Key result
Metabolic diseases drive higher FGF21 levels, but FGF21 does not causally increase cardiometabolic risk.
Why the study?
Although studies have suggested an association between FGF21 and obesity-related metabolic complications and CVD, whether FGF21 is a causative factor remained unknown.
Does genetic predisposition to altered FGF21 levels causally affect the risk of metabolic and cardiovascular diseases?
Observational
Does genetic predisposition to altered FGF21 levels causally affect the risk of metabolic and cardiovascular diseases?
Answers are grounded in this paper and cite their sources.
Mendelian randomization supports a causal association between NAFLD, obesity, and T2DM with FGF21, but finds no substantial evidence for a causal relationship with cardiovascular diseases.
Studies have covered a possible relevance between fibroblast growth factor 21 (FGF21) and obesity-related metabolic complications and cardiovascular disease (CVD). Nevertheless, whether FGF21 is a causative factor in these diseases is not known. Using a bidirectional, two-sample Mendelian randomization (MR) approach, this study sought to establish a causal relationship between FGF21 and seven metabolic diseases and six CVDs. A large-scale meta-analysis dataset of genome-wide association studies (GWAS) was analyzed to generate summary-level statistics for FGF21. The diseases we studied included non-alcoholic fatty liver disease (NAFLD), obesity, type 2 diabetes (T2DM), hypertension, gestational diabetes (GDM), gestational hypertension (GHTN), pre-eclampsia or eclampsia (PE), atherosclerosis, cardiomyopathy (CMP), coronary heart disease (CHD), coronary atherosclerosis, heart failure (HF), myocardial infarction (MI) and the corresponding summary GAWS data were retrieved from the FinnGen Biobank and IEU Open GWAS Project database. The inverse variance-weighted (IVW) algorithm was the primary approach utilized for the MR analysis. The MR-Egger regression and MR-PRESSO tests were implemented to evaluate horizontal pleiotropy. The heterogeneity of instrumental variables was subsequently assessed utilizing Cochran's Q statistics.When diseases are used as exposures, MR analysis results of the IVW method indicated that NAFLD (Beta=- 0.047, 95% CI=- 0.08 to - 0.014; p=0.006), obesity (Beta=0.087, 95% CI=0.021-0.153; p=0.009), T2DM (Beta=0.071, 95% CI=0.037-0.106; p<0.001) correlated causally with FGF21. Nevertheless, FGF21 was not causally related to the remaining metabolic diseases and CVDs, according to the results of the MR analysis (p>0.05). It was demonstrated that the aforementioned results were robust and devoid of pleiotropy.Our study supports a causal association between NAFLD, obesity, and T2DM with FGF21. No substantial evidence exists to establish a causal relationship between FGF21 and other diseases. This study provides opportunities for the early prevention and innovative therapy of NAFLD, obesity, and T2DM.
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He et al. (2025) conducted an observational in Metabolic and Cardiovascular Diseases. Genetically predicted metabolic and cardiovascular diseases was evaluated on FGF21 levels (Beta 0.071, 95% CI 0.037-0.106, p=<0.001). Genetically predicted NAFLD, obesity, and type 2 diabetes were causally associated with FGF21 levels (e.g., T2DM: Beta=0.071; 95% CI 0.037-0.106; p<0.001), but FGF21 did not cause these diseases.
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