Unique CYP2D6 activity distribution and genotype‐phenotype discordance in black Americans

Background Although CYP2D6 has been studied extensively in differentpopulation groups, relatively little is known for black Americans. Methods CYP2D6 activity was assessed with dextromethorphan in 283 black American subjects and correlated with their genotype (2D6*2 to *12, 2D6*14, 2D6*15, 2D6*17, 2...

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Veröffentlicht in:Clinical pharmacology and therapeutics 2002-07, Vol.72 (1), p.76-89
Hauptverfasser: Gaedigk, Andrea, Bradford, L. DiAnne, Marcucci, Kenda A., Leeder, J. Steven
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Bradford, L. DiAnne
Marcucci, Kenda A.
Leeder, J. Steven
description Background Although CYP2D6 has been studied extensively in differentpopulation groups, relatively little is known for black Americans. Methods CYP2D6 activity was assessed with dextromethorphan in 283 black American subjects and correlated with their genotype (2D6*2 to *12, 2D6*14, 2D6*15, 2D6*17, 2D6*18, and 2D6*29 and gene duplications). Volunteers provided information about ethnicity and concurrent medication, and they participated in either phenotyping (n = 225), genotyping (n = 251), or both (n = 193). Results The median urinary dextromethorphan/dextrorphan metabolic ratio (MR) indicated significantly lower CYP2D6 activity in the black American group (0.016) than in a white control population (0.0044; P = .0001) studied previously. The reduced function allele 2D6*17 was more common (frequency [f] = 0.395) among intermediate metabolizers (0.03 ≤ MR ≤ 0.3) than extensive metabolizers(MR ≤ 0.03; f = 0.148; P = .0001). Consistent with reduced function toward dextromethorphan of COS cell‐expressed 2D6.29 protein, 2D6*29 also was more frequent in intermediate metabolizers (f = 0.114) than in extensive metabolizers (f = 0.057; P = NS). Frequencies for 2D6*17 and 2D6*29 were f = 0.213 and 0.072, respectively. Of the 193 genotyped and phenotyped subjects, 14 were determined to be poor metabolizers, with dextromethorphan/dextrorphan ratios >0.3 (7.25%), but only 2 subjects(1.04%) carried 2 nonfunctional alleles (2D6*3/*4x2 and 2D6*4/*4). A new allelic variant, 2D6*40, was subsequently found in 2 discordant subjects (2D6*4/*40 and 2D6*6/*40), implying that the 18‐base pair (bp) insertion found in 2D6*40 renders it nonfunctional. The frequency of 2D6*40 was 0.006. For genotypes that contain 2D6*2, median MR values were consistently higherin black Americans than in white subjects, indicating that other unidentified factors also contribute to lower CYP2D6 activity in black Americans. Conclusions The lower CYP2D6 activity observed in a black American population is in part attributable to the presence of variant alleles that occur at a higher frequency in this population than in white subjects. Additional studies are required to ascertain the pharmacokinetic and pharmacodynamic consequences of these pharmacogenetic data in black Americans. Clinical Pharmacology & Therapeutics (2002) 72, 76–89; doi: 10.1067/mcp.2002.125783
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DiAnne ; Marcucci, Kenda A. ; Leeder, J. Steven</creator><creatorcontrib>Gaedigk, Andrea ; Bradford, L. DiAnne ; Marcucci, Kenda A. ; Leeder, J. Steven</creatorcontrib><description>Background Although CYP2D6 has been studied extensively in differentpopulation groups, relatively little is known for black Americans. Methods CYP2D6 activity was assessed with dextromethorphan in 283 black American subjects and correlated with their genotype (2D6*2 to *12, 2D6*14, 2D6*15, 2D6*17, 2D6*18, and 2D6*29 and gene duplications). Volunteers provided information about ethnicity and concurrent medication, and they participated in either phenotyping (n = 225), genotyping (n = 251), or both (n = 193). Results The median urinary dextromethorphan/dextrorphan metabolic ratio (MR) indicated significantly lower CYP2D6 activity in the black American group (0.016) than in a white control population (0.0044; P = .0001) studied previously. The reduced function allele 2D6*17 was more common (frequency [f] = 0.395) among intermediate metabolizers (0.03 ≤ MR ≤ 0.3) than extensive metabolizers(MR ≤ 0.03; f = 0.148; P = .0001). Consistent with reduced function toward dextromethorphan of COS cell‐expressed 2D6.29 protein, 2D6*29 also was more frequent in intermediate metabolizers (f = 0.114) than in extensive metabolizers (f = 0.057; P = NS). Frequencies for 2D6*17 and 2D6*29 were f = 0.213 and 0.072, respectively. Of the 193 genotyped and phenotyped subjects, 14 were determined to be poor metabolizers, with dextromethorphan/dextrorphan ratios &gt;0.3 (7.25%), but only 2 subjects(1.04%) carried 2 nonfunctional alleles (2D6*3/*4x2 and 2D6*4/*4). A new allelic variant, 2D6*40, was subsequently found in 2 discordant subjects (2D6*4/*40 and 2D6*6/*40), implying that the 18‐base pair (bp) insertion found in 2D6*40 renders it nonfunctional. The frequency of 2D6*40 was 0.006. For genotypes that contain 2D6*2, median MR values were consistently higherin black Americans than in white subjects, indicating that other unidentified factors also contribute to lower CYP2D6 activity in black Americans. Conclusions The lower CYP2D6 activity observed in a black American population is in part attributable to the presence of variant alleles that occur at a higher frequency in this population than in white subjects. Additional studies are required to ascertain the pharmacokinetic and pharmacodynamic consequences of these pharmacogenetic data in black Americans. 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DiAnne</creatorcontrib><creatorcontrib>Marcucci, Kenda A.</creatorcontrib><creatorcontrib>Leeder, J. Steven</creatorcontrib><title>Unique CYP2D6 activity distribution and genotype‐phenotype discordance in black Americans</title><title>Clinical pharmacology and therapeutics</title><addtitle>Clin Pharmacol Ther</addtitle><description>Background Although CYP2D6 has been studied extensively in differentpopulation groups, relatively little is known for black Americans. Methods CYP2D6 activity was assessed with dextromethorphan in 283 black American subjects and correlated with their genotype (2D6*2 to *12, 2D6*14, 2D6*15, 2D6*17, 2D6*18, and 2D6*29 and gene duplications). Volunteers provided information about ethnicity and concurrent medication, and they participated in either phenotyping (n = 225), genotyping (n = 251), or both (n = 193). Results The median urinary dextromethorphan/dextrorphan metabolic ratio (MR) indicated significantly lower CYP2D6 activity in the black American group (0.016) than in a white control population (0.0044; P = .0001) studied previously. The reduced function allele 2D6*17 was more common (frequency [f] = 0.395) among intermediate metabolizers (0.03 ≤ MR ≤ 0.3) than extensive metabolizers(MR ≤ 0.03; f = 0.148; P = .0001). Consistent with reduced function toward dextromethorphan of COS cell‐expressed 2D6.29 protein, 2D6*29 also was more frequent in intermediate metabolizers (f = 0.114) than in extensive metabolizers (f = 0.057; P = NS). Frequencies for 2D6*17 and 2D6*29 were f = 0.213 and 0.072, respectively. Of the 193 genotyped and phenotyped subjects, 14 were determined to be poor metabolizers, with dextromethorphan/dextrorphan ratios &gt;0.3 (7.25%), but only 2 subjects(1.04%) carried 2 nonfunctional alleles (2D6*3/*4x2 and 2D6*4/*4). A new allelic variant, 2D6*40, was subsequently found in 2 discordant subjects (2D6*4/*40 and 2D6*6/*40), implying that the 18‐base pair (bp) insertion found in 2D6*40 renders it nonfunctional. The frequency of 2D6*40 was 0.006. For genotypes that contain 2D6*2, median MR values were consistently higherin black Americans than in white subjects, indicating that other unidentified factors also contribute to lower CYP2D6 activity in black Americans. Conclusions The lower CYP2D6 activity observed in a black American population is in part attributable to the presence of variant alleles that occur at a higher frequency in this population than in white subjects. Additional studies are required to ascertain the pharmacokinetic and pharmacodynamic consequences of these pharmacogenetic data in black Americans. Clinical Pharmacology &amp; Therapeutics (2002) 72, 76–89; doi: 10.1067/mcp.2002.125783</description><subject>Adolescent</subject><subject>Adult</subject><subject>Alleles</subject><subject>Animals</subject><subject>Antitussive Agents</subject><subject>Biological and medical sciences</subject><subject>Black or African American</subject><subject>Black People - genetics</subject><subject>COS Cells</subject><subject>Cytochrome P-450 CYP2D6 - genetics</subject><subject>Dextromethorphan</subject><subject>DNA Primers</subject><subject>Female</subject><subject>Gene Frequency</subject><subject>General pharmacology</subject><subject>Genotype</subject><subject>Humans</subject><subject>Kinetics</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions</subject><subject>Pharmacology. Drug treatments</subject><subject>Phenotype</subject><subject>Polymorphism, Genetic</subject><subject>United States</subject><subject>White People</subject><issn>0009-9236</issn><issn>1532-6535</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkLtu2zAUhomgQey4mbMVWppNDi_iRd0C5dIABuLBHooMBEVSKRPdSsotvOUR-ox9klKwAI-ZeEh85z88HwCXCC4RZPy60f0SQ4iXCFMuyAmYI0pwyiihn8AcQpinOSZsBs5DeI3XLBfiDMwQRjS2sTl43rbu184mxY81vmWJ0oP77YZ9YlwYvCt3g-vaRLUmebFtN-x7--_9b_9zqkdKd96oVtvEtUlZK_2W3DTWO63a8BmcVqoO9mI6F2B7f7cpvqerp4fH4maV6oxRnlZlrlApWKUqZijMubJEGIi5otxmJTVEGY55xUtOMEVGKEFhJoi1WDCaI7IAV4fc3ndxlzDIJv7L1rVqbbcLkqM8E4KyCF4fQO27ELytZO9do_xeIihHnzL6lKNPefAZO75M0buysebITwIj8HUCVNCqrnx04cKRI4JgyMegbwfuj6vt_qO5slhvitV6Mz4xTv4DgRqQng</recordid><startdate>200207</startdate><enddate>200207</enddate><creator>Gaedigk, Andrea</creator><creator>Bradford, L. 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Steven</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4657-fb9a1b86faf6d5097ae38d027a57e4b5d3ad727f7b73251d8a850483ee2865913</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Alleles</topic><topic>Animals</topic><topic>Antitussive Agents</topic><topic>Biological and medical sciences</topic><topic>Black or African American</topic><topic>Black People - genetics</topic><topic>COS Cells</topic><topic>Cytochrome P-450 CYP2D6 - genetics</topic><topic>Dextromethorphan</topic><topic>DNA Primers</topic><topic>Female</topic><topic>Gene Frequency</topic><topic>General pharmacology</topic><topic>Genotype</topic><topic>Humans</topic><topic>Kinetics</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions</topic><topic>Pharmacology. Drug treatments</topic><topic>Phenotype</topic><topic>Polymorphism, Genetic</topic><topic>United States</topic><topic>White People</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gaedigk, Andrea</creatorcontrib><creatorcontrib>Bradford, L. DiAnne</creatorcontrib><creatorcontrib>Marcucci, Kenda A.</creatorcontrib><creatorcontrib>Leeder, J. Steven</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Clinical pharmacology and therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gaedigk, Andrea</au><au>Bradford, L. DiAnne</au><au>Marcucci, Kenda A.</au><au>Leeder, J. Steven</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Unique CYP2D6 activity distribution and genotype‐phenotype discordance in black Americans</atitle><jtitle>Clinical pharmacology and therapeutics</jtitle><addtitle>Clin Pharmacol Ther</addtitle><date>2002-07</date><risdate>2002</risdate><volume>72</volume><issue>1</issue><spage>76</spage><epage>89</epage><pages>76-89</pages><issn>0009-9236</issn><eissn>1532-6535</eissn><coden>CLPTAT</coden><abstract>Background Although CYP2D6 has been studied extensively in differentpopulation groups, relatively little is known for black Americans. Methods CYP2D6 activity was assessed with dextromethorphan in 283 black American subjects and correlated with their genotype (2D6*2 to *12, 2D6*14, 2D6*15, 2D6*17, 2D6*18, and 2D6*29 and gene duplications). Volunteers provided information about ethnicity and concurrent medication, and they participated in either phenotyping (n = 225), genotyping (n = 251), or both (n = 193). Results The median urinary dextromethorphan/dextrorphan metabolic ratio (MR) indicated significantly lower CYP2D6 activity in the black American group (0.016) than in a white control population (0.0044; P = .0001) studied previously. The reduced function allele 2D6*17 was more common (frequency [f] = 0.395) among intermediate metabolizers (0.03 ≤ MR ≤ 0.3) than extensive metabolizers(MR ≤ 0.03; f = 0.148; P = .0001). Consistent with reduced function toward dextromethorphan of COS cell‐expressed 2D6.29 protein, 2D6*29 also was more frequent in intermediate metabolizers (f = 0.114) than in extensive metabolizers (f = 0.057; P = NS). Frequencies for 2D6*17 and 2D6*29 were f = 0.213 and 0.072, respectively. Of the 193 genotyped and phenotyped subjects, 14 were determined to be poor metabolizers, with dextromethorphan/dextrorphan ratios &gt;0.3 (7.25%), but only 2 subjects(1.04%) carried 2 nonfunctional alleles (2D6*3/*4x2 and 2D6*4/*4). A new allelic variant, 2D6*40, was subsequently found in 2 discordant subjects (2D6*4/*40 and 2D6*6/*40), implying that the 18‐base pair (bp) insertion found in 2D6*40 renders it nonfunctional. The frequency of 2D6*40 was 0.006. For genotypes that contain 2D6*2, median MR values were consistently higherin black Americans than in white subjects, indicating that other unidentified factors also contribute to lower CYP2D6 activity in black Americans. Conclusions The lower CYP2D6 activity observed in a black American population is in part attributable to the presence of variant alleles that occur at a higher frequency in this population than in white subjects. Additional studies are required to ascertain the pharmacokinetic and pharmacodynamic consequences of these pharmacogenetic data in black Americans. Clinical Pharmacology &amp; Therapeutics (2002) 72, 76–89; doi: 10.1067/mcp.2002.125783</abstract><cop>New York, NY</cop><pub>Nature Publishing</pub><pmid>12152006</pmid><doi>10.1067/mcp.2002.125783</doi><tpages>14</tpages></addata></record>
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subjects Adolescent
Adult
Alleles
Animals
Antitussive Agents
Biological and medical sciences
Black or African American
Black People - genetics
COS Cells
Cytochrome P-450 CYP2D6 - genetics
Dextromethorphan
DNA Primers
Female
Gene Frequency
General pharmacology
Genotype
Humans
Kinetics
Male
Medical sciences
Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions
Pharmacology. Drug treatments
Phenotype
Polymorphism, Genetic
United States
White People
title Unique CYP2D6 activity distribution and genotype‐phenotype discordance in black Americans
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