Genome-Wide Association Study of Beta-Blocker Survival Benefit in Black and White Patients with Heart Failure with Reduced Ejection Fraction
In patients with heart failure with reduced ejection fraction (HFrEF), individual responses to beta-blockers vary. Candidate gene pharmacogenetic studies yielded significant but inconsistent results, and they may have missed important associations. Our objective was to use an unbiased genome-wide as...
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| Format: | Article |
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MDPI AG
2023-10-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/14/11/2019 |
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| author | Jasmine A. Luzum Alessandra M. Campos-Staffico Jia Li Ruicong She Hongsheng Gui Edward L. Peterson Bin Liu Hani N. Sabbah Mark P. Donahue William E. Kraus L. Keoki Williams David E. Lanfear |
| author_facet | Jasmine A. Luzum Alessandra M. Campos-Staffico Jia Li Ruicong She Hongsheng Gui Edward L. Peterson Bin Liu Hani N. Sabbah Mark P. Donahue William E. Kraus L. Keoki Williams David E. Lanfear |
| author_sort | Jasmine A. Luzum |
| collection | DOAJ |
| description | In patients with heart failure with reduced ejection fraction (HFrEF), individual responses to beta-blockers vary. Candidate gene pharmacogenetic studies yielded significant but inconsistent results, and they may have missed important associations. Our objective was to use an unbiased genome-wide association study (GWAS) to identify loci influencing beta-blocker survival benefit in HFrEF patients. Genetic variant × beta-blocker exposure interactions were tested in Cox proportional hazards models for all-cause mortality stratified by self-identified race. The models were adjusted for clinical risk factors and propensity scores. A prospective HFrEF registry (469 black and 459 white patients) was used for discovery, and linkage disequilibrium (LD) clumped variants with a beta-blocker interaction of <i>p</i> < 5 × 10<sup>−5</sup>, were tested for Bonferroni-corrected validation in a multicenter HFrEF clinical trial (288 black and 579 white patients). A total of 229 and 18 variants in black and white HFrEF patients, respectively, had interactions with beta-blocker exposure at <i>p</i> < 5 × 10<sup>−5</sup> upon discovery. After LD-clumping, 100 variants and 4 variants in the black and white patients, respectively, remained for validation but none reached statistical significance. In conclusion, genetic variants of potential interest were identified in a discovery-based GWAS of beta-blocker survival benefit in HFrEF patients, but none were validated in an independent dataset. Larger cohorts or alternative approaches, such as polygenic scores, are needed. |
| first_indexed | 2024-03-09T16:47:53Z |
| format | Article |
| id | doaj.art-67a986ad93234f35b6c00bb19f52ad83 |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-09T16:47:53Z |
| publishDate | 2023-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-67a986ad93234f35b6c00bb19f52ad832023-11-24T14:43:45ZengMDPI AGGenes2073-44252023-10-011411201910.3390/genes14112019Genome-Wide Association Study of Beta-Blocker Survival Benefit in Black and White Patients with Heart Failure with Reduced Ejection FractionJasmine A. Luzum0Alessandra M. Campos-Staffico1Jia Li2Ruicong She3Hongsheng Gui4Edward L. Peterson5Bin Liu6Hani N. Sabbah7Mark P. Donahue8William E. Kraus9L. Keoki Williams10David E. Lanfear11Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI 48109, USADepartment of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI 48109, USADepartment of Public Health Sciences, Henry Ford Health System, Detroit, MI 48202, USADepartment of Public Health Sciences, Henry Ford Health System, Detroit, MI 48202, USACenter for Individualized and Genomic Medicine Research (CIGMA), Henry Ford Health System, Detroit, MI 48202, USADepartment of Public Health Sciences, Henry Ford Health System, Detroit, MI 48202, USADepartment of Public Health Sciences, Henry Ford Health System, Detroit, MI 48202, USAHeart and Vascular Institute, Henry Ford Health System, Detroit, MI 48202, USASchool of Medicine, Duke University, Durham, NC 27710, USASchool of Medicine, Duke University, Durham, NC 27710, USACenter for Individualized and Genomic Medicine Research (CIGMA), Henry Ford Health System, Detroit, MI 48202, USACenter for Individualized and Genomic Medicine Research (CIGMA), Henry Ford Health System, Detroit, MI 48202, USAIn patients with heart failure with reduced ejection fraction (HFrEF), individual responses to beta-blockers vary. Candidate gene pharmacogenetic studies yielded significant but inconsistent results, and they may have missed important associations. Our objective was to use an unbiased genome-wide association study (GWAS) to identify loci influencing beta-blocker survival benefit in HFrEF patients. Genetic variant × beta-blocker exposure interactions were tested in Cox proportional hazards models for all-cause mortality stratified by self-identified race. The models were adjusted for clinical risk factors and propensity scores. A prospective HFrEF registry (469 black and 459 white patients) was used for discovery, and linkage disequilibrium (LD) clumped variants with a beta-blocker interaction of <i>p</i> < 5 × 10<sup>−5</sup>, were tested for Bonferroni-corrected validation in a multicenter HFrEF clinical trial (288 black and 579 white patients). A total of 229 and 18 variants in black and white HFrEF patients, respectively, had interactions with beta-blocker exposure at <i>p</i> < 5 × 10<sup>−5</sup> upon discovery. After LD-clumping, 100 variants and 4 variants in the black and white patients, respectively, remained for validation but none reached statistical significance. In conclusion, genetic variants of potential interest were identified in a discovery-based GWAS of beta-blocker survival benefit in HFrEF patients, but none were validated in an independent dataset. Larger cohorts or alternative approaches, such as polygenic scores, are needed.https://www.mdpi.com/2073-4425/14/11/2019beta-blockerheart failure with reduced ejection fractionsurvivalgenome-wide association study |
| spellingShingle | Jasmine A. Luzum Alessandra M. Campos-Staffico Jia Li Ruicong She Hongsheng Gui Edward L. Peterson Bin Liu Hani N. Sabbah Mark P. Donahue William E. Kraus L. Keoki Williams David E. Lanfear Genome-Wide Association Study of Beta-Blocker Survival Benefit in Black and White Patients with Heart Failure with Reduced Ejection Fraction Genes beta-blocker heart failure with reduced ejection fraction survival genome-wide association study |
| title | Genome-Wide Association Study of Beta-Blocker Survival Benefit in Black and White Patients with Heart Failure with Reduced Ejection Fraction |
| title_full | Genome-Wide Association Study of Beta-Blocker Survival Benefit in Black and White Patients with Heart Failure with Reduced Ejection Fraction |
| title_fullStr | Genome-Wide Association Study of Beta-Blocker Survival Benefit in Black and White Patients with Heart Failure with Reduced Ejection Fraction |
| title_full_unstemmed | Genome-Wide Association Study of Beta-Blocker Survival Benefit in Black and White Patients with Heart Failure with Reduced Ejection Fraction |
| title_short | Genome-Wide Association Study of Beta-Blocker Survival Benefit in Black and White Patients with Heart Failure with Reduced Ejection Fraction |
| title_sort | genome wide association study of beta blocker survival benefit in black and white patients with heart failure with reduced ejection fraction |
| topic | beta-blocker heart failure with reduced ejection fraction survival genome-wide association study |
| url | https://www.mdpi.com/2073-4425/14/11/2019 |
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