Pharmacogenetic meta-analysis of baseline risk factors, pharmacodynamic, efficacy and tolerability endpoints from two large global cardiovascular outcomes trials for darapladib
Darapladib, a lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor, failed to demonstrate efficacy for the primary endpoints in two large phase III cardiovascular outcomes trials, one in stable coronary heart disease patients (STABILITY) and one in acute coronary syndrome (SOLID-TIMI 52). No...
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| creator | Yeo, Astrid Li, Li Warren, Liling Aponte, Jennifer Fraser, Dana King, Karen Johansson, Kelley Barnes, Allison MacPhee, Colin Davies, Richard Chissoe, Stephanie Tarka, Elizabeth O'Donoghue, Michelle L White, Harvey D Wallentin, Lars Waterworth, Dawn |
| description | Darapladib, a lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor, failed to demonstrate efficacy for the primary endpoints in two large phase III cardiovascular outcomes trials, one in stable coronary heart disease patients (STABILITY) and one in acute coronary syndrome (SOLID-TIMI 52). No major safety signals were observed but tolerability issues of diarrhea and odor were common (up to 13%). We hypothesized that genetic variants associated with Lp-PLA2 activity may influence efficacy and tolerability and therefore performed a comprehensive pharmacogenetic analysis of both trials. We genotyped patients within the STABILITY and SOLID-TIMI 52 trials who provided a DNA sample and consent (n = 13,577 and 10,404 respectively, representing 86% and 82% of the trial participants) using genome-wide arrays with exome content and performed imputation using a 1000 Genomes reference panel. We investigated baseline and change from baseline in Lp-PLA2 activity, two efficacy endpoints (major coronary events and myocardial infarction) as well as tolerability parameters at genome-wide and candidate gene level using a meta-analytic approach. We replicated associations of published loci on baseline Lp-PLA2 activity (APOE, CELSR2, LPA, PLA2G7, LDLR and SCARB1) and identified three novel loci (TOMM5, FRMD5 and LPL) using the GWAS-significance threshold P≤5E-08. Review of the PLA2G7 gene (encoding Lp-PLA2) within these datasets identified V279F null allele carriers as well as three other rare exonic null alleles within various ethnic groups, however none of these variants nor any other loci associated with Lp-PLA2 activity at baseline were associated with any of the drug response endpoints. The analysis of darapladib efficacy endpoints, despite low power, identified six low frequency loci with main genotype effect (though with borderline imputation scores) and one common locus (minor allele frequency 0.24) with genotype by treatment interaction effect passing the GWAS-significance threshold. This locus conferred risk in placebo subjects, hazard ratio (HR) 1.22 with 95% confidence interval (CI) 1.11-1.33, but was protective in darapladib subjects, HR 0.79 (95% CI 0.71-0.88). No major loci for tolerability were found. Thus, genetic analysis confirmed and extended the influence of lipoprotein loci on Lp-PLA2 levels, identified some novel null alleles in the PLA2G7 gene, and only identified one potentially efficacious subgroup within these two large clinical trials. |
| doi_str_mv | 10.1371/journal.pone.0182115 |
| format | Article |
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No major safety signals were observed but tolerability issues of diarrhea and odor were common (up to 13%). We hypothesized that genetic variants associated with Lp-PLA2 activity may influence efficacy and tolerability and therefore performed a comprehensive pharmacogenetic analysis of both trials. We genotyped patients within the STABILITY and SOLID-TIMI 52 trials who provided a DNA sample and consent (n = 13,577 and 10,404 respectively, representing 86% and 82% of the trial participants) using genome-wide arrays with exome content and performed imputation using a 1000 Genomes reference panel. We investigated baseline and change from baseline in Lp-PLA2 activity, two efficacy endpoints (major coronary events and myocardial infarction) as well as tolerability parameters at genome-wide and candidate gene level using a meta-analytic approach. We replicated associations of published loci on baseline Lp-PLA2 activity (APOE, CELSR2, LPA, PLA2G7, LDLR and SCARB1) and identified three novel loci (TOMM5, FRMD5 and LPL) using the GWAS-significance threshold P≤5E-08. Review of the PLA2G7 gene (encoding Lp-PLA2) within these datasets identified V279F null allele carriers as well as three other rare exonic null alleles within various ethnic groups, however none of these variants nor any other loci associated with Lp-PLA2 activity at baseline were associated with any of the drug response endpoints. The analysis of darapladib efficacy endpoints, despite low power, identified six low frequency loci with main genotype effect (though with borderline imputation scores) and one common locus (minor allele frequency 0.24) with genotype by treatment interaction effect passing the GWAS-significance threshold. This locus conferred risk in placebo subjects, hazard ratio (HR) 1.22 with 95% confidence interval (CI) 1.11-1.33, but was protective in darapladib subjects, HR 0.79 (95% CI 0.71-0.88). No major loci for tolerability were found. Thus, genetic analysis confirmed and extended the influence of lipoprotein loci on Lp-PLA2 levels, identified some novel null alleles in the PLA2G7 gene, and only identified one potentially efficacious subgroup within these two large clinical trials.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0182115</identifier><identifier>PMID: 28753643</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>1-Alkyl-2-acetylglycerophosphocholine Esterase - antagonists & inhibitors ; 1-Alkyl-2-acetylglycerophosphocholine Esterase - genetics ; Aged ; Alleles ; Apolipoprotein E ; Benzaldehydes - adverse effects ; Benzaldehydes - pharmacokinetics ; Benzaldehydes - therapeutic use ; Bioinformatics ; Biology and Life Sciences ; Cardiovascular disease ; Cardiovascular diseases ; Care and treatment ; Clinical trials ; Clinical Trials as Topic ; Confidence intervals ; Coronary artery disease ; Coronary Disease - drug therapy ; Coronary Disease - genetics ; Coronary Disease - metabolism ; Coronary vessels ; Deoxyribonucleic acid ; Diarrhea ; DNA ; Effectiveness ; Enzymes ; Female ; Gene expression ; Gene frequency ; Genetic analysis ; Genetic aspects ; Genetic diversity ; Genetic variance ; Genetics ; Genomes ; Genotypes ; Heart ; Heart attack ; Heart attacks ; Heart diseases ; Humans ; Lipids ; Lipoproteins ; Loci ; Low density lipoprotein receptors ; Male ; Mathematical analysis ; Medical research ; Medicine ; Medicine and Health Sciences ; Meta-analysis ; Metabolism ; Middle Aged ; Minority & ethnic groups ; Myocardial infarction ; Odor ; Odors ; Oximes - adverse effects ; Oximes - pharmacokinetics ; Oximes - therapeutic use ; Patients ; Pharmacodynamics ; Pharmacology ; Phospholipase ; Phospholipase A2 ; Phospholipase A2 Inhibitors - adverse effects ; Phospholipase A2 Inhibitors - pharmacokinetics ; Phospholipase A2 Inhibitors - therapeutic use ; Physical Sciences ; Population ; Principal components analysis ; Research and Analysis Methods ; Risk analysis ; Risk Factors ; Stability analysis ; Studies</subject><ispartof>PloS one, 2017-07, Vol.12 (7), p.e0182115-e0182115</ispartof><rights>COPYRIGHT 2017 Public Library of Science</rights><rights>2017 Yeo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2017 Yeo et al 2017 Yeo et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c729t-3f20837d0944b1a580fb375f2ed563a2a9b346c567683a5537a2e2133a0af97c3</citedby><cites>FETCH-LOGICAL-c729t-3f20837d0944b1a580fb375f2ed563a2a9b346c567683a5537a2e2133a0af97c3</cites><orcidid>0000-0001-7043-4865 ; 0000-0003-0378-6531 ; 0000-0003-2043-4757 ; 0000-0002-4542-0784 ; 0000-0002-9226-1317 ; 0000-0003-1680-0232</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533343/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533343/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,551,724,777,781,861,882,2096,2915,23847,27905,27906,53772,53774,79349,79350</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28753643$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-332837$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><contributor>Norata, Giuseppe Danilo</contributor><creatorcontrib>Yeo, Astrid</creatorcontrib><creatorcontrib>Li, Li</creatorcontrib><creatorcontrib>Warren, Liling</creatorcontrib><creatorcontrib>Aponte, Jennifer</creatorcontrib><creatorcontrib>Fraser, Dana</creatorcontrib><creatorcontrib>King, Karen</creatorcontrib><creatorcontrib>Johansson, Kelley</creatorcontrib><creatorcontrib>Barnes, Allison</creatorcontrib><creatorcontrib>MacPhee, Colin</creatorcontrib><creatorcontrib>Davies, Richard</creatorcontrib><creatorcontrib>Chissoe, Stephanie</creatorcontrib><creatorcontrib>Tarka, Elizabeth</creatorcontrib><creatorcontrib>O'Donoghue, Michelle L</creatorcontrib><creatorcontrib>White, Harvey D</creatorcontrib><creatorcontrib>Wallentin, Lars</creatorcontrib><creatorcontrib>Waterworth, Dawn</creatorcontrib><title>Pharmacogenetic meta-analysis of baseline risk factors, pharmacodynamic, efficacy and tolerability endpoints from two large global cardiovascular outcomes trials for darapladib</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Darapladib, a lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor, failed to demonstrate efficacy for the primary endpoints in two large phase III cardiovascular outcomes trials, one in stable coronary heart disease patients (STABILITY) and one in acute coronary syndrome (SOLID-TIMI 52). No major safety signals were observed but tolerability issues of diarrhea and odor were common (up to 13%). We hypothesized that genetic variants associated with Lp-PLA2 activity may influence efficacy and tolerability and therefore performed a comprehensive pharmacogenetic analysis of both trials. We genotyped patients within the STABILITY and SOLID-TIMI 52 trials who provided a DNA sample and consent (n = 13,577 and 10,404 respectively, representing 86% and 82% of the trial participants) using genome-wide arrays with exome content and performed imputation using a 1000 Genomes reference panel. We investigated baseline and change from baseline in Lp-PLA2 activity, two efficacy endpoints (major coronary events and myocardial infarction) as well as tolerability parameters at genome-wide and candidate gene level using a meta-analytic approach. We replicated associations of published loci on baseline Lp-PLA2 activity (APOE, CELSR2, LPA, PLA2G7, LDLR and SCARB1) and identified three novel loci (TOMM5, FRMD5 and LPL) using the GWAS-significance threshold P≤5E-08. Review of the PLA2G7 gene (encoding Lp-PLA2) within these datasets identified V279F null allele carriers as well as three other rare exonic null alleles within various ethnic groups, however none of these variants nor any other loci associated with Lp-PLA2 activity at baseline were associated with any of the drug response endpoints. The analysis of darapladib efficacy endpoints, despite low power, identified six low frequency loci with main genotype effect (though with borderline imputation scores) and one common locus (minor allele frequency 0.24) with genotype by treatment interaction effect passing the GWAS-significance threshold. This locus conferred risk in placebo subjects, hazard ratio (HR) 1.22 with 95% confidence interval (CI) 1.11-1.33, but was protective in darapladib subjects, HR 0.79 (95% CI 0.71-0.88). No major loci for tolerability were found. Thus, genetic analysis confirmed and extended the influence of lipoprotein loci on Lp-PLA2 levels, identified some novel null alleles in the PLA2G7 gene, and only identified one potentially efficacious subgroup within these two large clinical trials.</description><subject>1-Alkyl-2-acetylglycerophosphocholine Esterase - antagonists & inhibitors</subject><subject>1-Alkyl-2-acetylglycerophosphocholine Esterase - genetics</subject><subject>Aged</subject><subject>Alleles</subject><subject>Apolipoprotein E</subject><subject>Benzaldehydes - adverse effects</subject><subject>Benzaldehydes - pharmacokinetics</subject><subject>Benzaldehydes - therapeutic use</subject><subject>Bioinformatics</subject><subject>Biology and Life Sciences</subject><subject>Cardiovascular disease</subject><subject>Cardiovascular diseases</subject><subject>Care and treatment</subject><subject>Clinical trials</subject><subject>Clinical Trials as Topic</subject><subject>Confidence intervals</subject><subject>Coronary artery disease</subject><subject>Coronary Disease - drug therapy</subject><subject>Coronary Disease - genetics</subject><subject>Coronary Disease - metabolism</subject><subject>Coronary vessels</subject><subject>Deoxyribonucleic acid</subject><subject>Diarrhea</subject><subject>DNA</subject><subject>Effectiveness</subject><subject>Enzymes</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene frequency</subject><subject>Genetic analysis</subject><subject>Genetic aspects</subject><subject>Genetic diversity</subject><subject>Genetic variance</subject><subject>Genetics</subject><subject>Genomes</subject><subject>Genotypes</subject><subject>Heart</subject><subject>Heart attack</subject><subject>Heart attacks</subject><subject>Heart diseases</subject><subject>Humans</subject><subject>Lipids</subject><subject>Lipoproteins</subject><subject>Loci</subject><subject>Low density lipoprotein receptors</subject><subject>Male</subject><subject>Mathematical analysis</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Meta-analysis</subject><subject>Metabolism</subject><subject>Middle Aged</subject><subject>Minority & ethnic groups</subject><subject>Myocardial infarction</subject><subject>Odor</subject><subject>Odors</subject><subject>Oximes - adverse effects</subject><subject>Oximes - pharmacokinetics</subject><subject>Oximes - therapeutic use</subject><subject>Patients</subject><subject>Pharmacodynamics</subject><subject>Pharmacology</subject><subject>Phospholipase</subject><subject>Phospholipase A2</subject><subject>Phospholipase A2 Inhibitors - adverse effects</subject><subject>Phospholipase A2 Inhibitors - pharmacokinetics</subject><subject>Phospholipase A2 Inhibitors - therapeutic use</subject><subject>Physical Sciences</subject><subject>Population</subject><subject>Principal components analysis</subject><subject>Research and Analysis 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meta-analysis of baseline risk factors, pharmacodynamic, efficacy and tolerability endpoints from two large global cardiovascular outcomes trials for darapladib</title><author>Yeo, Astrid ; Li, Li ; Warren, Liling ; Aponte, Jennifer ; Fraser, Dana ; King, Karen ; Johansson, Kelley ; Barnes, Allison ; MacPhee, Colin ; Davies, Richard ; Chissoe, Stephanie ; Tarka, Elizabeth ; O'Donoghue, Michelle L ; White, Harvey D ; Wallentin, Lars ; Waterworth, Dawn</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c729t-3f20837d0944b1a580fb375f2ed563a2a9b346c567683a5537a2e2133a0af97c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>1-Alkyl-2-acetylglycerophosphocholine Esterase - antagonists & inhibitors</topic><topic>1-Alkyl-2-acetylglycerophosphocholine Esterase - genetics</topic><topic>Aged</topic><topic>Alleles</topic><topic>Apolipoprotein E</topic><topic>Benzaldehydes - adverse effects</topic><topic>Benzaldehydes - pharmacokinetics</topic><topic>Benzaldehydes - therapeutic use</topic><topic>Bioinformatics</topic><topic>Biology and Life Sciences</topic><topic>Cardiovascular disease</topic><topic>Cardiovascular diseases</topic><topic>Care and treatment</topic><topic>Clinical trials</topic><topic>Clinical Trials as Topic</topic><topic>Confidence intervals</topic><topic>Coronary artery disease</topic><topic>Coronary Disease - drug therapy</topic><topic>Coronary Disease - genetics</topic><topic>Coronary Disease - metabolism</topic><topic>Coronary vessels</topic><topic>Deoxyribonucleic acid</topic><topic>Diarrhea</topic><topic>DNA</topic><topic>Effectiveness</topic><topic>Enzymes</topic><topic>Female</topic><topic>Gene expression</topic><topic>Gene frequency</topic><topic>Genetic analysis</topic><topic>Genetic aspects</topic><topic>Genetic diversity</topic><topic>Genetic variance</topic><topic>Genetics</topic><topic>Genomes</topic><topic>Genotypes</topic><topic>Heart</topic><topic>Heart attack</topic><topic>Heart attacks</topic><topic>Heart diseases</topic><topic>Humans</topic><topic>Lipids</topic><topic>Lipoproteins</topic><topic>Loci</topic><topic>Low density lipoprotein receptors</topic><topic>Male</topic><topic>Mathematical analysis</topic><topic>Medical research</topic><topic>Medicine</topic><topic>Medicine and Health Sciences</topic><topic>Meta-analysis</topic><topic>Metabolism</topic><topic>Middle Aged</topic><topic>Minority & ethnic groups</topic><topic>Myocardial infarction</topic><topic>Odor</topic><topic>Odors</topic><topic>Oximes - adverse effects</topic><topic>Oximes - pharmacokinetics</topic><topic>Oximes - therapeutic use</topic><topic>Patients</topic><topic>Pharmacodynamics</topic><topic>Pharmacology</topic><topic>Phospholipase</topic><topic>Phospholipase A2</topic><topic>Phospholipase A2 Inhibitors - adverse effects</topic><topic>Phospholipase A2 Inhibitors - pharmacokinetics</topic><topic>Phospholipase A2 Inhibitors - therapeutic use</topic><topic>Physical Sciences</topic><topic>Population</topic><topic>Principal components analysis</topic><topic>Research and Analysis Methods</topic><topic>Risk analysis</topic><topic>Risk Factors</topic><topic>Stability analysis</topic><topic>Studies</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yeo, Astrid</creatorcontrib><creatorcontrib>Li, Li</creatorcontrib><creatorcontrib>Warren, Liling</creatorcontrib><creatorcontrib>Aponte, Jennifer</creatorcontrib><creatorcontrib>Fraser, Dana</creatorcontrib><creatorcontrib>King, Karen</creatorcontrib><creatorcontrib>Johansson, Kelley</creatorcontrib><creatorcontrib>Barnes, Allison</creatorcontrib><creatorcontrib>MacPhee, Colin</creatorcontrib><creatorcontrib>Davies, Richard</creatorcontrib><creatorcontrib>Chissoe, Stephanie</creatorcontrib><creatorcontrib>Tarka, Elizabeth</creatorcontrib><creatorcontrib>O'Donoghue, Michelle L</creatorcontrib><creatorcontrib>White, Harvey D</creatorcontrib><creatorcontrib>Wallentin, Lars</creatorcontrib><creatorcontrib>Waterworth, Dawn</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering 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(Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>SWEPUB Uppsala universitet full text</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SWEPUB Uppsala universitet</collection><collection>SwePub Articles full text</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yeo, Astrid</au><au>Li, Li</au><au>Warren, Liling</au><au>Aponte, Jennifer</au><au>Fraser, Dana</au><au>King, Karen</au><au>Johansson, Kelley</au><au>Barnes, Allison</au><au>MacPhee, Colin</au><au>Davies, Richard</au><au>Chissoe, Stephanie</au><au>Tarka, Elizabeth</au><au>O'Donoghue, Michelle L</au><au>White, Harvey D</au><au>Wallentin, Lars</au><au>Waterworth, Dawn</au><au>Norata, Giuseppe Danilo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pharmacogenetic meta-analysis of baseline risk factors, pharmacodynamic, efficacy and tolerability endpoints from two large global cardiovascular outcomes trials for darapladib</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2017-07-28</date><risdate>2017</risdate><volume>12</volume><issue>7</issue><spage>e0182115</spage><epage>e0182115</epage><pages>e0182115-e0182115</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Darapladib, a lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor, failed to demonstrate efficacy for the primary endpoints in two large phase III cardiovascular outcomes trials, one in stable coronary heart disease patients (STABILITY) and one in acute coronary syndrome (SOLID-TIMI 52). No major safety signals were observed but tolerability issues of diarrhea and odor were common (up to 13%). We hypothesized that genetic variants associated with Lp-PLA2 activity may influence efficacy and tolerability and therefore performed a comprehensive pharmacogenetic analysis of both trials. We genotyped patients within the STABILITY and SOLID-TIMI 52 trials who provided a DNA sample and consent (n = 13,577 and 10,404 respectively, representing 86% and 82% of the trial participants) using genome-wide arrays with exome content and performed imputation using a 1000 Genomes reference panel. We investigated baseline and change from baseline in Lp-PLA2 activity, two efficacy endpoints (major coronary events and myocardial infarction) as well as tolerability parameters at genome-wide and candidate gene level using a meta-analytic approach. We replicated associations of published loci on baseline Lp-PLA2 activity (APOE, CELSR2, LPA, PLA2G7, LDLR and SCARB1) and identified three novel loci (TOMM5, FRMD5 and LPL) using the GWAS-significance threshold P≤5E-08. Review of the PLA2G7 gene (encoding Lp-PLA2) within these datasets identified V279F null allele carriers as well as three other rare exonic null alleles within various ethnic groups, however none of these variants nor any other loci associated with Lp-PLA2 activity at baseline were associated with any of the drug response endpoints. The analysis of darapladib efficacy endpoints, despite low power, identified six low frequency loci with main genotype effect (though with borderline imputation scores) and one common locus (minor allele frequency 0.24) with genotype by treatment interaction effect passing the GWAS-significance threshold. This locus conferred risk in placebo subjects, hazard ratio (HR) 1.22 with 95% confidence interval (CI) 1.11-1.33, but was protective in darapladib subjects, HR 0.79 (95% CI 0.71-0.88). No major loci for tolerability were found. Thus, genetic analysis confirmed and extended the influence of lipoprotein loci on Lp-PLA2 levels, identified some novel null alleles in the PLA2G7 gene, and only identified one potentially efficacious subgroup within these two large clinical trials.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28753643</pmid><doi>10.1371/journal.pone.0182115</doi><tpages>e0182115</tpages><orcidid>https://orcid.org/0000-0001-7043-4865</orcidid><orcidid>https://orcid.org/0000-0003-0378-6531</orcidid><orcidid>https://orcid.org/0000-0003-2043-4757</orcidid><orcidid>https://orcid.org/0000-0002-4542-0784</orcidid><orcidid>https://orcid.org/0000-0002-9226-1317</orcidid><orcidid>https://orcid.org/0000-0003-1680-0232</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2017-07, Vol.12 (7), p.e0182115-e0182115 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1991550926 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; SWEPUB Freely available online; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | 1-Alkyl-2-acetylglycerophosphocholine Esterase - antagonists & inhibitors 1-Alkyl-2-acetylglycerophosphocholine Esterase - genetics Aged Alleles Apolipoprotein E Benzaldehydes - adverse effects Benzaldehydes - pharmacokinetics Benzaldehydes - therapeutic use Bioinformatics Biology and Life Sciences Cardiovascular disease Cardiovascular diseases Care and treatment Clinical trials Clinical Trials as Topic Confidence intervals Coronary artery disease Coronary Disease - drug therapy Coronary Disease - genetics Coronary Disease - metabolism Coronary vessels Deoxyribonucleic acid Diarrhea DNA Effectiveness Enzymes Female Gene expression Gene frequency Genetic analysis Genetic aspects Genetic diversity Genetic variance Genetics Genomes Genotypes Heart Heart attack Heart attacks Heart diseases Humans Lipids Lipoproteins Loci Low density lipoprotein receptors Male Mathematical analysis Medical research Medicine Medicine and Health Sciences Meta-analysis Metabolism Middle Aged Minority & ethnic groups Myocardial infarction Odor Odors Oximes - adverse effects Oximes - pharmacokinetics Oximes - therapeutic use Patients Pharmacodynamics Pharmacology Phospholipase Phospholipase A2 Phospholipase A2 Inhibitors - adverse effects Phospholipase A2 Inhibitors - pharmacokinetics Phospholipase A2 Inhibitors - therapeutic use Physical Sciences Population Principal components analysis Research and Analysis Methods Risk analysis Risk Factors Stability analysis Studies |
| title | Pharmacogenetic meta-analysis of baseline risk factors, pharmacodynamic, efficacy and tolerability endpoints from two large global cardiovascular outcomes trials for darapladib |
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