Association between dried fruit intake and DNA methylation: A Multivariable Mendelian Randomization Analysis

Abstract Background Observational studies have reported associations between dried fruit intake and DNA methylation(DNAm). However, inherent flaws in observational study designs make them susceptible to confounding and reverse causality bias. Consequently, it is unclear whether a causal association exists. In the present study, we aimed to investigate the causal associations between dried fruit intake and DNAm. Methods We performed two-sample Mendelian randomization (MR) using the IEU Open GWAS database aggregated data. Forty-three single nucleotide polymorphisms (SNPs) associated with dried fruit intake as instrumental variables (IVs) were selected as exposure. DNAm outcomes include Gran (estimated granulocyte proportions); AgeAccelGrim(GrimAge acceleration); Hannum (Hannum age acceleration); IEAA(Intrinsic epigenetic age acceleration), AgeAccelPheno( PhenoAge acceleration), and DNAmPAIadjAge (DNAm-estimated plasminogen activator inhibitor-1 levels). Inverse variance weighted (IVW) method was the primary method for MR analysis, complemented by four other MR methods to ensure the stability and reliability of the results. Additional sensitivity analyses were also performed. The direct effects of dried fruit intake on DNAm were estimated using multivariable mendelian randomization (MVMR). Results Univariate MR results showed that for each standard deviation increase in dried fruit intake, the risk of AgeAccelGrim was reduced by 77.7% [odds ratio (OR) = 0.223, 95% confidence interval (CI) = 0.081–0.612; P IVW =3.588×10 − 3 ], and the risk of AgeAccelPheno was reduced by 81.7% (OR = 0.183, 95%CI = 0.054–0.621, P IVW =6.426×10 − 3 ). However, the effects on Gran( P IVW =0.264), Hannum( P IVW =0.299), IEAA( P IVW =0.700), and DNAmPAIadjAge( P IVW =0.051) were not statistically significant. MVMR results adjusting for the potential effects of confounders showed that the causal relationship between dried fruit intake and AgeAccelGrim ( P IVW =2.482×10 − 2 ) persisted, but the effect on AgeAccelPheno ( P IVW =0.052) was not statistically significant. Sensitivity analysis showed that our results were stable and reliable. Conclusion Our MR findings suggest that increased dried fruit intake is associated with slower AgeAccelGrim, providing a promising avenue for exploring the beneficial effects of dried fruit intake on lifespan extension.