Portal de Periódicos da CAPES

Validation of a Polygenic Score for Beta-Blocker Survival Benefit in Patients With Heart Failure Using the United Kingdom Biobank

2023; Wolters Kluwer; Volume: 16; Issue: 2 Linguagem: Inglês

10.1161/circgen.121.003835

2574-8300

David E. Lanfear, Jasmine A. Luzum, Ruicong She, Jia Li, Hani N. Sabbah, Nicole Zeld, Bin Liu, Edward L. Peterson, L. Keoki Williams,

Cardiac Valve Diseases and Treatments

HomeCirculation: Genomic and Precision MedicineVol. 16, No. 2Validation of a Polygenic Score for Beta-Blocker Survival Benefit in Patients With Heart Failure Using the United Kingdom Biobank Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBValidation of a Polygenic Score for Beta-Blocker Survival Benefit in Patients With Heart Failure Using the United Kingdom Biobank David E. Lanfear, Jasmine A. Luzum, Ruicong She, Jia Li, Hani N. Sabbah, Nicole Zeld, Bin Liu, Edward Peterson and L. Keoki Williams David E. LanfearDavid E. Lanfear Correspondence to: David E. Lanfear, MD, MS, Henry Ford Health System, 2799 W Grand Blvd, K14 Detroit, MI 48202. Email E-mail Address: [email protected] https://orcid.org/0000-0001-6471-1483 Center for Individualized and Genomic Medicine Research (CIGMA), Department of Internal Medicine, Henry Ford Hospital, Detroit, MI (D.E.L., J.A.L., N.Z., L.K.W.). Heart and Vascular Institute (D.E.L., H.N.S.), Henry Ford Health System, Detroit, MI. Search for more papers by this author , Jasmine A. LuzumJasmine A. Luzum https://orcid.org/0000-0003-3639-717X Center for Individualized and Genomic Medicine Research (CIGMA), Department of Internal Medicine, Henry Ford Hospital, Detroit, MI (D.E.L., J.A.L., N.Z., L.K.W.). Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI (J.A.L.). Search for more papers by this author , Ruicong SheRuicong She Department of Public Health Sciences (R.S., J.L., B.L., E.P.), Henry Ford Health System, Detroit, MI. Search for more papers by this author , Jia LiJia Li https://orcid.org/0000-0002-5931-3058 Department of Public Health Sciences (R.S., J.L., B.L., E.P.), Henry Ford Health System, Detroit, MI. Search for more papers by this author , Hani N. SabbahHani N. Sabbah https://orcid.org/0000-0002-2850-6105 Heart and Vascular Institute (D.E.L., H.N.S.), Henry Ford Health System, Detroit, MI. Search for more papers by this author , Nicole ZeldNicole Zeld https://orcid.org/0000-0001-9096-8071 Center for Individualized and Genomic Medicine Research (CIGMA), Department of Internal Medicine, Henry Ford Hospital, Detroit, MI (D.E.L., J.A.L., N.Z., L.K.W.). Search for more papers by this author , Bin LiuBin Liu https://orcid.org/0000-0002-3280-9336 Department of Public Health Sciences (R.S., J.L., B.L., E.P.), Henry Ford Health System, Detroit, MI. Search for more papers by this author , Edward PetersonEdward Peterson Department of Public Health Sciences (R.S., J.L., B.L., E.P.), Henry Ford Health System, Detroit, MI. Search for more papers by this author and L. Keoki WilliamsL. Keoki Williams https://orcid.org/0000-0002-7592-5791 Center for Individualized and Genomic Medicine Research (CIGMA), Department of Internal Medicine, Henry Ford Hospital, Detroit, MI (D.E.L., J.A.L., N.Z., L.K.W.). Search for more papers by this author Originally published3 Mar 2023https://doi.org/10.1161/CIRCGEN.121.003835Circulation: Genomic and Precision Medicine. 2023;16Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: March 3, 2023: Ahead of Print Heart failure (HF) is a major public health problem and beta-blockers (BB) are cornerstone therapy for HF with reduced ejection fraction. However, individual patients’ responses to BB vary substantially and clinical characteristics are not powerful enough predictors to target therapy, thus consensus guidelines recommend BB for all HF with reduced ejection fraction patients without contraindication.1 Previous pharmacogenetic associations of BB showed proof of concept but lacked validation and clinical utility.2 We recently created and validated, in ~1200 European ancestry HF with reduced ejection fraction patients, a novel polygenic response predictor (PRP) for BB in HF with reduced ejection fraction.3 The PRP identified ~25% of patients with substantial survival benefit of BB (hazard ratio [HR], 0.19 [95% CI, 0.06–0.65]), distinct from the remaining patients with little survival benefit (HR, 0.84 [95% CI, 0.53–1.32]). This provocative finding requires additional validation prior to prospective testing, so we sought replication using another large, independent dataset. The United Kingdom Biobank (UKB) contains health and genetic data on hundreds of thousands of participants from the United Kingdom, including medication prescription data. We tested the BB-PRP in the UKB using similar approaches as the original publication.3We identified White patients with HF diagnosis, genetic data, vital status, and prescription data in the UKB. BB-exposure was tabulated using dose, number of tablets, and prescription frequency, to generate an exposure metric that is a proportion of target exposure (based on HF clinical trials) similar to previously work.3,4 The PRP is tabulated from genotype at 44 loci across the genome and was calculated exactly as previously described including using the original beta-coefficients.3 Overall, there was 2% missingness of genotypes needed for score calculation, which were imputed by random draw from the distribution of each SNP. UKB enrollment date was the index date for patients with prevalent HF, otherwise the index date was the date of first HF diagnosis. Time from index date to all-cause mortality was tabulated. The statistical analysis used proportional hazards models adjusted for Meta-analysis Global Group in Chronic Heart Failure (MAGGIC) score,5 BB propensity score, PRP, BB exposure, and BB exposure*PRPcategory interaction, with BB as a continuous time-updating variable, PRP main effect as a continuous variable, and PRPcategory dichotomized at the original cutoff value (≤68 predicted responder versus >68 non-responder).3 Since left ventricular ejection fraction (LVEF) was only available in 255 patients, it was omitted from the MAGGIC calculation, and we included all participants regardless of LVEF. We tested similar models stratified by PRPcategory. The assumption of proportional hazards was assessed by visual inspection of plots of survival, survival time, and log(-log(survival time), which were consistent with proportionality. We depicted survival curves separated by PRPcategory and high versus low BB exposure (first versus third quartile, respectively, which were no BB and 54% target exposure). All analyses were performed in SAS 9.4 (SAS Institute, Cary, NC).Among 7141 patients with HF, 34% were women, 54% had coronary disease, 33% had atrial fibrillation, and 51% had baseline BB usage. The cohort mean PRP was 81 (±18), with n=1642 (23%) responders and n=5499 non-responders. No baseline characteristics differed significantly across PRPcategory. Over a median follow-up of 5.2 years, there were 1014 deaths (14.2%), 212 (12.9%) in responders, and 802 (14.6%) in non-responders. The results are summarized in the Figure. In the total cohort, the PRP main effect was not significant (HR=0.99; P=0.92) while the interaction of PRPcategory*BB-exposure was significant (P=0.044; ß=0.576). In stratified analyses, PRP-responders had strong survival benefit associated with BB (HR, 0.57 [95% CI, 0.33–1.00]; P=0.052), while the PRP-non-responders showed little BB effect (HR, 0.90, [95% CI, 0.70–1.15]; P=0.388). Exploratory analyses in a subgroup of patients with diagnostic codes indicative of low LVEF subtype or a known low LVEF (n=1107, 135 deaths) showed no significant PRPcategory*BB interaction (P=0.34), despite a larger interaction effect estimate (ß=0.85, HR=0.32 in PRP-responders versus 0.75 in PRP-non-responders).Download figureDownload PowerPointFigure. Survival curves from Cox modeling depicting first quartile (solid) versus third quartile (dotted) of beta-blocker exposure, separated by polygenic response predictor (PRP) categories (red are predicted responders and blue are predicted non-responders). The space between the dotted and solid lines (of the same color) represents the survival impact of beta-blocker exposure. Top embedded table is the output of the primary analysis. The bottom table shows results stratified by PRP category (predicted responder versus predicted non-responder).Overall, these findings are consistent with our earlier work, indicating that the PRP-predicted responders had substantial survival benefit with BB while the PRP-predicted non-responders did not. There are some limitations, such as lack of LVEF in most UKB participants and lack of medication dispensing data. However, these should bias toward the null, and the large sample size should compensate for some potential misclassification. Further, unrestricting LVEF potentially broadens the relevance of these findings. Since only survival was examined, other benefits of BB (eg, heartrate or reverse remodeling) remain to be investigated. Finally, the most important limitation is that this score pertains solely to European ancestry, and there remains urgent need for improvements in polygenic scores for diverse populations. In conclusion, the BB-PRP replicated in HF patients from the UKB regardless of LVEF. This innovative tool could be the first effective genomic guide for BB therapy in HF and now requires testing in a clinical trial. While not yet widely applied in many medications or disease states, the polygenic score approach to drug response is theoretically generalizable, warranting additional investigation.Article InformationSources of FundingThis research was supported by the National Heart, Lung, and Blood Institute (Lanfear R01HL103871, R01HL132154; Williams R01HL118267, R01HL141845; Luzum K08HL146990, L30HL110279). Dr Lanfear is also supported in part by the National Institute for Minority Health and Disparities (P50MD017351). Dr Keoki Williams is also supported in part by the National Institute of Allergy and Infectious Diseases (R01AI079139) and the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK064695, R01DK113003).Disclosures Dr Lanfear is a consultant for Abbott Laboratories, Amgen, Astra Zeneca, Cytokinetics, Illumina, Janssen, Martin Pharmaceuticals, Vicardia, and DCRI (Novartis) and has participated in clinical research from Amgen, AstraZeneca, Bayer, Critical Diagnostics, Lilly, Somalogic, and Janssen, and has a patent (held by Henry Ford Health System) for the beta blocker polygenic score. Dr Sabbah is consultant to Arena Pharmaceuticals, ViCardia, Stealth Biotherapeutics and Impulse Dynamics, Inc and has received research funding from Novartis, Arena Pharmaceuticals, and Impulse Dynamics, Inc. The other authors report no conflicts.FootnotesFor Sources of Funding and Disclosures, see page XXX.Correspondence to: David E. Lanfear, MD, MS, Henry Ford Health System, 2799 W Grand Blvd, K14 Detroit, MI 48202. Email dlanfea1@hfhs.orgReferences1. Writing C, Maddox TM, Januzzi JL, Allen LA, Breathett K, Butler J, Davis LL, Fonarow GC, Ibrahim NE, Lindenfeld J, et al. 2021 update to the 2017 acc expert consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the american college of cardiology solution set oversight committee.J Am Coll Cardiol. 2021; 77:772–810. doi: 10.1016/j.jacc.2020.11.022CrossrefMedlineGoogle Scholar2. Talameh JA, Lanfear DE. Pharmacogenetics in chronic heart failure: new developments and current challenges.Curr Heart Fail Rep. 2012; 9:23–32. doi: 10.1007/s11897-011-0076-2CrossrefMedlineGoogle Scholar3. Lanfear DE, Luzum JA, She R, Gui H, Donahue MP, O’Connor CM, Adams KF, Sanders-van Wijk S, Zeld N, Maeder MT, et al. Polygenic score for beta-blocker survival benefit in european ancestry patients with reduced ejection fraction heart failure.Circ Heart Fail. 2020; 13:e007012. doi: 10.1161/CIRCHEARTFAILURE.119.007012LinkGoogle Scholar4. Lanfear DE, Hrobowski T, Peterson EL, Wells K, Swadia T, Spertus JA, Williams LK. Association of beta blocker exposure with outcomes in heart failure differs between african american and white patients.Circ Heart Fail. 2012; 5:202. doi: 10.1161/CIRCHEARTFAILURE.111.965780LinkGoogle Scholar5. Pocock SJ, Ariti CA, McMurray JJ, Maggioni A, Kober L, Squire IB, Swedberg K, Dobson J, Poppe KK, Whalley GA, et al; Meta-Analysis Global Group in Chronic Heart Failure. Predicting survival in heart failure: a risk score based on 39 372 patients from 30 studies.Eur Heart J. 2013; 34:1404–1413. doi: 10.1093/eurheartj/ehs337CrossrefMedlineGoogle Scholar eLetters(0) eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate. Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page. Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetailsCited By Luzum J, Campos-Staffico A, Li J, She R, Gui H, Peterson E, Liu B, Sabbah H, Donahue M, Kraus W, Williams L and Lanfear D (2023) Genome-Wide Association Study of Beta-Blocker Survival Benefit in Black and White Patients with Heart Failure with Reduced Ejection Fraction, Genes, 10.3390/genes14112019, 14:11, (2019) Oni‐Orisan A, Tuteja S, Hoffecker G, Smith D, Castrichini M, Crews K, Murphy W, Nguyen N, Huang Y, Lteif C, Friede K, Tantisira K, Aminkeng F, Voora D, Cavallari L, Whirl‐Carrillo M, Duarte J and Luzum J (2023) An Introductory Tutorial on Cardiovascular Pharmacogenetics for Healthcare Providers, Clinical Pharmacology & Therapeutics, 10.1002/cpt.2957, 114:2, (275-287), Online publication date: 1-Aug-2023. April 2023Vol 16, Issue 2 Advertisement Article Information Metrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/CIRCGEN.121.003835PMID: 36866666 Originally publishedMarch 3, 2023 Keywordsadrenergic beta antagonistsgenome wide association studyheart failureprecision medicinesurvivalPDF download Advertisement Subjects Heart Failure Precision Medicine