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Although the role of fat mass- and obesity-associated (FTO) gene variants in obesity risk is well established, their potential associations with HR changes during and after physical activity (independent of adiposity) have not yet been fully elucidated. This study examined whether common FTO polymorphisms (rs9939609, rs1121980, rs1558902, and rs9941349) and an exploratory FTO multi-variant score (MVSFTO), representing regional variation across the high-LD FTO locus, are associated with HR responses to a brief submaximal exercise stimulus. A population-based cohort of Hungarian adults (n = 660) completed the YMCA 3-min step test, with HR measured at rest, at first-minute post-exercise (HRaft), and at 5- (HR5min) and 10-min recovery (HR10min). Acute HR response (\u0394HR) and percent of predicted maximal HR (HRmax%) were calculated. Linear regression analyses showed no association between any FTO variant and resting HR (all p &gt; 0.05). In contrast, all four candidate SNPs demonstrated significant negative associations with HRaft (\u03b2 \u2248 \u22123.6 to \u22124.2, all p \u2264 0.005), \u0394HR (\u03b2 \u2248 \u22123.7 to \u22123.9, p \u2264 0.005), and HRmax% (\u03b2 \u2248 \u22122.5, p = 0.001). The MVSFTO revealed even more pronounced and consistent associations: higher MVSFTO burden was associated with lower HRaft (\u03b2 = \u22124.19, p = 0.001), HR5min (\u03b2 = \u22122.06, p = 0.004), HR10min (\u03b2 = \u22121.15, p = 0.009), \u0394HR (\u03b2 = \u22124.04, p = 0.001), and HRmax% (\u03b2 = \u22122.47, p = 0.001). Exploratory four-way mediation decompositions and saturated structural equation models indicated that these inverse associations remained statistically robust after multivariable adjustment for measured BMI and leisure-time physical activity (all direct paths p \u2264 0.001). Furthermore, multi-trait latent cluster analysis identified distinct phenotypic profiles consistent with these findings, showing that individuals with high MVSFTO burden and moderate physical activity exhibit blunted exercise HR reactivity across recovery phases. Rather than establishing biological causality or clinical cardiovascular benefit, these observational findings demonstrate that regional FTO locus variation captured by the multi-variant score is statistically associated with inter-individual variability in short-term post-exercise HR reactivity, providing hypothesis-generating insights that warrant validation in prospective cohorts and interventional exercise trials.<\/jats:p>","DOI":"10.3390\/biology15181607","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T14:39:24Z","timestamp":1789137564000},"page":"1607","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Associations Between FTO (Fat Mass- and Obesity-Associated) Gene Allelic Load and Heart Rate Responses to Submaximal Exercise in Humans: A Cross-Sectional Study"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-8271-2248","authenticated-orcid":false,"given":"Habib","family":"Al Ashkar","sequence":"first","affiliation":[{"name":"Doctoral School of Health Sciences, University of Debrecen, 4032 Debrecen, Hungary"},{"name":"HUN-REN-UD Public Health Research Group, Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9256-3756","authenticated-orcid":false,"given":"Nora","family":"Kovacs","sequence":"additional","affiliation":[{"name":"HUN-REN-UD Public Health Research Group, Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"},{"name":"Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9864-3570","authenticated-orcid":false,"given":"Karoly","family":"Nagy","sequence":"additional","affiliation":[{"name":"Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9679-6669","authenticated-orcid":false,"given":"Roza","family":"Adany","sequence":"additional","affiliation":[{"name":"HUN-REN-UD Public Health Research Group, Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"},{"name":"Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"},{"name":"National Laboratory for Health Security, Center for Epidemiology and Surveillance, Semmelweis University, 1089 Budapest, Hungary"},{"name":"Department of Preventive Medicine and Public Health, Semmelweis University, 1089 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5539-907X","authenticated-orcid":false,"given":"Peter","family":"Piko","sequence":"additional","affiliation":[{"name":"Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"},{"name":"National Laboratory for Health Security, Center for Epidemiology and Surveillance, Semmelweis University, 1089 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,11]]},"reference":[{"key":"ref_1","unstructured":"World Obesity Federation (2024). 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