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A combined genome-wide linkage and association approach to find susceptibility loci for platelet function phenotypes in European American and African American families with coronary artery disease

BACKGROUND: The inability of aspirin (ASA) to adequately suppress platelet aggregation is associated with future risk of coronary artery disease (CAD). Heritability studies of agonist-induced platelet function phenotypes suggest that genetic variation may be responsible for ASA responsiveness. In th...

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Autores principales: Mathias, Rasika A, Kim, Yoonhee, Sung, Heejong, Yanek, Lisa R, Mantese, VJ, Hererra-Galeano, J Enrique, Ruczinski, Ingo, Wilson, Alexander F, Faraday, Nauder, Becker, Lewis C, Becker, Diane M
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2890666/
https://www.ncbi.nlm.nih.gov/pubmed/20529293
http://dx.doi.org/10.1186/1755-8794-3-22
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author Mathias, Rasika A
Kim, Yoonhee
Sung, Heejong
Yanek, Lisa R
Mantese, VJ
Hererra-Galeano, J Enrique
Ruczinski, Ingo
Wilson, Alexander F
Faraday, Nauder
Becker, Lewis C
Becker, Diane M
author_facet Mathias, Rasika A
Kim, Yoonhee
Sung, Heejong
Yanek, Lisa R
Mantese, VJ
Hererra-Galeano, J Enrique
Ruczinski, Ingo
Wilson, Alexander F
Faraday, Nauder
Becker, Lewis C
Becker, Diane M
author_sort Mathias, Rasika A
collection PubMed
description BACKGROUND: The inability of aspirin (ASA) to adequately suppress platelet aggregation is associated with future risk of coronary artery disease (CAD). Heritability studies of agonist-induced platelet function phenotypes suggest that genetic variation may be responsible for ASA responsiveness. In this study, we leverage independent information from genome-wide linkage and association data to determine loci controlling platelet phenotypes before and after treatment with ASA. METHODS: Clinical data on 37 agonist-induced platelet function phenotypes were evaluated before and after a 2-week trial of ASA (81 mg/day) in 1231 European American and 846 African American healthy subjects with a family history of premature CAD. Principal component analysis was performed to minimize the number of independent factors underlying the covariance of these various phenotypes. Multi-point sib-pair based linkage analysis was performed using a microsatellite marker set, and single-SNP association tests were performed using markers from the Illumina 1 M genotyping chip from deCODE Genetics, Inc. All analyses were performed separately within each ethnic group. RESULTS: Several genomic regions appear to be linked to ASA response factors: a 10 cM region in African Americans on chromosome 5q11.2 had several STRs with suggestive (p-value < 7 × 10(-4)) and significant (p-value < 2 × 10(-5)) linkage to post aspirin platelet response to ADP, and ten additional factors had suggestive evidence for linkage (p-value < 7 × 10(-4)) to thirteen genomic regions. All but one of these factors were aspirin response variables. While the strength of genome-wide SNP association signals for factors showing evidence for linkage is limited, especially at the strict thresholds of genome-wide criteria (N = 9 SNPs for 11 factors), more signals were considered significant when the association signal was weighted by evidence for linkage (N = 30 SNPs). CONCLUSIONS: Our study supports the hypothesis that platelet phenotypes in response to ASA likely have genetic control and the combined approach of linkage and association offers an alternative approach to prioritizing regions of interest for subsequent follow-up.
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spelling pubmed-28906662010-06-24 A combined genome-wide linkage and association approach to find susceptibility loci for platelet function phenotypes in European American and African American families with coronary artery disease Mathias, Rasika A Kim, Yoonhee Sung, Heejong Yanek, Lisa R Mantese, VJ Hererra-Galeano, J Enrique Ruczinski, Ingo Wilson, Alexander F Faraday, Nauder Becker, Lewis C Becker, Diane M BMC Med Genomics Research article BACKGROUND: The inability of aspirin (ASA) to adequately suppress platelet aggregation is associated with future risk of coronary artery disease (CAD). Heritability studies of agonist-induced platelet function phenotypes suggest that genetic variation may be responsible for ASA responsiveness. In this study, we leverage independent information from genome-wide linkage and association data to determine loci controlling platelet phenotypes before and after treatment with ASA. METHODS: Clinical data on 37 agonist-induced platelet function phenotypes were evaluated before and after a 2-week trial of ASA (81 mg/day) in 1231 European American and 846 African American healthy subjects with a family history of premature CAD. Principal component analysis was performed to minimize the number of independent factors underlying the covariance of these various phenotypes. Multi-point sib-pair based linkage analysis was performed using a microsatellite marker set, and single-SNP association tests were performed using markers from the Illumina 1 M genotyping chip from deCODE Genetics, Inc. All analyses were performed separately within each ethnic group. RESULTS: Several genomic regions appear to be linked to ASA response factors: a 10 cM region in African Americans on chromosome 5q11.2 had several STRs with suggestive (p-value < 7 × 10(-4)) and significant (p-value < 2 × 10(-5)) linkage to post aspirin platelet response to ADP, and ten additional factors had suggestive evidence for linkage (p-value < 7 × 10(-4)) to thirteen genomic regions. All but one of these factors were aspirin response variables. While the strength of genome-wide SNP association signals for factors showing evidence for linkage is limited, especially at the strict thresholds of genome-wide criteria (N = 9 SNPs for 11 factors), more signals were considered significant when the association signal was weighted by evidence for linkage (N = 30 SNPs). CONCLUSIONS: Our study supports the hypothesis that platelet phenotypes in response to ASA likely have genetic control and the combined approach of linkage and association offers an alternative approach to prioritizing regions of interest for subsequent follow-up. BioMed Central 2010-06-07 /pmc/articles/PMC2890666/ /pubmed/20529293 http://dx.doi.org/10.1186/1755-8794-3-22 Text en Copyright ©2010 Mathias et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research article
Mathias, Rasika A
Kim, Yoonhee
Sung, Heejong
Yanek, Lisa R
Mantese, VJ
Hererra-Galeano, J Enrique
Ruczinski, Ingo
Wilson, Alexander F
Faraday, Nauder
Becker, Lewis C
Becker, Diane M
A combined genome-wide linkage and association approach to find susceptibility loci for platelet function phenotypes in European American and African American families with coronary artery disease
title A combined genome-wide linkage and association approach to find susceptibility loci for platelet function phenotypes in European American and African American families with coronary artery disease
title_full A combined genome-wide linkage and association approach to find susceptibility loci for platelet function phenotypes in European American and African American families with coronary artery disease
title_fullStr A combined genome-wide linkage and association approach to find susceptibility loci for platelet function phenotypes in European American and African American families with coronary artery disease
title_full_unstemmed A combined genome-wide linkage and association approach to find susceptibility loci for platelet function phenotypes in European American and African American families with coronary artery disease
title_short A combined genome-wide linkage and association approach to find susceptibility loci for platelet function phenotypes in European American and African American families with coronary artery disease
title_sort combined genome-wide linkage and association approach to find susceptibility loci for platelet function phenotypes in european american and african american families with coronary artery disease
topic Research article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2890666/
https://www.ncbi.nlm.nih.gov/pubmed/20529293
http://dx.doi.org/10.1186/1755-8794-3-22
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