in an unselected clinical sample we used the Affymetrix 6.0 gene array chip to genotype self-identified European Americans (N = 326), African Americans (N = 324) and Hispanics (N = 327) from the medical practice of Mount Sinai Medical Center in Manhattan, NY. Additional data from US minority groups and Brazil were used for external comparison. Substantial variation in ancestral origin was observed for both African Americans and Hispanics; data from the latter group overlapped with both Mexican Americans and Brazilians in the external data sets. A pooled analysis of the African Americans and Hispanics from NY demonstrated a broad continuum of ancestral origin making classification by race/ethnicity uninformative. Selected loci harboring variants associated with medical traits and drug response confirmed substantial within- and between-group heterogeneity. As a consequence of these complementary levels of heterogeneity group labels offered no guidance at the individual level. These findings demonstrate the complexity involved in clinical translation of the results from genome-wide association studies and suggest that in the genomic era conventional racial/ethnic labels are of little value.PLoS ONE 05/2011; 6(5):e19166. DOI:10.1371/journal.pone.0019166 · 3.53 Impact Factor
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ABSTRACT: This institutional retrospective review studied Ewing sarcomas from 1987-2011. Among 135 patients, 127 (19 Hispanic and 108 white/non-Hispanic) were analyzed (excluding small sample sized groups) finding 15% Hispanic, 85% non-Hispanic, 27% <18 years, 21% >40 years and 1-272 months follow-up (median 41). Age was significantly associated with overall survival (OS) (p = 0.01), whereby <18 years had a higher probability of 5-year survival (OS 61%) than >40 years (OS 37.6%). Ethnicity was marginally statistically significant (OS, p = 0.065); whereby median survival was clinically significant (white non-Hispanic 63 months and Hispanic 23 months). Hispanic ethnicity and older age are independent poor prognostic factors.Fetal and pediatric pathology 10/2012; 32(4). DOI:10.3109/15513815.2012.721480 · 0.40 Impact Factor
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ABSTRACT: The kidney plays a vital role in the body's defense against potentially toxic xenobiotics and metabolic waste products through elimination pathways. In particular, secretory transporters in the proximal tubule are major determinants of the disposition of xenobiotics, including many prescription drugs. In the past decade, considerable progress has been made in understanding the impact of renal transporters on the disposition of many clinically used drugs. In addition, renal transporters have been implicated as sites for numerous clinically important drug-drug interactions. This review begins with a description of renal drug handling and presents relevant equations for the calculation of renal clearance, including filtration and secretory clearance. In addition, data on the localization, expression, substrates, and inhibitors of renal drug transporters are tabulated. The recent US Food and Drug Administration drug-drug interaction draft guidance as it pertains to the study of renal drug transporters is presented. Renal drug elimination in special populations and transporter splicing variants are also described. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 53 is January 06, 2013. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.Annual Review of Pharmacology 11/2012; DOI:10.1146/annurev-pharmtox-011112-140317 · 18.52 Impact Factor