Mendelian randomization meta-analysis links genetically predicted obesity traits to increased heart failure risk

BackgroundObesity is a major public health concern and has been implicated in the pathogenesis of heart failure (HF). However, the causal nature of this relationship remains to be comprehensively elucidated through robust genetic epidemiological approaches.ObjectiveThis systematic review and meta-analysis aimed to synthesize evidence from Mendelian randomization (MR) studies regarding the causal effects of genetically predicted obesity and related anthropometric traits on HF and its subtypes.MethodsA comprehensive literature search was conducted across PubMed, Google Scholar, Web of Science, Embase, and the Cochrane Library for studies published up to October 2025. Study quality was assessed, and random-effects meta-analysis were performed where applicable.ResultGenetically predicted adult BMI was significantly associated with increased HF risk across European (ORSD: 1.79; 95% CI: 1.64–1.94), and East Asian ancestries (ORkg/m2: 2.17; 95% CI: 1.79–2.63). A significant association was also observed for HF with preserved ejection fraction (HFpEF) in European-ancestry individuals (ORSD: 2.68; 95% CI: 1.07–4.28). Childhood body size traits were associated with HF (ORSD: 1.30; 95% CI: 1.21–1.39). Fat mass, WC, WHR, and unfavorable adiposity were also identified as causal risk factors. Tissue-specific analyses indicated that both brain- and adipose-tissue-specific genetic instruments for BMI were associated with elevated HF risk.ConclusionThis study provides robust MR evidence supporting a causal role of multiple obesity-related traits, particularly adult BMI, in the development of HF across diverse populations. Further MR studies in non-European populations and investigations into specific pathways are warranted to enhance generalizability and mechanistic understanding.Systematic Review Registrationcrd.york.ac.uk/PROSPERO/display_record.php?RecordID=576216 identifier, CRD42024576216.