{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T18:18:27Z","timestamp":1793038707866,"version":"4.5.0"},"reference-count":27,"publisher":"American Medical Association (AMA)","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Cardiol"],"published-print":{"date-parts":[[2024,11,1]]},"abstract":"<jats:sec id=\"ab-hoi240042-4\"><jats:title>Importance<\/jats:title><jats:p>The population prevalence of cardiac transthyretin amyloidosis (ATTR) caused by pathogenic variation in the <jats:italic>TTR<\/jats:italic> gene (vATTR) is unknown.<\/jats:p><\/jats:sec><jats:sec id=\"ab-hoi240042-5\"><jats:title>Objective<\/jats:title><jats:p>To estimate the population prevalence of disease-causing <jats:italic>TTR<\/jats:italic> variants and evaluate associated phenotypes and outcomes.<\/jats:p><\/jats:sec><jats:sec id=\"ab-hoi240042-6\"><jats:title>Design, Setting, and Participants<\/jats:title><jats:p>This population-based cohort study analyzed UK Biobank (UKB) participants with whole-exome sequencing, electrocardiogram, and cardiovascular magnetic resonance data. Participants were enrolled from 2006 to 2010, with a median follow-up of 12 (IQR, 11-13) years (cutoff date for the analysis, March 12, 2024). Sixty-two candidate <jats:italic>TTR<\/jats:italic> variants were extracted based on rarity (minor allele frequency \u22640.0001) and\/or previously described associations with amyloidosis if more frequent.<\/jats:p><\/jats:sec><jats:sec id=\"ab-hoi240042-7\"><jats:title>Exposure<\/jats:title><jats:p>Carrier status for <jats:italic>TTR <\/jats:italic>variants.<\/jats:p><\/jats:sec><jats:sec id=\"ab-hoi240042-8\"><jats:title>Main Outcomes and Measures<\/jats:title><jats:p>Associations of <jats:italic>TTR<\/jats:italic> carrier status with vATTR prevalence and cardiovascular imaging and electrocardiogram traits were explored using descriptive statistics. Associations between <jats:italic>TTR<\/jats:italic> carrier status and atrial fibrillation, conduction disease, heart failure, and all-cause mortality were evaluated using adjusted Cox proportional hazards models. Genotypic and diagnostic concordance was examined using <jats:italic>International Statistical Classification of Diseases, Tenth Revision<\/jats:italic> codes from the hospital record.<\/jats:p><\/jats:sec><jats:sec id=\"ab-hoi240042-9\"><jats:title>Results<\/jats:title><jats:p>The overall cohort included 469\u202f789 UKB participants (mean [SD] age, 56.5 [8.1] years; 54.2% female and 45.8% male). A likely pathogenic\/pathogenic (LP\/P) <jats:italic>TTR<\/jats:italic> variant was detected in 473 (0.1%) participants, with Val142Ile being the most prevalent (367 [77.6%]); 91 individuals (0.02%) were carriers of a variant of unknown significance . The overall prevalence of LP\/P variants was 0.02% (105 of 444\u202f243) in participants with European ancestry and 4.3% (321 of 7533) in participants with African ancestry. The LP\/P variants were associated with higher left ventricular mass indexed to body surface area (\u03b2\u2009=\u20094.66; 95% CI, 1.87-7.44), and Val142Ile was associated with a longer PR interval (\u03b2\u2009=\u200918.34; 95% CI, 5.41-31.27). The LP\/P carrier status was associated with a higher risk of heart failure (hazard ratio [HR], 2.68; 95% CI, 1.75-4.12) and conduction disease (HR, 1.88; 95% CI, 1.25-2.83). Higher all-cause mortality risk was observed for non-Val142Ile LP\/P variants (HR, 1.98; 95% CI, 1.06-3.67). Thirteen participants (2.8%) with LP\/P variants had diagnostic codes compatible with cardiac or neurologic amyloidosis. Variants of unknown significance were not associated with outcomes.<\/jats:p><\/jats:sec><jats:sec id=\"ab-hoi240042-10\"><jats:title>Conclusions and Relevance<\/jats:title><jats:p>This study found that approximately 1 in 1000 UKB participants were LP\/P <jats:italic>TTR<\/jats:italic> variant carriers, exceeding previously reported prevalence. The findings emphasize the need for clinical vigilance in identifying individuals at risk of developing vATTR and associated poor outcomes.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamacardio.2024.2190","type":"journal-article","created":{"date-parts":[[2024,8,28]],"date-time":"2024-08-28T15:34:44Z","timestamp":1724859284000},"page":"964","source":"Crossref","is-referenced-by-count":25,"title":["Prevalence, Cardiac Phenotype, and Outcomes of Transthyretin Variants in the UK Biobank Population"],"prefix":"10.1001","volume":"9","author":[{"given":"Nay","family":"Aung","sequence":"first","affiliation":[{"name":"William Harvey Research Institute, Queen Mary University of London, United Kingdom"},{"name":"Barts Heart Centre, St Bartholomew\u2019s Hospital, Barts Health NHS Trust, West Smithfield, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah L.","family":"Nicholls","sequence":"additional","affiliation":[{"name":"William Harvey Research Institute, Queen Mary University of London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. Anwar A.","family":"Chahal","sequence":"additional","affiliation":[{"name":"William Harvey Research Institute, Queen Mary University of London, United Kingdom"},{"name":"Barts Heart Centre, St Bartholomew\u2019s Hospital, Barts Health NHS Trust, West Smithfield, London, United Kingdom"},{"name":"Center for Inherited Cardiovascular Diseases, WellSpan Health, York, Pennsylvania"},{"name":"Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed Y.","family":"Khanji","sequence":"additional","affiliation":[{"name":"William Harvey Research Institute, Queen Mary University of London, United Kingdom"},{"name":"Barts Heart Centre, St Bartholomew\u2019s Hospital, Barts Health NHS Trust, West Smithfield, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Rauseo","sequence":"additional","affiliation":[{"name":"William Harvey Research Institute, Queen Mary University of London, United Kingdom"},{"name":"Barts Heart Centre, St Bartholomew\u2019s Hospital, Barts Health NHS Trust, West Smithfield, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sucharitha","family":"Chadalavada","sequence":"additional","affiliation":[{"name":"William Harvey Research Institute, Queen Mary University of London, United Kingdom"},{"name":"Barts Heart Centre, St Bartholomew\u2019s Hospital, Barts Health NHS Trust, West Smithfield, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen E.","family":"Petersen","sequence":"additional","affiliation":[{"name":"William Harvey Research Institute, Queen Mary University of London, United Kingdom"},{"name":"Barts Heart Centre, St Bartholomew\u2019s Hospital, Barts Health NHS Trust, West Smithfield, London, United Kingdom"},{"name":"Health Data Research, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia B.","family":"Munroe","sequence":"additional","affiliation":[{"name":"William Harvey Research Institute, Queen Mary University of London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Perry M.","family":"Elliott","sequence":"additional","affiliation":[{"name":"Barts Heart Centre, St Bartholomew\u2019s Hospital, Barts Health NHS Trust, West Smithfield, London, United Kingdom"},{"name":"Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis R.","family":"Lopes","sequence":"additional","affiliation":[{"name":"Barts Heart Centre, St Bartholomew\u2019s Hospital, Barts Health NHS Trust, West Smithfield, London, United Kingdom"},{"name":"Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","reference":[{"issue":"19","key":"hoi240042r1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.120.016614","article-title":"Specific therapy for transthyretin cardiac amyloidosis: a systematic literature review and evidence-based recommendations.","volume":"9","author":"Marques","year":"2020","journal-title":"J Am Heart Assoc"},{"issue":"2","key":"hoi240042r2","doi-asserted-by":"publisher","first-page":"17","DOI":"10.14797\/mdcvj.1066","article-title":"ATTR epidemiology, genetics, and prognostic factors.","volume":"18","author":"Obi","year":"2022","journal-title":"Methodist Debakey Cardiovasc J"},{"key":"hoi240042r3","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/1750-1172-8-31","article-title":"Guideline of transthyretin-related hereditary amyloidosis for clinicians.","volume":"8","author":"Ando","year":"2013","journal-title":"Orphanet J Rare Dis"},{"issue":"1","key":"hoi240042r4","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1186\/s13023-022-02359-w","article-title":"Clinical and genetic profile of patients enrolled in the Transthyretin Amyloidosis Outcomes Survey (THAOS): 14-year update.","volume":"17","author":"Dispenzieri","year":"2022","journal-title":"Orphanet J Rare Dis"},{"issue":"3","key":"hoi240042r5","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1056\/NEJMoa2303765","article-title":"Phase 1 trial of antibody NI006 for depletion of cardiac transthyretin amyloid.","volume":"389","author":"Garcia-Pavia","year":"2023","journal-title":"N Engl J Med"},{"issue":"1","key":"hoi240042r6","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.120.008193","article-title":"Long-term survival with tafamidis in patients with transthyretin amyloid cardiomyopathy.","volume":"15","author":"Elliott","year":"2022","journal-title":"Circ Heart Fail"},{"issue":"4","key":"hoi240042r7","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1016\/j.jaccao.2022.07.007","article-title":"Prognosis of transthyretin cardiac amyloidosis without heart failure symptoms.","volume":"4","author":"Gonzalez-Lopez","year":"2022","journal-title":"JACC CardioOncol"},{"issue":"5","key":"hoi240042r8","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGEN.121.003356","article-title":"Prevalence and outcomes of p.Val142Ile TTR amyloidosis cardiomyopathy: a systematic review.","volume":"14","author":"Chandrashekar","year":"2021","journal-title":"Circ Genom Precis Med"},{"issue":"3","key":"hoi240042r9","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1001779","article-title":"UK Biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age.","volume":"12","author":"Sudlow","year":"2015","journal-title":"PLoS Med"},{"issue":"7726","key":"hoi240042r10","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1038\/s41586-018-0579-z","article-title":"The UK Biobank resource with deep phenotyping and genomic data.","volume":"562","author":"Bycroft","year":"2018","journal-title":"Nature"},{"key":"hoi240042r11","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1186\/s12968-016-0227-4","article-title":"UK Biobank\u2019s cardiovascular magnetic resonance protocol.","volume":"18","author":"Petersen","year":"2016","journal-title":"J Cardiovasc Magn Reson"},{"issue":"446","key":"hoi240042r12","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1080\/01621459.1999.10474144","article-title":"A proportional hazards model for the subdistribution of a competing risk.","volume":"94","author":"Fine","year":"1999","journal-title":"J Am Stat Assoc"},{"key":"hoi240042r13","doi-asserted-by":"publisher","first-page":"S31","DOI":"10.4103\/sja.SJA_543_18","article-title":"The STROBE guidelines.","volume":"13","author":"Cuschieri","year":"2019","journal-title":"Saudi J Anaesth"},{"issue":"1","key":"hoi240042r14","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1186\/s12968-018-0471-x","article-title":"Automated cardiovascular magnetic resonance image analysis with fully convolutional networks.","volume":"20","author":"Bai","year":"2018","journal-title":"J Cardiovasc Magn Reson"},{"issue":"16","key":"hoi240042r15","doi-asserted-by":"publisher","first-page":"1318","DOI":"10.1161\/CIRCULATIONAHA.119.041161","article-title":"Genome-wide analysis of left ventricular image-derived phenotypes identifies fourteen loci associated with cardiac morphogenesis and heart failure development.","volume":"140","author":"Aung","year":"2019","journal-title":"Circulation"},{"issue":"1","key":"hoi240042r16","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1186\/1532-429X-12-69","article-title":"Shortened Modified Look-Locker Inversion recovery (ShMOLLI) for clinical myocardial T1-mapping at 1.5 and 3 T within a 9 heartbeat breathhold.","volume":"12","author":"Piechnik","year":"2010","journal-title":"J Cardiovasc Magn Reson"},{"issue":"2","key":"hoi240042r18","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1161\/CIRCULATIONAHA.121.058143","article-title":"Frequency, penetrance, and variable expressivity of dilated cardiomyopathy-associated putative pathogenic gene variants in UK Biobank participants.","volume":"146","author":"Shah","year":"2022","journal-title":"Circulation"},{"issue":"7886","key":"hoi240042r19","doi-asserted-by":"publisher","first-page":"628","DOI":"10.1038\/s41586-021-04103-z","article-title":"Exome sequencing and analysis of 454,787 UK Biobank participants.","volume":"599","author":"Backman","year":"2021","journal-title":"Nature"},{"issue":"1","key":"hoi240042r20","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1186\/s13059-016-0974-4","article-title":"The Ensembl Variant Effect Predictor.","volume":"17","author":"McLaren","year":"2016","journal-title":"Genome Biol"},{"issue":"5","key":"hoi240042r21","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"issue":"3","key":"hoi240042r23","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1016\/j.cardfail.2021.09.015","article-title":"Clinical implications of the amyloidogenic v122i transthyretin variant in the general population.","volume":"28","author":"Kozlitina","year":"2022","journal-title":"J Card Fail"},{"issue":"9","key":"hoi240042r24","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.116.003352","article-title":"Afro-Caribbean heart failure in the United Kingdom: cause, outcomes, and ATTR V122I cardiac amyloidosis.","volume":"9","author":"Dungu","year":"2016","journal-title":"Circ Heart Fail"},{"issue":"14","key":"hoi240042r25","doi-asserted-by":"publisher","first-page":"1368","DOI":"10.1001\/jama.2022.2896","article-title":"Association of transthyretin Val122Ile variant with incident heart failure among Black individuals.","volume":"327","author":"Parcha","year":"2022","journal-title":"JAMA"},{"issue":"5","key":"hoi240042r26","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1038\/s41431-019-0337-1","article-title":"Estimating the prevalence of allelic variants in the transthyretin gene by analysing large-scale sequencing data.","volume":"27","author":"Lahuerta Pueyo","year":"2019","journal-title":"Eur J Hum Genet"},{"issue":"21","key":"hoi240042r27","doi-asserted-by":"publisher","first-page":"1824","DOI":"10.1001\/jama.2024.4467","article-title":"Cardiovascular burden of the V142I transthyretin variant.","volume":"331","author":"Selvaraj","year":"2024","journal-title":"JAMA"},{"key":"hoi240042r17","volume-title":"12SLTM ECG Analysis Program Physician\u2019s Guide 2036070-006, Revision C","author":"Marquette","year":"2012"},{"key":"hoi240042r22","unstructured":"Devleesschauwer? B, Togerson? P, Charlier? J, . prevalence: Tools for prevalence assessment studies. R package version 0.4.1. The Comprehensive R Archive Network; 2022. Accessed March 12, 2024. https:\/\/cran.r-project.org\/package=prevalence"}],"container-title":["JAMA Cardiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamacardiology\/articlepdf\/2822884\/jamacardiology_aung_2024_oi_240042_1730392592.46074.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,13]],"date-time":"2024-11-13T16:40:25Z","timestamp":1731516025000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamacardiology\/fullarticle\/2822884"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,1]]},"references-count":27,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2024,11,1]]}},"URL":"https:\/\/doi.org\/10.1001\/jamacardio.2024.2190","relation":{},"ISSN":["2380-6583"],"issn-type":[{"value":"2380-6583","type":"print"}],"subject":[],"published":{"date-parts":[[2024,11,1]]}}}