000163044 001__ 163044
000163044 005__ 20251009133841.0
000163044 0247_ $$2doi$$a10.1161/CIRCGEN.124.004978
000163044 0248_ $$2sideral$$a145539
000163044 037__ $$aART-2025-145539
000163044 041__ $$aeng
000163044 100__ $$aYoung, William J.
000163044 245__ $$aRelationships of Circulating Plasma Metabolites With the QT Interval in a Large Population Cohort
000163044 260__ $$c2025
000163044 5060_ $$aAccess copy available to the general public$$fUnrestricted
000163044 5203_ $$aBACKGROUND: There is a higher prevalence of heart rate corrected QT (QTc) prolongation in patients with diabetes and metabolic syndrome. QT interval genome-wide association studies have identified candidate genes for cardiac energy metabolism, and experimental studies suggest that polyunsaturated fatty acids have direct effects on ion channel function. Despite this, there has been limited study of metabolite concentration relationships with QT intervals. METHODS: In 21 056 UK Biobank participants with same-day electrocardiograms and plasma profiling of 100 metabolites, per-metabolite regression analyses with the QTc were performed adjusting for clinically relevant variables. Participants with ischemic heart disease or heart failure were excluded. Significant metabolites (P<5×10–4) that replicated in an independent UK Biobank sample (N=5304), underwent Least Absolute Shrinkage and Selection Operator regression with clinical
variables to identify top predictors and calculate the QTc variance explained. Two-sample Mendelian randomization and locus-level colocalization analyses were performed to test for causal relationships and shared genetic etiologies, respectively. RESULTS: Twenty-two metabolites were associated with the QTc in main and replication regression analyses, including ketone bodies, fatty acids, glycolysis-related molecules, and amino acids. Top associations were 3-hydroxybutyrate (8.9 ms), acetone (7.9 ms), and polyunsaturated fatty acids (–7.3 ms), when comparing the highest versus lowest deciles. A combined metabolite and clinical variables Least Absolute Shrinkage and Selection Operator model significantly increased the QTc variance explained compared with the clinical-only model (11.2% versus 7.7%; P=0.002). There was support for a causal relationship between Linoleic acid to fatty acid ratio and the QTc, and evidence for colocalization for 15 metabolites at 7 QT loci, including CASR for citrate and glutamine. CONCLUSIONS: In the largest study of metabolite-QTc relationships, we identify 22 associated metabolites and clinically relevant effect sizes, with evidence for genetic support. For the first time, we report a potentially protective effect of polyunsaturated fatty acids in humans. These metabolites may be risk factors in acquired and congenital long-QT syndrome and warrant additional investigation for arrhythmia risk stratification.
000163044 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttps://creativecommons.org/licenses/by/4.0/deed.es
000163044 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000163044 700__ $$aSanghvi, Mihir M.
000163044 700__ $$0(orcid)0000-0003-4130-5866$$aRamírez, Julia$$uUniversidad de Zaragoza
000163044 700__ $$aOrini, Michele
000163044 700__ $$avan Duijvenboden, Stefan
000163044 700__ $$aWarren, Helen R.
000163044 700__ $$aTinker, Andrew
000163044 700__ $$aLambiase, Pier D.
000163044 700__ $$aMunroe, Patricia B.
000163044 7102_ $$15008$$2800$$aUniversidad de Zaragoza$$bDpto. Ingeniería Electrón.Com.$$cÁrea Teoría Señal y Comunicac.
000163044 773__ $$g(2025), [11 pp.]$$pCirc., Genom. precis. med.$$tCirculation. Genomic and precision medicine$$x2574-8300
000163044 8564_ $$s866320$$uhttps://zaguan.unizar.es/record/163044/files/texto_completo.pdf$$yVersión publicada
000163044 8564_ $$s2771731$$uhttps://zaguan.unizar.es/record/163044/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000163044 909CO $$ooai:zaguan.unizar.es:163044$$particulos$$pdriver
000163044 951__ $$a2025-10-09-13:25:56
000163044 980__ $$aARTICLE